DO NOT DELAY CANCER TREATMENT

 The COVID-19 pandemic has meant delays in cancer screening, diagnosis, and treatment — and a new study shows just how deadly delaying cancer treatment can be. The study found evidence that longer time to starting treatment after diagnosis was generally associated with higher mortality across several common cancers, most notably for colon and early-stage lung cancer. "There is a limit to how long we can safely defer treatment for cancer therapies, pandemic or not, which may be shorter than we think," lead author Eugene Cone, MD, Combined Harvard Program in Urologic Oncology, Massachusetts General Hospital and Brigham & Women's Hospital, Boston, told Medscape Medical News. "When you consider that cancer screening may have been delayed during the pandemic, which would further increase the period between developing a disease and getting therapy, timely treatment for cancer has never been more important," Cone added. The study was published online December 14 in JAMA Network Open. The Sooner the Better Using the National Cancer Database, Cone and colleagues identified roughly 2.24 million patients diagnosed with nonmetastatic breast (52%), prostate (38%), colon (4%) and non-small cell lung cancer (NSCLC, 6%) between 2004 and 2015. Treatment and outcome data were analyzed from January to March 2020. The time-to-treatment initiation (TTI) – the interval between cancer diagnosis and receipt of curative-intent therapy – was categorized as 8 to 60 days (reference), 61 to 120 days, 121 to 180 days, and 181 to 365 days. Median TTI was 32 days for breast, 79 days for prostate, 41 days for NSCLC, and 26 days for colon cancer. All four cancers benefitted to some degree from a short interval between diagnosis and therapy, the researchers found. Across all four cancers, increasing TTI was generally associated with higher predicted mortality at 5 and 10 years, although the degree varied by cancer type and stage. The most pronounced association between increasing TTI and mortality was observed for colon and lung cancer. For example, for stage III colon cancer, 5- and 10-year predicted mortality was 38.9% and 54%, respectively, with TTI of 61 to 120 days, and increased to 47.8% and 63.8%, respectively, with TTI of 181 to 365 days. Each additional 60-day delay was associated with a 3.2% to 6% increase in 5-year mortality for stage III colon cancer and a 0.9% to 4.6% increase for stage I colon cancer, with a longer 10-year time horizon showing larger effect sizes with increasing TTI. For stage I NSCLC, 5- and 10-year predicted mortality was 47.4% and 72.6%, respectively, with TTI of 61 to 120 days compared with 47.6% and 72.8%, respectively, with TTI of 181 to 365 days. For stage I NSCLC, there was a 4% to 6.2% absolute increase in 5-year mortality for increased TTI groups compared with the 8- to 60-day reference group, with larger effect sizes on 10-year mortality. The data precluded conclusions about stage II NSCLC. "For prostate cancer, deferral of treatment by even a few months was associated with a significant impact on mortality," Cone told Medscape Medical News. For high-risk prostate cancer, 5- and 10-year predicted mortality was 12.8% and 31.2%, respectively, with TTI of 61-120 days increasing to 14.1% and 33.8%, respectively with TTI at 181-365 days. For intermediate-risk prostate cancer, 5- and 10-year predicted mortality was 7.4% and 20.4% with TTI of 61-120 days vs 8.3% and 22.6% with TTI at 181-365 days. Cancer Treatment Delays Are Deadly: 5- and 10-Year Data 1/4/2021 https://www.medscape.com/viewarticle/943242_print https://www.medscape.com/viewarticle/943242_print 2/2 The data show all-cause mortality differences of 2.2% at 5 years and 4.6% at 10 years between high-risk prostate cancer patients who were treated expeditiously vs those waiting 4 to 6 months and differences of 0.9% at 5 years and 2.4% at 10 years for similar intermediate-risk patients. No Surprises Turning to breast cancer, increased TTI was associated with the most negative survival effects for stage II and III breast cancer. For stage II breast cancer, for example, 5- and 10-year predicted mortality was 17.7% and 30.5%, respectively, with TTI of 61- 120 days vs 21.7% and 36.5% with TTI at 181-365 days. Even for stage I breast cancer patients, there were significant differences in all-cause mortality with delayed definitive therapy, although the effect size is clinically small, the researchers report. Patients with stage IA or IB breast cancer who were not treated until 61 to 120 days after diagnosis had 1.3% and 2.3% increased mortality at 5 years and 10 years, respectively, and those waiting longer suffered even greater increases in mortality. "As such, our analysis underscores the importance of timely definitive treatment, even for stage I breast cancer," the authors write. Charles Shapiro, MD, director of translational breast cancer research for the Mount Sinai Health System, New York City, was not surprised by the data. The observation that delays in initiating cancer treatment are associated with worse survival is "not new, as delays in primary surgical treatments and chemotherapy for early-stage disease is an adverse prognostic factor for clinical outcomes," Shapiro told Medscape Medical News. "The bottom line is primary surgery and the start of chemotherapy should probably occur as soon as clinically feasible," said Shapiro, who was not involved in the study. The authors of an accompanying editorial agree. This study supports avoiding unnecessary treatment delays and prioritizing timely cancer care, even during the COVID-19 pandemic, write Laura Van Metre Baum, MD, Division of Hematology and Oncology, Vanderbilt University, Nashville, Tennessee and colleagues. They note, however, that primary care, "the most important conduit for cancer screening and initial evaluation of new symptoms, has been the hardest hit economically and the most subject to profound disruption and restructuring during the current COVID19 pandemic. "In many centers, cancer care delivery has been disrupted and nonstandard therapies offered in an effort to minimize exposure of this high-risk group to the virus. The implications in appropriately balancing the urgency of cancer care and the threat of COVID-19 exposure in the pandemic are more complex," the editorialists conclude. Cone, Shapiro, and Van Metre Baum have disclosed no relevant financial relationships. 

INCREASED LEVEL OF ANTICOAGULATION NOT USEFUK IN COVID

 Parts of three linked studies investigating increased levels of anticoagulation in hospitalized COVID-19 patients have been "paused" because of futility and safety concerns, a statement from the US National Heart, Lung, and Blood Institute (NHLBI) confirms.

The trials involved are the RE;MAP-CAP, ACTIV-4, and ATTACC studies.

All three trials have paused enrollment of critically ill COVID-19 patients requiring intensive care unit support for whom therapeutic doses of anticoagulation drugs did not reduce the need for organ support, the NHLBI statement notes.

The statement also says that a potential for harm in this subgroup could not be excluded, noting that increased bleeding is a known complication of full-dose anticoagulation. The trials are working urgently to undertake additional analyses, which will be made available as soon as possible.   

The three clinical trial platforms are working together to test the effects of full therapeutic doses of anticoagulants vs lower prophylactic doses in COVID-19 patients.

Informed by the deliberations of the data safety monitoring boards of these trials, all of the trial sites have paused enrollment of the most critically ill hospitalized patients with COVID-19. 

Enrollment continues in the trials for moderately ill hospitalized COVID-19 patients, the statement notes.  

"Whether the use of full-dose compared to low-dose anticoagulants leads to better outcomes in hospitalized patients with less COVID-19 severe disease remains a very important question," the NHLBI statement says.

Patients who require full dose anticoagulants for another medical indication are not included in these trials.

The statement explains that COVID-19 is associated with significant inflammation and clinical and pathologic evidence of widespread blood clots. These trials were launched because clinicians have observed that many patients ill with COVID-19, including those who have died from the disease, formed blood clots throughout their bodies, even in their smallest blood vessels. This unusual clotting can cause multiple health complications, including lung failure, myocardial infarction, and stroke. 

The three trials are the result of a collaboration between major international partners. The trials include: the Randomized, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) Therapeutic Anticoagulation; Accelerating COVID-19 Therapeutic Interventions and Vaccines-4 (ACTIV-4) Antithrombotics Inpatient; and Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC).

The trials, which span four continents, have the common goal of assessing the benefit of full doses of anticoagulants to treat moderately ill or critically ill adults hospitalized for COVID-19, compared with a lower dose often used to prevent blood clots in hospitalized patients.

In the United States, the ACTIV-4 trial is being led by a collaborative effort involving a number of universities, including the University of Pittsburgh and New York University.  

The trials are supported by multiple international funding organizations including the National Institutes of Health, Canadian Institutes of Health Research, the National Institute for Health Research (UK), the National Health and Medical Research Council (Australia), and the PREPARE and RECOVER consortia (European Union).

Risk-Benefit Ratio 'Not Favorable'

Judith Hochman, MD, director of the Clinical Cardiovascular Research Center at NYU Langone, who is principal investigator of the ACTIV-4 trial, explained to Medscape Medical News that all three trials are looking at the same question — whether full-dose therapeutic anticoagulation is superior to low-dose prophylactic anticoagulation with heparin or low molecular weight heparin in patients hospitalized with COVID-19.

The three trials started off slightly differently: REMAP began with only ICU patients but has broadened to include non-ICU patients as well, ATTACC started off with only non-ICU patients but has broadened to include ICU patients as well, and ACTIV-4 enrolled both ICU and non-ICU patients from the beginning.

The NHLBI is funding ACTIV-4, but the three trials are harmonizing the collection and review of data so they have greater power to show a result. "The vast majority of COVID trials are underpowered to come to any conclusions, so it is important to collaborate in this way," Hochman noted.

Elaborating on the reasons for pausing enrolment in the ICU cohort, she said, "We know full dose anticoagulation increases the risk of bleeding — that would be expected. But what we didn't know was whether it would have a greater efficacy compared to low-prophylactic doses in reducing critical illness. The primary endpoint of these trials in this ICU group was the number of organ support-free days — the number of days patients do not require vasopressor support, mechanical ventilation or high flow oxygen. Results so far show that the chance of seeing a difference in this outcome is very small if we continue," she said.    

"Given that the trial is unlikely to show a benefit and we know these full therapeutic doses of anticoagulation cause an increased bleeding risk, then there will not be a favorable risk-benefit."

The trial also has a key secondary endpoint of thrombotic events but that has not been analyzed and is not part of the current decision.

All three trials are continuing in the non-ICU patient group. These non-ICU patients make up 80% of the ACTIV-4 trial, more in the ATTACC trial, and less in the REMAP trial, Hochman reported. 

"It is very important to stress that these results do not apply to patients already on full dose anticoagulants for an approved indication," she cautioned. "We already know these patients with an approved indication for full dose anticoagulation have a positive risk benefit ratio, and they should not be concerned about the current findings. These trials are trying to prevent clots in critically ill patients who do not have an approved indication for full dose anticoagulation."

Asked how she recommends clinicians now treat these critically ill COVID patients in the ICU in terms of anticoagulation, Hochman said they have to use their clinical judgement. "Prophylactic doses of heparin/low molecular weight heparin are still indicated," she said. "Some centers are trying a slightly higher prophylactic dose but we don't have data on that yet."

Speculating on why the full dose anticoagulation did not show benefit, she suggested it might be too late in the course of the disease to make any difference. "What we've observed at autopsy is thrombi in the microcirculation as well as the large vessels. It may be too late to treat all those thrombi," she said. "We are still hopeful that higher doses of anticoagulation may show benefit earlier in the course of the disease."

The ACTIV-4 trial is actually made up of three different studies of anticoagulation in COVID-19 patients. ACTIV-4a is this study in hospitalized patients randomized to full-dose versus prophylactic-dose anticoagulation with heparin/LMW heparin.

The ACTIV-4b study is being conducted in nonhospitalized COVID patients looking at outpatient use of antithrombotic medication (aspirin or apixaban), and ACTIV-4c includes COVID-19 patients after they have been discharged from hospital and is testing low dose apixaban or placebo.

"The current announcement has no effect on ACTIV-4b or ACTIV-4c," Hochman noted.

Many Questions Remain

Commenting for Medscape Medical News, Gregg Stone, MD, Mount Sinai Heart Health System, New York, explained that autopsies in patients who have died of COVID-19 have shown widespread arterial and venous thrombosis, often not clinically evident, raising the hypothesis that anticoagulation might benefit such patients.

"Several questions arise," Stone said, including 1) whether any prophylactic anticoagulation is better than none; 2) whether full-dose anticoagulation is better than prophylactic-dose anticoagulation; 3) whether a new oral anticoagulant is more or less safe and/or efficacious than a heparin formulation; 4) whether anticoagulation is more likely to have a favorable safety and effectiveness endpoint in the early or late stages of the disease, he said.

"ACTIV-4 is addressing issues 2 and 4, but not issues 1 and 3," Stone said. "The [Data and Safety Monitoring Board (DSMB)] has now recommended pausing enrolment of those patients ill enough to be admitted to an ICU, but not earlier, suggesting that once the disease has progressed to a severe stage, full-dose anticoagulation is not beneficial (and may be harmful). Perhaps this is not a surprising finding."

But he says there is still a great deal that is not known. "Questions remaining include: What are the event rates that led to this pause? How ill were these patients? Were most intubated already with [acute respiratory distress syndrome] or was there similar lack of efficacy and possible harm in those not yet intubated, and/or with lesser radiographic abnormalities? What were the bleeding complications and the profile of the patients in whom bleeding occurred? And more."

Stone is part of a Mount Sinai group conducting the Freedom COVID-19 Anticoagulation trial in which 3600 hospitalized but less critically ill patients who are not intubated are randomized 1:1:1 to prophylactic-dose enoxaparin, full-dose enoxaparin, or apixaban.

"Given the different enrolment criteria and the fact that ACTIV-4 is continuing enrolment into the less severe strata, I don't anticipate major changes to our trial," he commented.

Similarly, other ongoing trials investigating different regimens of anticoagulation in COVID-19 patients will need to consider whether their studies need modification based on enrolment criteria and DSMB guidance, he said.

As to advice for practitioners, Stone recommends that they offer their patients participation in one of the ongoing randomized trials so these questions can be expeditiously answered. For those not within a randomized trial, because COVID-19 patients are at increased risk for bleeding, he recommends prophylactic-dose (and not full-dose) anticoagulation for those not at excessive risk for and without a definite indication for full-dose anticoagulation.

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Medscape Medical News © 2020 

A NOVEL ANTI-HER2 TREATMENT APPROVED BY FDA

 A new monoclonal antibody that targets HER2+ in breast cancer, margetuximab-cmkb (Margenza), has been approved by the Food and Drug Administration (FDA).

The new drug is indicated for use in combination with chemotherapy for the treatment of patients with metastatic HER2-positive breast cancer who have already received two or more prior anti-HER2 regimens, with at least one for metastatic disease.

Margetuximab-cmkb is also the first HER2-targeted therapy shown to improve progression-free survival (PFS) as compared with the first ever HER2-targeted agent, trastuzumab (Herceptin) in a head-to-head phase 3 clinical trial (known as SOPHIA).

"Early detection and treatment have had a positive impact on the survival of patients with breast cancer, but the prognosis for people diagnosed with metastatic breast cancer remains poor, and additional treatments are needed," said Hope S. Rugo, MD, director of Breast Oncology and Clinical Trials Education, University of California San Francisco Diller Family Comprehensive Cancer Center, San Francisco, California, in a company press release.

"As the only HER2-targeted agent to have shown a PFS improvement vs trastuzumab in a head-to-head phase 3 clinical trial, margetuximab with chemotherapy represents the newest treatment option for patients who have progressed on available HER2-directed therapies," said Rugo, who is an investigator in the SOPHIA trial.

Like trastuzumab, margetuximab-cmkb binds HER2 with high specificity and affinity and disrupts signaling that drives cell proliferation and survival, but margetuximab binds with elevated affinity to both the lower- and higher-affinity forms of CD16A, an Fc gamma receptor important for antibody dependent cell-mediated cytotoxicity against tumor cells, according to the manufacturer.

Details of the Pivotal Trail

The SOPHIA trial was a randomized, open-label phase 3 clinical trial that compared margetuximab-cmkb plus chemotherapy to trastuzumab plus chemotherapy in both arms, in patients with HER2-positive metastatic breast cancer, who had previously been treated with anti-HER2-targeted therapies. All patients in the cohort had previously received trastuzumab, all but one patient had previously also received pertuzumab, and most of the patients (91%) had also been treated with ado-trastuzumab emtansine, or T-DM1.

The trial randomly assigned 536 patients to receive either margetuximab-cmkb A (n = 266) given intravenously at 15 mg/kg every 3 weeks or trastuzumab (n = 270) given intravenously at 6 mg/kg (or 8 mg/kg for loading dose) every 3 weeks in combination with either capecitabine, eribulin (Halaven), gemcitabine, or vinorelbine, given at the standard doses.

As compared with trastuzumab, margetuximab plus chemotherapy led to a significant 24% reduction in the risk for progression or death compared (HR = 0.76).

The median PFS also favored margetuximab (5.8 months vs 4.9 months), as did the overall response rate (22% vs 16%).

The final overall survival analysis is expected in the second half of 2021.

Common adverse events associated with the margetuximab regimen included fatigue/asthenia (57%), nausea (33%), diarrhea (25%), and vomiting (21%). Infusion-related reactions occurred in 13% of patients receiving margetuximab, and almost all were grade 1 or 2, with only 1.5% at grade 3.

The product also carries a boxed warning for left ventricular dysfunction and embryo-fetal toxicity.

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DO NOT USE TEXTURED BREAST IMPLANTS

 Numerous studies have demonstrated that textured breast implants predispose women who undergo breast reconstruction to breast implant-associated anaplastic large-cell lymphoma.

Now, an analysis of new data from a cohort study of 650 women who underwent total mastectomy and breast reconstruction demonstrates a significant association between textured implants, increased distant breast cancer recurrence, and decreased disease-free survival (DFS).

These associations were independent of tumor stage and estrogen receptor (ER) status, according to Sa Ik Bang, MD, PhD, of the Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, and colleagues.

"We observed a statistically significant association between textured implant use and decreased DFS with an increased risk of recurrence," the investigators write in their article, which was published in JAMA Surgery in October.

"We believe that this study raises an urgent need for further well-designed investigations, which either may refute the findings of this study with more solid evidence and reassure patients or may produce similar results and lead to increased caution in breast cancer surveillance," they write.

The results were "unexpected," the researchers note. Instead of providing evidence that might relieve anxiety for patients with textured implants, "the results may amplify survivors' concern regarding the potentially detrimental implications of a textured implant for oncologic outcomes," they say.

In an accompanying commentary, Michael R. Cassidy, MD, and Daniel S. Roh, MD, PhD, Boston University School of Medicine, Boston, Massachusetts, called the study's preliminary data "both alarming and intriguing" and agreed that "larger, multi-institutional analysis is critical to confirming these findings."

Many reconstructive surgeons have abandoned the use of textured implants, the editorialists note. This study should convince those who haven't to make sure patients are aware of the risks, they emphasize.

"Given the association of textured implants with ALCL [anaplastic large-cell lymphoma], and now the suggestion that they are associated with increased risk for breast cancer recurrence, surgeons who choose textured implants should counsel their patients with breast cancer about their possible consequences," the pair write.

Editorialists Cassidy and Roh express concern that important details were missing from the analysis and presentation. Data on adjuvant endocrine therapy were not included, even though 85% of the cohort had ER-positive breast cancer, they point out.

Similarly, 21% of patients had ERBB2 (formerly, HER2-positive) disease, but no targeted ERBB2 agents were included in the list of adjuvant therapy regimens.

"Therefore, whether the recurrences were associated with inadequate systemic therapy remains unclear," Cassidy and Roh say. "A table that details the history and treatment of the 28 patients with breast cancer recurrence would be helpful in interpreting this study."

Including data from patients who underwent mastectomy for breast cancer recurrence rather than restricting the analysis to data from primary breast cancer cases alone had the effect of "further confounding matters," they add.

Study Details

For the study, Bang and colleagues identified patients with breast cancer who had undergone total mastectomy and immediate two-stage tissue expander/implant reconstruction from a single tertiary referral center database. Patients were categorized into two groups: those who received a smooth implant during reconstruction (39.9%), and those who were given a textured implant (60.1%).

Data analysis showed that 28 women (4.1%) were diagnosed with any type of breast cancer recurrence during the follow-up period. Of these, 23 received a textured implant, and five received a smooth implant.

The 5-year local and regional recurrence-free survival rate was 96.7; the rate did not differ significantly between the two implant groups.

The 5-year DFS was 95.2%, but there was a statistically significant association with lower DFS in the textured-implant group compared with the smooth-implant group after adjusting for ER status and tumor stage (hazard ratio [HR], 3.054; 95% CI; P = .02).

On multivariable analysis, there was a similar textured implant–specific association with worse DFS among patients with ER-positive cancer (HR, 3.130; 95% CI; P = .04) and invasive cancer (HR, 3.044; 95% CI; P = .03). The most pronounced association between textured-implant use and a lower rate of DFS was observed among patients with stage II or III cancer (HR, 8.874; 95% CI, P = .04).

Bang and colleagues note several study limitations. The sample size of the single-institution study was small, and the 4-year follow-up period after implant insertion was inadequate, they say, "especially for ER-positive breast cancer."

Bang and study coauthors as well as editorialists Cassidy and Roh have disclosed no relevant financial relationships.

JAMA Surg. Published online on October 7, 2020. Abstract, Commentary

IMMUNOTHERAPY INCREASES SECOND NEOPLASM AND CARDIAC EVENTS6

  Over a decade, the use of immune-checkpoint inhibitors (ICIs) for metastatic melanoma appears to have led to a shift in the pattern of second primary cancers, according to a population-based cohort study.

"Cancer immunotherapy has significantly improved clinical outcomes," said Dr. Wen Jiang of the University of Texas Southwestern Medical Center, in Dallas. "As a result, patients with metastatic melanoma that were previously considered as terminal now live for extended period of time. This resulted in many of these patients now increasingly being diagnosed with a second primary cancer down the road."

"Our study," he told Reuters Health by email, "showed that the advent of cancer immunotherapy has also changed how these second primary cancers manifest, in terms of the type of second cancer a survivor who was treated with immunotherapy may develop later in life."

Dr. Jiang and his colleagues tapped into the Surveillance, Epidemiology, and End Results (SEER) database to assess differences before and after the U.S. Food and Drug Administration (FDA) first approved use of ICIs. Ipilimumab was approved in 2011 for metastatic melanoma, followed by other ICIs such as nivolumab and pembrolizumab.

The researchers used data on more than 5000 patients who were diagnosed between 2005 and 2016. From 2005 to 2010, the standardized incidence ratio (SIR) for small-intestine cancer was 3.24 and this rose to 9.23 between 2011 and 2016.

Corresponding SIRs for lung and bronchus cancer were 1.93 and 1.54 and for myeloma 7.29 and 5.90.

Compared to the general population, in those who survived the first primary melanoma in the earlier period, the overall risk of developing a second primary cancer was 65% higher. Between 2011 and 2016, this risk was 98% higher.

Thus, concluded Dr. Jiang, "the clinical implication of our study is that long-term follow-up in these cancer survivors, particularly those treated with immunotherapy would be needed to find these second primary cancers early, and provide rationale of potential screening in high-risk patients."

Dermatologist Dr. Michael A. Marchetti of Memorial Sloan Kettering Cancer Center, in New York City, was not convinced by the findings. He told Reuters Health by email that "there wasn't a robust signal to suggest a statistically or clinically significant change in the risk of second primary cancers (SPCs) in the pre- and post-ICIs periods."

"I disagree with the authors' conclusions that additional screening tests for SPCs are warranted in this population, given the low absolute risk of SPCs and the high absolute risk of all-cause death," he said.

Dr. Marchetti, who has studied metastatic melanoma and immune-checkpoint inhibitors, concluded, "Observational studies like these suffer from many limitations, as the authors pointed out, and analyses of the incidence rates of some individual second primary cancers were particularly limited by small numbers of observed cases."

Immune checkpoint inhibitors (ICIs) increase the risk of cardiac events, including fatal heart attack and stroke, in patients with cancer, an analysis of Danish national registry data suggests.

About 10% of 743 registry participants with lung cancer and 6.6% of 145 with malignant melanoma experienced a cardiac event in the 12 months after starting treatment with either of the programmed death-1 (PD-1) inhibitors pembrolizumab or nivolumab. Similarly, 7.5% of 212 patients with malignant melanoma who received the CTLA-4 inhibitor ipilimumab experienced a cardiac event, report Maria D'Souza, MD, a postdoctoral research fellow in cardiology at Herlev og Gentofte Hospital, Hellerup, Denmark, and colleagues.

Within 6 months of treatment initiation, the patients with lung cancer or malignant melanoma who received PD-1 inhibitors had increased rates of cardiac events, compared with those who did not receive the treatment (hazard ratios [HRs], 2.14 and 4.30, respectively). The risk increased nearly fivefold in those who received the CTLA-4 inhibitor (HR, 4.93).

After 6 months, the risk increased slightly in those with lung cancer receiving a PD-1 inhibitor (HR, 2.26), but was no longer statistically significant for those with melanoma who received a PD-1 inhibitor and decreased slightly for those receiving the CTLA-4 inhibitor (HR, 3.48).

Cardiac events associated with immune checkpoint inhibition included heart failure, arrhythmia, myocarditis, pericarditis, and heart-related death, the researchers note.

Their findings were reported online December 9 in the European Heart Journal.

The researchers looked at 25,573 consecutive patients in the Danish national registries who were diagnosed with lung cancer or malignant melanoma between 2011 and 2017.

"We found that these risks were higher than previously estimated by drug safety studies, which have suggested that around 0.03-1% of people treated with immune checkpoint inhibitors develop myocarditis or pericarditis within one year; our results show that 1.8% will," D'Souza explains in a press statement.

She and her colleagues also observed that cardiac events continued to occur beyond the initial 6 months after treatment, contrary to prior findings showing that most adverse heart effects occur within the first few weeks or months after treatment initiation.

"The findings urge increased awareness of cardiac events in patients receiving ICI," they conclude.

In an accompanying editorial, Matthias Totzeck, MD, of the West German Heart and Vascular Center, University Hospital Essen, Germany, and colleagues concur and suggest adding the term "ICI-related cardiovascular disease" to the list of potential ICI complications, and ramping up efforts to increase awareness of these toxicities.

"Longer term steps include broadening collaborations with our oncology and pharmaceutical partners, and expanded clinical research efforts in parallel and based on innovative basic experimental insights," they write. "These and other steps are needed to move this forward so we can improve cardiovascular outcomes among our cancer patients treated with an ICI."

This study was supported by The Danish Heart Foundation and The VELUX Foundation. D'Souza reported grants from these foundations during the course of the study. The editorial was supported by the National Institutes of Health/National Heart Lung, and Blood Institute. Totzeck reported personal funding and advisory fees from Bayer Vital, Astra Zeneca, Daiichi Sankyo, and Bristol Myers Squibb.

Eur Heart J. 2020;ehaa884, ehaa959. Full text, Editorial

ADJUVANT OSIMETRINIB APPROVED BY FDA

 On December 18, the U.S. Food and Drug Administration (FDA) approved osimertinib (Tagrisso) for adjuvant therapy after tumor resection in patients with non–small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.

ADAURA

Efficacy was demonstrated in the randomized, double-blind, placebo-controlled ADAURA trial. The study included patients with NSCLC and EGFR exon 19 deletions or exon 21 L858R mutations who had undergone a complete tumor resection, with or without prior adjuvant chemotherapy.

Eligible patients with resectable tumors (stage IB­–IIIA) were required to have predominantly nonsquamous histology and EGFR exon 19 deletions or exon 21 L858R mutations identified prospectively from tumor tissue in a central laboratory by the cobas EGFR Mutation Test. A total of 682 patients were randomly assigned 1:1 to receive osimertinib at 80 mg orally once daily or placebo following recovery from surgery and standard adjuvant chemotherapy, if given.

The major efficacy outcome measure was disease-free survival in patients with stage II–IIIA NSCLC determined by investigator assessment. Median disease-free survival was not reached (range = 38.8 months–not evaluable) in patients treated with osimertinib compared with 19.6 months (range = 16.6–24.5 months) in patients treated with placebo (hazard ratio [HR] = 0.17, 95% confidence interval [CI] = 0.12–0.23, P < .0001). Disease-free survival in the overall study population was a secondary efficacy outcome measure; the median was not reached (range = not evaluable–not evaluable) in patients in the osimertinib arm compared with 27.5 months (range = 22­–36 months) in the placebo arm (HR = 0.20, 95% CI = 0.15–0.27, P < .0001).

The most commonly reported (> 20%) adverse reactions in patients taking osimertinib, including laboratory abnormalities, were lymphopenia, leukopenia, thrombocytopenia, diarrhea, anemia, rash, musculoskeletal pain, nail toxicity, neutropenia, dry skin, stomatitis, fatigue, and cough.

The recommended osimertinib dose for adjuvant treatment of early-stage NSCLC is 80 mg orally once daily, with or without food, until disease recurrence, unacceptable toxicity, or for up to 3 years.

PEMBROLIZUMAB FOR TNBC

 As reported in The Lancet by Javier Cortes, MD, and colleagues, the phase III KEYNOTE-355 trial has shown that the addition of pembrolizumab to chemotherapy improved progression-free survival among previously untreated patients with locally recurrent inoperable or metastatic triple-negative breast cancer with a PD-L1 expression combined positive score (CPS) of ≥ 10.

The trial supported the November 2020 U.S. Food and Drug Administration accelerated approval of pembrolizumab for use in combination with chemotherapy for treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer and tumors expressing PD-L1 with a CPS ≥ 10.

Javier Cortes, MD

KEYNOTE-355 Details

The double-blind trial included 847 patients (intention-to-treat population) from sites in 29 countries. They were randomly assigned 2:1 between January 2017 and June 2018 to receive pembrolizumab at 200 mg every 3 weeks plus chemotherapy consisting of physician’s choice of nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin (n = 566) or placebo plus chemotherapy (n = 281). Chemotherapy consisted of nab-paclitaxel at 100 mg/m² on days 1, 8, and 15 every 28 days; paclitaxel at 90 mg/m² on days 1, 8, and 15 every 28 days; or gemcitabine at 1,000 mg/m² plus carboplatin area under the curve = 2 on days 1 and 8 every 21 days. Chemotherapy administration was open label. Pembrolizumab or placebo were continued for up to 35 administrations, with chemotherapy continued at investigator’s discretion or until disease progression or unacceptable toxicity.

The dual primary endpoints were progression-free survival and overall survival assessed in the PD-L1 CPS ≥ 10, CPS ≥ 1, and intention-to-treat populations. The definitive assessment of progression-free survival was done at the current interim analysis; follow-up to assess overall survival is ongoing. A hierarchical testing strategy was used for progression-free survival, with testing done first in the CPS ≥ 10 population (prespecified statistical criterion of α = .00411), then in the CPS ≥ 1 population (α = .00111), and then in the intention-to-treat population (α = .00111).

In the pembrolizumab vs control groups, 220 vs 103 patients had CPS ≥ 10 and 425 vs 211 had CPS ≥ 1. Among all patients, disease status was de novo metastatic in 30% in the pembrolizumab/chemotherapy group vs 30% in the placebo/chemotherapy group, recurrent metastatic in 68% vs 66%, and locally recurrent inoperable in 2% vs 4%.

Progression-Free Survival

At the second interim analysis data cutoff in December 2019, median follow-up was 25.9 months (interquartile range [IQR] = 22.8–29.9 months) in the pembrolizumab group and 26.3 months (IQR = 22.7–29.7 months) in the control group.   

Among patients with CPS ≥ 10, median progression-free survival was 9.7 months in the pembrolizumab group vs 5.6 months in the control group (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.49–0.86, P = .0012; primary objective met). Progression-free survival at 6 and 12 months was 65.0% vs 46.9% and 39.1% vs 23.0%. According to chemotherapy regimen, hazard ratios were 0.57 (95% CI = 0.34–0.95) for nab-paclitaxel, 0.33 (95% CI = 0.14–0.76) for paclitaxel, and 0.77 (95% CI = 0.53–1.11) for gemcitabine/carboplatin. Median progression-free survival among 524 patients with CPS < 10 was 5.8 vs 5.7 months (HR = 0.94, 95% CI = 0.76–1.16).

KEY POINTS

• Pembrolizumab/chemotherapy significantly prolonged progression-free survival vs placebo/chemotherapy among patients with PD-L1 CPS ≥ 10.
• The benefit of pembrolizumab increased along with increasing PD-L1 CPS.

Median progression-free survival was 7.6 vs 5.6 months (HR = 0.74, 95% CI =  0.61–0.90, P = .0014; not significant) among patients with CPS ≥ 1, with 6- and 12-month rates of 56.4% vs 46.6% and 31.7% vs 19.4%, and 7.5 vs 5.6 months (HR = 0.82, 95% CI =  0.69-0.97; not tested due to hierarchical testing) among the intention-to-treat population, with 6- and 12-month rates of 55.4% vs 47.8% and 29.8% vs 20.9%.

Median progression-free survival was 6.3 vs 6.2 months (HR = 1.08, 95% CI = 0.77–1.53) among 211 patients with CPS < 1 and 9.5 vs 5.4 months (HR = 0.61, 95% CI = 0.43–0.87) among 204 patients with CPS ≥ 20.

Adverse Events

Grade ≥ 3 treatment-related adverse event rates occurred in 68% of patients in the pembrolizumab group vs 67% of the control group, with the most common in the pembrolizumab group including neutropenia (30% vs 30%), decreased neutrophil count (17% vs 20%), anemia (16% vs 15%), and increased alanine aminotransferase (6% vs 5%). Treatment-related adverse events led to death in two patients (< 1%) in the pembrolizumab group—with causes consisting of acute kidney injury in one and pneumonia in one—and in no patients in the control group.

Immune-mediated adverse events of any grade occurred in 26% vs 6% of patients, with the most common in the pembrolizumab group being hypothyroidism (15%) and hyperthyroidism (5%). Grade ≥ 3 events occurred in 5% vs 0%, with the most common in the pembrolizumab group being severe skin reaction (2%). No patients died due to immune-mediated adverse events.

The investigators concluded, “Pembrolizumab/chemotherapy showed a significant and clinically meaningful improvement in progression-free survival vs placebo/chemotherapy among patients with metastatic triple-negative breast cancer with CPS of 10 or more. These findings suggest a role for the addition of pembrolizumab to standard chemotherapy for the first-line treatment of metastatic triple-negative breast cancer.”

Dr. Cortes, of the International Breast Cancer Center, Quiron Group, Madrid and Barcelona, is the corresponding author for The Lancet article.

Disclosure: The study was supported by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc. For full disclosures of the study authors, visit thelancet.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

NEOADJUVANT CHEMO FOR ENDOMETRIAL CANCER

 In a National Cancer Database analysis reported in JAMA Network Open, Tobias et al found that receipt of neoadjuvant chemotherapy was associated with improved short-term but not long-term survival vs primary debulking surgery in patients with metastatic endometrial cancer.

As stated by the investigators, “Although primary debulking surgery is often considered the criterion standard for treatment of stage IV endometrial cancer, primary debulking surgery is associated with significant morbidity and poor survival. Neoadjuvant chemotherapy has been proposed as an alternative treatment strategy.”

“The results of this cohort study suggest that women treated with primary debulking surgery are at increased risk of early death but have a more favorable long-term prognosis. In contrast, results suggest that women treated with neoadjuvant chemotherapy, particularly if they ultimately undergo surgery, may have superior survival in the short term.”

— Tobias et al

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Study Details

The study involved National Cancer Database data on 4,890 women with stage IV endometrial cancer treated from January 2010 to December 2015. Patients had to be aged ≤ 70 years with minimal comorbidity (comorbidity score = 0). Women were stratified based on receipt of neoadjuvant chemotherapy or primary debulking surgery.

Key Findings

Overall, neoadjuvant chemotherapy was used in 952 women (19.5%), with use increasing from 106 (16.0%) of 661 women in 2010 to 224 (23.9%) of 938 women in 2015 (P < .001).

In multivariate analysis, use of neoadjuvant chemotherapy was associated with more recent year of diagnosis (risk ratio [RR] = 1.42, 95% confidence interval [CI] =1.21–1.79, for 2015 vs 2010), stage IVB vs IVA disease (RR = 1.31, 95% CI = 1.03–1.67), and serous vs endometrioid histology (RR = 1.38, 95% CI = 1.13–1.69).

In a propensity score–balanced cohort, use of neoadjuvant chemotherapy exhibited an association with overall survival that varied over time from diagnosis. In intention-to-treat analysis, neoadjuvant chemotherapy was associated with improved survival vs primary debulking surgery for approximately 3 months (HRs for mortality = 0.56, 95% CI = 0.39–0.80, in month 1 and 0.81, 95% CI = 0.66–0.99 in month 2), with hazard ratios being similar for months 3 and 4; the survival curves crossed after 4 months, and neoadjuvant chemotherapy was associated with worse survival from month 5 onward (HR = 1.17, 95% CI = 1.03–1.33).

Among women who started treatment with surgery, 3,139 (79.7%) ultimately received chemotherapy. Among those who initiated neoadjuvant chemotherapy, 555 (58.3%) underwent surgery. In a per-protocol analysis that included only women who received both chemotherapy and surgery in either sequence, use of neoadjuvant chemotherapy was associated with improved survival for the first 8 months after diagnosis (HR at 6 months = 0.79, 95% CI = 0.63–0.98). The survival curves crossed after 9 months, with neoadjuvant chemotherapy being associated with poorer survival thereafter (HR at 12 months = 1.22, 95% CI = 1.04–1.43).

The investigators concluded, “The results of this cohort study suggest that women treated with primary debulking surgery are at increased risk of early death but have a more favorable long-term prognosis. In contrast, results suggest that women treated with neoadjuvant chemotherapy, particularly if they ultimately undergo surgery, may have superior survival in the short term. Based on these findings, neoadjuvant chemotherapy may be appropriate for select patients with advanced uterine serous carcinoma.”

Jason D. Wright, MD, of the Division of Gynecologic Oncology, Columbia University College of Physicians and Surgeons, is the corresponding author for the JAMA Network Open article.

Disclosure: For full disclosures of the study authors, visit jamanetwork.com.

COVID VACCINE NEWS

 Phase 3 interim trial results from the Oxford/AstraZeneca vaccine have just been published in The Lancet. Previously, interim results were issued in a press release.

In today's paper, for participants who received two standard doses, vaccine efficacy was 62.1%.

In participants who received a low dose followed by a standard dose, efficacy was 90.0%.

This was described as "intriguingly high compared with the other findings in the study. Although there is a possibility that chance might play a part in such divergent results."

Professor Andrew Pollard, director of the Oxford Vaccine Group, Department of Paediatrics, University of Oxford, told a news briefing hosted by the Science Media Centre that the half dose, full dose approach that gave the best results wasn't planned. He dismissed concerns about the age of participants in that group saying the result "doesn't appear to be an age phenomenon".

Overall vaccine efficacy across both groups was 70.4%.

Regulators and UK vaccination advisers would have to assess which regimen might be selected for approval, Prof Pollard said.

The vaccine was found to be safe, the authors said, with only three out of 23,745 participants over a median of 3.4 months experiencing serious adverse events that were possibly related to a vaccine; one in the vaccine arm, one in the control arm, and one in a participant who remains masked to group allocation. All participants have recovered or are recovering, and remain in the trial.

The paper said: "A case of transverse myelitis was reported 14 days after ChAdOx1 nCoV-19 booster vaccination as being possibly related to vaccination, with the independent neurological committee considering the most likely diagnosis to be of an idiopathic, short segment, spinal cord demyelination."

Prof Pollard said: "I think today is an important landmark for us because the data package that is in this paper is being put forward to regulators to consider and to scrutinise so there's these two different aspects of scrutiny, there's the scientific peer review for publication, and also the regulatory processes which I'm sure we'll hear more about in the weeks ahead."

Professor Sarah Gilbert, Jenner Institute, Nuffield Department of Medicine, University of Oxford, said: "This is a really good day in the UK. This is probably the best day we've had in 2020. Not only today are we seeing the first rollout of NHS vaccinations against COVID-19, from our side we're able to present to you our data in a full peer reviewed publication."

Reaction

In a linked comment, Dr Maria Deloria Knoll and Dr Chizoba Wonodi, Johns Hopkins Bloomberg School of Public Health, USA, who were not involved in the study, said: "Despite the outstanding questions and challenges in delivering these vaccines, it is hard not to be excited about these findings and now the existence of three safe and efficacious COVID-19 vaccines, with 57 more in clinical trials."

Professor Stephen Evans, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, commented: "These results reflect the headlines given in previous press releases, but with both a fuller explanation of what was done and more detail around the uncertainty in the estimates of efficacy.

"The unfortunate [half dose] measurement technique problem that occurred with some doses produced in Italy is going to be seen by some as raising questions about this trial. It is clear however, that national and international regulators were fully apprised of what had happened and a plan for analysis was determined prior to knowledge of the results." 

This article originally appeared on Medscape UK, part of the Medscape Professional Network.

For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube.

Coronavirus vaccines have become a reality, as they are now being approved and authorized for use in a growing number of countries including the United States. The U.S. Food and Drug Administration has just issued emergency authorization for the use of the COVID-19 vaccine produced by Pfizer and BioNTech. Close behind is the vaccine developed by Moderna, which has also applied to the FDA for emergency authorization.

The efficacy of a two-dose administration of the vaccine has been pegged at 95.0%, and the FDA has said that the 95% credible interval for the vaccine efficacy was 90.3%-97.6%. But as with many initial clinical trials, whether for drugs or vaccines, not all populations were represented in the trial cohort, including individuals who are immunocompromised. At the current time, it is largely unknown how safe or effective the vaccine may be in this large population, many of whom are at high risk for serious COVID-19 complications.

At a special session held during the recent annual meeting of the American Society of Hematology, Anthony Fauci, MD, the nation's leading infectious disease expert, said that individuals with compromised immune systems, whether because of chemotherapy or a bone marrow transplant, should plan to be vaccinated when the opportunity arises.

In response to a question from ASH President Stephanie J. Lee, MD, of the Fred Hutchinson Cancer Center, Seattle, Fauci emphasized that, despite being excluded from clinical trials, this population should get vaccinated. "I think we should recommend that they get vaccinated," he said. "I mean, it is clear that, if you are on immunosuppressive agents, history tells us that you're not going to have as robust a response as if you had an intact immune system that was not being compromised. But some degree of immunity is better than no degree of immunity."

That does seem to be the consensus among experts who spoke in interviews: that as long as these are not live attenuated vaccines, they hold no specific risk to an immunocompromised patient, other than any factors specific to the individual that could be a contraindication.

"Patients, family members, friends, and work contacts should be encouraged to receive the vaccine," said William Stohl, MD, PhD, chief of the division of rheumatology at the University of Southern California, Los Angeles. "Clinicians should advise patients to obtain the vaccine sooner rather than later."

Kevin C. Wang, MD, PhD, of the department of dermatology at Stanford (Calif.) University, agreed. "I am 100% with Fauci. Everyone should get the vaccine, even if it may not be as effective," he said. "I would treat it exactly like the flu vaccines that we recommend folks get every year."

Wang noted that he couldn't think of any contraindications unless the immunosuppressed patients have a history of severe allergic reactions to prior vaccinations. "But I would even say patients with history of cancer, upon recommendation of their oncologists, are likely to be suitable candidates for the vaccine," he added. "I would say clinicians should approach counseling the same way they counsel patients for the flu vaccine, and as far as I know, there are no concerns for systemic drugs commonly used in dermatology patients."

However, guidance has not yet been issued from either the FDA or the Centers for Disease Control and Prevention regarding the use of the vaccine in immunocompromised individuals. Given the lack of data, the FDA has said that "it will be something that providers will need to consider on an individual basis," and that individuals should consult with physicians to weigh the potential benefits and potential risks.

The CDC's Advisory Committee on Immunization Practices has said that clinicians need more guidance on whether to use the vaccine in pregnant or breastfeeding women, the immunocompromised, or those who have a history of allergies. The CDC itself has not yet released its formal guidance on vaccine use.

COVID-19 Vaccines

Vaccines typically require years of research and testing before reaching the clinic, but this year researchers embarked on a global effort to develop safe and effective coronavirus vaccines in record time. Both the Pfizer/BioNTech and Moderna vaccines have only a few months of phase 3 clinical trial data, so much remains unknown about them, including their duration of effect and any long-term safety signals. In addition to excluding immunocompromised individuals, the clinical trials did not include children or pregnant women, so data are lacking for several population subgroups.

But these will not be the only vaccines available, as the pipeline is already becoming crowded. U.S. clinical trial data from a vaccine jointly being developed by Oxford-AstraZeneca, could potentially be ready, along with a request for FDA emergency use authorization, by late January 2021.

In addition, China and Russia have released vaccines, and there are currently 61 vaccines being investigated in clinical trials and at least 85 preclinical products under active investigation.

The vaccine candidates are using both conventional and novel mechanisms of action to elicit an immune response in patients. Conventional methods include attenuated inactivated (killed) virus and recombinant viral protein vaccines to develop immunity. Novel approaches include replication-deficient, adenovirus vector-based vaccines that contain the viral protein, and mRNA-based vaccines, such as the Pfizer and Moderna vaccines, that encode for a SARS-CoV-2 spike protein.

"The special vaccine concern for immunocompromised individuals is introduction of a live virus," Stohl said. "Neither the Moderna nor Pfizer vaccines are live viruses, so there should be no special contraindication for such individuals."

Live vaccine should be avoided in immunocompromised patients, and currently, live SARS-CoV-2 vaccines are only being developed in India and Turkey.

It is not unusual for vaccine trials to begin with cohorts that exclude participants with various health conditions, including those who are immunocompromised. These groups are generally then evaluated in phase 4 trials, or postmarketing surveillance. While the precise number of immunosuppressed adults in the United States is not known, the numbers are believed to be rising because of increased life expectancy among immunosuppressed adults as a result of advances in treatment and new and wider indications for therapies that can affect the immune system.

According to data from the 2013 National Health Interview Survey, an estimated 2.7% of U.S. adults are immunosuppressed. This population covers a broad array of health conditions and medical specialties; people living with inflammatory or autoimmune conditions, such as inflammatory rheumatic diseases (rheumatoid arthritis, axial spondyloarthritis, lupus); inflammatory bowel disease (Crohn's disease and ulcerative colitis); psoriasis; multiple sclerosis; organ transplant recipients; patients undergoing chemotherapy; and life-long immunosuppression attributable to HIV infection.

As the vaccines begin to roll out and become available, how should clinicians advise their patients, in the absence of any clinical trial data?

Risk vs. Benefit

Gilaad Kaplan, MD, MPH, a gastroenterologist and professor of medicine at the University of Calgary (Alta.), noted that the inflammatory bowel disease (IBD) community has dealt with tremendous anxiety during the pandemic because many are immunocompromised because of the medications they use to treat their disease.

"For example, many patients with IBD are on biologics like anti-TNF [tumor necrosis factor] therapies, which are also used in other immune-mediated inflammatory diseases such as rheumatoid arthritis," he said. "Understandably, individuals with IBD on immunosuppressive medications are concerned about the risk of severe complications due to COVID-19."

The entire IBD community, along with the world, celebrated the announcement that multiple vaccines are protective against SARS-CoV-2, he noted. "Vaccines offer the potential to reduce the spread of COVID-19, allowing society to revert back to normalcy," Kaplan said. "Moreover, for vulnerable populations, including those who are immunocompromised, vaccines offer the potential to directly protect them from the morbidity and mortality associated with COVID-19."

That said, even though the news of vaccines are extremely promising, some cautions must be raised regarding their use in immunocompromised populations, such as persons with IBD. "The current trials, to my knowledge, did not include immunocompromised individuals and thus, we can only extrapolate from what we know from other trials of different vaccines," he explained. "We know from prior vaccines studies that the immune response following vaccination is less robust in those who are immunocompromised as compared to a healthy control population."

Kaplan also pointed to recent reports of allergic reactions that have been reported in healthy individuals. "We don't know whether side effects, like allergic reactions, may be different in unstudied populations," he said. "Thus, the medical and scientific community should prioritize clinical studies of safety and effectiveness of COVID-19 vaccines in immunocompromised populations."

So, what does this mean for an individual with an immune-mediated inflammatory disease like Crohn's disease or ulcerative colitis who is immunocompromised? Kaplan explained that it is a balance between the potential harm of being infected with COVID-19 and the uncertainty of receiving a vaccine in an understudied population. For those who are highly susceptible to dying from COVID-19, such as an older adult with IBD, or someone who faces high exposure, such as a health care worker, the potential protection of the vaccine greatly outweighs the uncertainty.

"However, for individuals who are at otherwise lower risk – for example, young and able to work from home – then waiting a few extra months for postmarketing surveillance studies in immunocompromised populations may be a reasonable approach, as long as these individuals are taking great care to avoid infection," he said.

No Waiting Needed

Joel M. Gelfand, MD, MSCE, professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia, feels that the newly approved vaccine should be safe for most of his patients.

"Patients with psoriatic disease should get the mRNA-based COVID-19 vaccine as soon as possible based on eligibility as determined by the CDC and local public health officials," he said. "It is not a live vaccine, and therefore patients on biologics or other immune-modulating or immune-suppressing treatment can receive it."

However, the impact of psoriasis treatment on immune response to the mRNA-based vaccines is not known. Gelfand noted that, extrapolating from the vaccine literature, there is some evidence that methotrexate reduces response to the influenza vaccine. "However, the clinical significance of this finding is not clear," he said. "Since the mRNA vaccine needs to be taken twice, a few weeks apart, I do not recommend interrupting or delaying treatment for psoriatic disease while undergoing vaccination for COVID-19."

Given the reports of allergic reactions, he added that it is advisable for patients with a history of life-threatening allergic reactions such as anaphylaxis or who have been advised to carry an epinephrine autoinjector, to talk with their health care provider to determine if COVID-19 vaccination is medically appropriate.

The National Psoriasis Foundation has issued guidance on COVID-19, explained Steven R. Feldman, MD, PhD, professor of dermatology, pathology, and social sciences & health policy at Wake Forest University, Winston-Salem, N.C., who is also a member of the committee that is working on those guidelines and keeping them up to date. "We are in the process of updating the guidelines with information on COVID vaccines," he said.

He agreed that there are no contraindications for psoriasis patients to receive the vaccine, regardless of whether they are on immunosuppressive treatment, even though definitive data are lacking. "Fortunately, there's a lot of good data coming out of Italy that patients with psoriasis on biologics do not appear to be at increased risk of getting COVID or of having worse outcomes from COVID," he said.

Patients are going to ask about the vaccines, and when counseling them, clinicians should discuss the available data, the residual uncertainty, and patients' concerns should be considered, Feldman explained. "There may be some concern that steroids and cyclosporine would reduce the effectiveness of vaccines, but there is no concern that any of the drugs would cause increased risk from nonlive vaccines."

He added that there is evidence that "patients on biologics who receive nonlive vaccines do develop antibody responses and are immunized."

Boosting Efficacy

Even prior to making their announcement, the American College of Rheumatology had said that they would endorse the vaccine for all patients, explained rheumatologist Brett Smith, DO, from Blount Memorial Physicians Group and East Tennessee Children's Hospital, Alcoa. "The vaccine is safe for all patients, but the problem may be that it's not as effective," he said. "But we don't know that because it hasn't been tested."

With other vaccines, biologic medicines are held for 2 weeks before and afterwards, to get the best response. "But some patients don't want to stop the medication," Smith said. "They are afraid that their symptoms will return."

As for counseling patients as to whether they should receive this vaccine, he explained that he typically doesn't try to sway patients one way or another until they are really high risk. "When I counsel, it really depends on the individual situation. And for this vaccine, we have to be open to the fact that many people have already made up their mind."

There are a lot of questions regarding the vaccine. One is the short time frame of development. "Vaccines typically take 6-10 years to come on the market, and this one is now available after a 3-month study," Smith said. "Some have already decided that it's too new for them."

The process is also new, and patients need to understand that it doesn't contain an active virus and "you can't catch coronavirus from it."

Smith also explained that, because the vaccine may be less effective in a person using biologic therapies, there is currently no information available on repeat vaccination. "These are all unanswered questions," he said. "If the antibodies wane in a short time, can we be revaccinated and in what time frame? We just don't know that yet."

Philip D. Bonomi, MD, a professor of medical oncology at Rush Medical College, Chicago, explained that one way to ensure a more optimal response to the vaccine would be to wait until the patient has finished chemotherapy. "The vaccine can be offered at that time, and in the meantime, they can take other steps to avoid infection," he said. "If they are very immunosuppressed, it isn't worth trying to give the vaccine."

Cancer patients should be encouraged to stay as healthy as possible, and to wear masks and social distance. "It's a comprehensive approach. Eat healthy, avoid alcohol and tobacco, and exercise. [These things] will help boost the immune system," Bonomi said. "Family members should be encouraged to get vaccinated, which will help them avoid infection and exposing the patient."

Jim Boonyaratanakornkit, MD, PhD, an infectious disease specialist who cares for cancer patients at the Fred Hutchinson Cancer Research Center, agreed. "Giving a vaccine right after a transplant is a futile endeavor," he said. "We need to wait 6 months to have an immune response."

He pointed out there may be a continuing higher number of cases, with high levels peaking in Washington in February and March. "Close friends and family should be vaccinated if possible," he said, "which will help interrupt transmission."

The vaccines are using new platforms that are totally different, and there is no clear data as to how long the antibodies will persist. "We know that they last for at least 4 months," said Boonyaratanakornkit. "We don't know what level of antibody will protect them from COVID-19 infection. Current studies are being conducted, but we don't have that information for anyone yet.

In mid-November, Pfizer/BioNTech were the first with surprising positive protection interim data for their coronavirus vaccine, BNT162b2. A week later, Moderna released interim efficacy results showing its coronavirus vaccine, mRNA-1273, also protected patients from developing SARS-CoV-2 infections. Both studies included mostly healthy adults. A diverse ethnic and racial vaccinated population was included. A reasonable number of persons aged over 65 years, and persons with stable compromising medical conditions were included. Adolescents aged 16 years and over were included. Younger adolescents have been vaccinated or such studies are in the planning or early implementation stage as 2020 came to a close.

 

These are new and revolutionary vaccines, although the ability to inject mRNA into animals dates back to 1990, technological advances today make it a reality.¹ Traditional vaccines typically involve injection with antigens such as purified proteins or polysaccharides or inactivated/attenuated viruses. mRNA vaccines work differently. They do not contain antigens. Instead, they contain a blueprint for the antigen in the form of genetic material, mRNA. In the case of Pfizer's and Moderna's vaccines, the mRNA provides the genetic information to synthesize the spike protein that the SARS-CoV-2 virus uses to attach to and infect human cells. Each type of vaccine is packaged in proprietary lipid nanoparticles to protect the mRNA from rapid degradation, and the nanoparticles serve as an adjuvant to attract immune cells to the site of injection. (The properties of the respective lipid nanoparticle packaging may be the factor that impacts storage requirements discussed below.) When injected into muscle (myocyte), the lipid nanoparticles containing the mRNA inside are taken into muscle cells, where the cytoplasmic ribosomes detect and decode the mRNA resulting in the production of the spike protein antigen. It should be noted that the mRNA does not enter the nucleus, where the genetic information (DNA) of a cell is located, and can't be reproduced or integrated into the DNA. The antigen is exported to the myocyte cell surface where the immune system's antigen presenting cells detect the protein, ingest it, and take it to regional lymph nodes where interactions with T cells and B cells results in antibodies, T cell–mediated immunity, and generation of immune memory T cells and B cells. A particular subset of T cells – cytotoxic or killer T cells – destroy cells that have been infected by a pathogen. The SARS-CoV-2 mRNA vaccine from Pfizer was reported to induce powerful cytotoxic T-cell responses. Results for Moderna's vaccine had not been reported at the time this column was prepared, but I anticipate the same positive results.

The revolutionary aspect of mRNA vaccines is the speed at which they can be designed and produced. This is why they lead the pack among the SARS-CoV-2 vaccine candidates and why the National Institute of Allergy and Infectious Diseases provided financial, technical, and/or clinical support. Indeed, once the amino acid sequence of a protein can be determined (a relatively easy task these days) it's straightforward to synthesize mRNA in the lab – and it can be done incredibly fast. It is reported that the mRNA code for the vaccine by Moderna was made in 2 days and production development was completed in about 2 months.²

A 2007 World Health Organization report noted that infectious diseases are emerging at "the historically unprecedented rate of one per year."³ Severe acute respiratory syndrome (SARS), Zika, Ebola, and avian and swine flu are recent examples. For most vaccines against emerging diseases, the challenge is about speed: developing and manufacturing a vaccine and getting it to persons who need it as quickly as possible. The current seasonal flu vaccine takes about 6 months to develop; it takes years for most of the traditional vaccines. That's why once the infrastructure is in place, mRNA vaccines may prove to offer a big advantage as vaccines against emerging pathogens.

Early Efficacy Results Have Been Surprising

Both vaccines were reported to produce about 95% efficacy in the final analysis. That was unexpectedly high because most vaccines for respiratory illness achieve efficacy of 60%-80%, e.g., flu vaccines. However, the efficacy rate may drop as time goes by because stimulation of short-term immunity would be in the earliest reported results.

Preventing SARS-CoV-2 cases is an important aspect of a coronavirus vaccine, but preventing severe illness is especially important considering that severe cases can result in prolonged intubation/artificial ventilation, prolonged disability and death. Pfizer/BioNTech had not released any data on the breakdown of severe cases as this column was finalized. In Moderna's clinical trial, a secondary endpoint analyzed severe cases of COVID-19 and included 30 severe cases (as defined in the study protocol) in this analysis. All 30 cases occurred in the placebo group and none in the mRNA-1273–vaccinated group. In the Pfizer/BioNTech trial there were too few cases of severe illness to calculate efficacy.

Duration of immunity and need to revaccinate after initial primary vaccination are unknowns. Study of induction of B- and T-cell memory and levels of long-term protection have not been reported thus far.

Could mRNA COVID-19 Vaccines Be Dangerous in the Long Term?

These will be the first-ever mRNA vaccines brought to market for humans. In order to receive Food and Drug Administration approval, the companies had to prove there were no immediate or short-term negative adverse effects from the vaccines. The companies reported that their independent data-monitoring committees hadn't "reported any serious safety concerns." However, fairly significant local reactions at the site of injection, fever, malaise, and fatigue occur with modest frequency following vaccinations with these products, reportedly in 10%-15% of vaccinees. Overall, the immediate reaction profile appears to be more severe than what occurs following seasonal influenza vaccination. When mass inoculations with these completely new and revolutionary vaccines begins, we will know virtually nothing about their long-term side effects. The possibility of systemic inflammatory responses that could lead to autoimmune conditions, persistence of the induced immunogen expression, development of autoreactive antibodies, and toxic effects of delivery components have been raised as theoretical concerns.^4-6 None of these theoretical risks have been observed to date and postmarketing phase 4 safety monitoring studies are in place from the Centers for Disease Control and Prevention and the companies that produce the vaccines. This is a risk public health authorities are willing to take because the risk to benefit calculation strongly favors taking theoretical risks, compared with clear benefits in preventing severe illnesses and death.

What About Availability?

Pfizer/BioNTech expects to be able to produce up to 50 million vaccine doses in 2020 and up to 1.3 billion doses in 2021. Moderna expects to produce 20 million doses by the end of 2020, and 500 million to 1 billion doses in 2021. Storage requirements are inherent to the composition of the vaccines with their differing lipid nanoparticle delivery systems. Pfizer/BioNTech's BNT162b2 has to be stored and transported at –80° C, which requires specialized freezers, which most doctors' offices and pharmacies are unlikely to have on site, or dry ice containers. Once the vaccine is thawed, it can only remain in the refrigerator for 24 hours. Moderna's mRNA-1273 will be much easier to distribute. The vaccine is stable in a standard freezer at –20° C for up to 6 months, in a refrigerator for up to 30 days within that 6-month shelf life, and at room temperature for up to 12 hours.

Timelines and Testing Other Vaccines

Strong efficacy data from the two leading SARS-CoV-2 vaccines and emergency-use authorization Food and Drug Administration approval suggest the window for testing additional vaccine candidates in the United States could soon start to close. Of the more than 200 vaccines in development for SARS-CoV-2, at least 7 have a chance of gathering pivotal data before the front-runners become broadly available.

Testing diverse vaccine candidates, based on different technologies, is important for ensuring sufficient supply and could lead to products with tolerability and safety profiles that make them better suited, or more attractive, to subsets of the population. Different vaccine antigens and technologies also may yield different durations of protection, a question that will not be answered until long after the first products are on the market.

AstraZeneca enrolled about 23,000 subjects into its two phase 3 trials of AZD1222 (ChAdOx1 nCoV-19): a 40,000-subject U.S. trial and a 10,000-subject study in Brazil. AstraZeneca's AZD1222, developed with the University of Oxford (England), uses a replication defective simian adenovirus vector called ChAdOx1.AZD1222 which encodes the SARS-CoV-2 spike protein. After injection, the viral vector delivers recombinant DNA that is decoded to mRNA, followed by mRNA decoding to become a protein. A serendipitous manufacturing error for the first 3,000 doses resulted in a half dose for those subjects before the error was discovered. Full doses were given to those subjects on second injections and those subjects showed 90% efficacy. Subjects who received 2 full doses showed 62% efficacy. A vaccine cannot be licensed based on 3,000 subjects so AstraZeneca has started a new phase 3 trial involving many more subjects to receive the combination lower dose followed by the full dose.

Johnson and Johnson (J&J) started its phase 3 trial evaluating a single dose of JNJ-78436735 in September. Phase 3 data may be reported by the end of2020. In November, J&J announced it was starting a second phase 3 trial to test two doses of the candidate. J&J's JNJ-78436735 encodes the SARS-CoV-2 spike protein in an adenovirus serotype 26 (Ad26) vector, which is one of the two adenovirus vectors used in Sputnik V, the Russian vaccine reported to have 90% efficacy at an early interim analysis.

Sanofi and Novavax are both developing protein-based vaccines, a proven modality. Sanofi, in partnership with GlaxoSmithKline started a phase 1/2 clinical trial in the Fall 2020 with plans to commence a phase 3 trial in late December. Sanofi developed the protein ingredients and GlaxoSmithKline added one of their novel adjuvants. Novavax expects data from a U.K. phase 3 trial of NVX-CoV2373 in early 2021 and began a U.S. phase 3 study in late November. NVX-CoV2373 was created using Novavax' recombinant nanoparticle technology to generate antigen derived from the coronavirus spike protein and contains Novavax's patented saponin-based Matrix-M adjuvant.

Inovio Pharmaceuticals was gearing up to start a U.S. phase 2/3 trial of DNA vaccine INO-4800 by the end of 2020.

After Moderna and Pfizer-BioNTech, CureVac has the next most advanced mRNA vaccine. It was planned that a phase 2b/3 trial of CVnCoV would be conducted in Europe, Latin America, Africa, and Asia. Sanofi is also developing a mRNA vaccine as a second product in addition to its protein vaccine.

Vaxxinity planned to begin phase 3 testing of UB-612, a multitope peptide–based vaccine, in Brazil by the end of 2020.

However, emergency-use authorizations for the Pfizer and Moderna vaccines could hinder trial recruitment in at least two ways. Given the gravity of the pandemic, some stakeholders believe it would be ethical to unblind ongoing trials to give subjects the opportunity to switch to a vaccine proven to be effective. Even if unblinding doesn't occur, as the two authorized vaccines start to become widely available, volunteering for clinical trials may become less attractive.

Pichichero is a specialist in pediatric infectious diseases, and director of the Research Institute at Rochester (N.Y.) General Hospital. He said he has no relevant financial disclosures. Email Pichichero at pdnews@mdedge.com.

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Earlier this week, Medscape spoke with Nora Disis, MD, about vaccinating cancer patients. Disis is a medical oncologist and director of both the Institute of Translational Health Sciences and the Cancer Vaccine Institute, the University of Washington, Seattle, Washington. As editor-in-chief of JAMA Oncology, she has watched COVID-19 developments in the oncology community over the past year.

Here are a few themes that Disis said oncologists should be aware of as vaccines eventually begin reaching cancer patients.

We should expect cancer patients to respond to vaccines. Historically, some believed that cancer patients would be unable to mount an immune response to vaccines. Data on other viral vaccines have shown otherwise. For example, there has been a long history of studies of flu vaccination in cancer patients, and in general, those vaccines confer protection. Likewise for pneumococcal vaccine, which, generally speaking, cancer patients should receive.

Special cases may include hematologic malignancies in which the immune system has been destroyed and profound immunosuppression occurs. Data on immunization during this immunosuppressed period are scarce, but what data are available suggest that once cancer patients are through this immunosuppressed period, they can be vaccinated successfully.

The type of vaccine will probably be important for cancer patients. Currently, there are 61 coronavirus vaccines in human clinical trials, and 17 have reached the final stages of testing. At least 85 preclinical vaccines are under active investigation in animals.

Both the Pfizer-BioNTech and Moderna COVID vaccines are mRNA type. There are many other types, including protein-based vaccines, viral vector vaccines based on adenoviruses, and inactivated or attenuated coronavirus vaccines.

The latter vaccines, particularly attenuated live virus vaccines, may not be a good choice for cancer patients. Especially in those with rapidly progressing disease or on chemotherapy, attenuated live viruses may cause a low-grade infection.

Incidentally, the technology used in the genetic, or mRNA, vaccines developed by both Pfizer-BioNTech and Moderna was initially developed for fighting cancer, and studies have shown that patients can generate immune responses to cancer-associated proteins with this type of vaccine.

These genetic vaccines could turn out to be the most effective for cancer patients, especially those with solid tumors.

Our understanding is very limited right now. Neither the Pfizer-BioNTech nor the Moderna early data discuss cancer patients. Two of the most important questions for cancer patients are dosing and booster scheduling. Potential defects in lymphocyte function among cancer patients may require unique initial dosing and booster schedules. In terms of timing, it is unclear how active therapy might affect a patient's immune response to vaccination and whether vaccines should be timed with therapy cycles.

Vaccine access may depend on whether cancer patients are viewed as a vulnerable population. Those at higher risk for severe COVID-19 clearly have a greater need for vaccination. While there are data suggesting that cancer patients are at higher risk, they are a bit murky, in part because cancer patients are a heterogeneous group. For example, there are data suggesting that lung and blood cancer patients fare worse. There is also a suggestion that, like in the general population, COVID risk in cancer patients remains driven by comorbidities.

It is likely, then, that personalized risk factors such as type of cancer therapy, site of disease, and comorbidities will shape individual choices about vaccination among cancer patients.

Scientists are now confident that a new variant of the SARS-CoV-2 virus is more contagious but say studies are underway to test its impact on containing COVID-19

What is different about this variant?

The new variant of the SARS-CoV-2 virus, known as VUI-202012/01, or lineage B.1.1.7, carries an unusually large number of mutations.

Three of the mutations have potential biological effects. These have been identified as:

• Mutation N501Y – one of six key contact residues within the receptor-binding domain that can increase binding affinity to human and murine ACE2.

• The spike deletion 69-70del that affects the capacity to evade human immune response

• Mutation P681H adjacent to the furin cleavage site

How was it identified?

The variant was identified by Public Health England monitoring, following a surge in cases seen in Kent and London.

The two earliest sampled genomes belonging to B.1.1.7 lineage were collected on 20 September in Kent, followed by another on 21 September in Greater London.

How widespread is it?

According to the COVID-19 Genomics Consortium UK (COG-UK), as of 15 December, there were 1623 genomes in the B.1.1.7 lineage.

Of these 519 were sampled in Greater London, 555 in Kent, 545 in other regions of the UK including both Scotland and Wales, and four in other countries.

Is it more contagious?

Genomic data suggests a growth rate of the new virus variant 71% higher (95% confidence level: 67% - 75%) than other variants.

Although it remains too early to say with certainty that the variant is responsible for increased numbers of cases, the New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG) said on 18 December that the variant had "demonstrated exponential growth during a period when national lockdown measures were in place".

The panel concluded that that VUI-202012/01 "demonstrates a substantial increase in transmissibility compared to other variants".

Is the new variant more dangerous? 

Sharon Peacock, executive director of COG-UK, told a briefing hosted by the Science Media Centre yesterday: "We have no evidence that there is an association with a worse outcome."

Prof Tom Connor, reader at the School of Biosciences, Cardiff University, said it was too early to be sure, as outcomes were determined after 28 days following diagnosis. "We're not at that point where you'd have that outcome information to do that analysis yet," he told the briefing.

Public Health England has said: "We currently have no evidence that the variant is more likely to cause severe disease or mortality – but we are continuing investigations to understand this better."

Is the UK alone in being identified with the variant?

Experts have suggested that UK science might be just better at identifying variant strains of the virus than most other countries.

According to Prof Connor, "It is probable that similar variants are popping up around the world.

"We are sequencing in the UK at a disproportionate rate to other people, which means that we have a much better system for catching this," he told the briefing.

Is there any evidence that children are spreaders now?

At a news conference this week, Boris Johnson evaded a commitment that all children would be back at school at the start of January, reflecting suggestions that school-age children might be spreading the virus.

Experts today said that there was no evidence this was the case.

However, Judith Breuer, professor of virology and co-director of the Division of Infection and Immunity at University College London said: "We know that coronavirus is spread very easily amongst children, so it wouldn't surprise me if eventually the SARS-CoV-2 virus ended up spreading amongst children."

Will the new variant be resistant to current vaccines? 

There is no current evidence that the new variant of SARS-CoV-2 will be resistant to COVID-19 vaccines.

PHE said this week that laboratory work was currently being undertaken as a priority to understand this.

Professor Ravi Gupta, professor of clinical microbiology at the University of Cambridge said that "the new variant is very unlikely to escape vaccines because vaccines elicit T-cell responses, antibody responses, and both of those responses are targeting multiple parts of the spike".

Ugur Sahin from BioNTech, whose COVID-19 vaccine was the first to be approved for emergency use worldwide, and in the UK, said he was confident the company's vaccine would remain effective against the new variant.

However, he acknowledged that more research was needed before he could confirm the efficacy.

Was this new variant unexpected?

It is not uncommon for viruses to undergo mutations; seasonal influenza mutates every year. Variants of SARS-CoV-2 have been observed in other countries, such as Spain.

Prof Tom Solomon, director of the NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, at the University of Liverpool, said: "SARS-CoV-2, the virus which causes COVID-19, is evolving and mutating all the time, as do all similar viruses. Such changes are completely to be expected."

Dr Jeremy Farrar, director of the Wellcome Trust, said the latest development showed there would still be surprises from SARS-CoV-2. "We have to remain humble and be prepared to adapt and respond to new and continued challenges as we move into 2021," he said.