CAN STATINS PREVENT ANTHRACYCLINE CARDIOTOXICITY?

 Evidence supporting the use of statins to protect against cardiotoxic chemotherapy has been strengthened with new data from a propensity-matched analysis.

Among women with breast cancer treated with anthracycline chemotherapy, statins were associated with a 55% lower risk of hospitalizations or emergency room visits for heart failure (HF) at 5 years (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.24 - 0.85).

The risk was 54% lower with statins among women whose cancer was treated with the monoclonal antibody trastuzumab (Herceptin, Genentech), although this did not achieve statistical significance (HR, 0.46; 95% CI, 0.20 - 1.07).

"I tend to be a skeptic in terms of how I design my research and my hypotheses, so I thought that if there was a protective effect it may be in the range of 20%, 30%, so I was surprised at how large the magnitude of protection was," Husam Abdel-Qadir, MD, PhD, Women's College Hospital, Toronto, Ontario, told theheart.org | Medscape Cardiology.

Dr Husam Abdel-Qadir

Exactly how cholesterol-lowering statins might reduce risk remains unknown, but they may ameliorate anthracycline- and trastuzumab-induced heart damage by decreasing production of reactive oxygen species and promoting cardiac muscle cell survival, the authors suggest in the study, published online January 6 in the Journal of the American Heart Association.

Abdel-Qadir noted that smaller, single-center observational studies have shown that women who undergo breast cancer chemotherapy and are taking a statin have less weakening of the heart muscle and a lower risk for incident HF. 

The present study extends these observations to a population-based sample that encompasses more patients than all previous studies combined and focuses on older women at high cardiovascular risk, he said.

The women had no prior HF and were at least 66 years old when newly diagnosed with early breast cancer in Ontario between 2007 and 2017. A total of 2545 were treated with anthracyclines and 1371 with trastuzumab, of whom 859 and 520, respectively, received at least two prescriptions for a statin in the year before starting chemotherapy.

More than 80% of cancers treated with anthracycline and more than 65% treated with trastuzumab were stage II or stage III. Similar to US practice, the most commonly used statins were rosuvastatin (46%) and atorvastatin (41%).

Women who received statins had more preexisting cardiovascular disease and associated risk factors, were older, and were more likely to live in lower-income neighborhoods.

After propensity score-matching, the median age was 69 in the anthracycline-treated cohort (666 pairs) and 71 in the trastuzumab-treated cohort (390 pairs).

At 5 years, the cumulative incidence of HF hospital presentations was 1.2% in statin-treated women and 2.9% in unexposed women in the anthracycline group, and 2.7% vs 3.7%, respectively, in the trastuzumab group."For women who already have an existing indication for a statin, this makes us feel even more strongly that these women should be treated with a statin before they start their cancer treatment," Abdel-Qadir said. "For women who are not on a statin and do not have another indication, I believe that the burden of proof to be able to add an extra medication to someone who is already going to be going through a lot needs to be high."

He noted that statins tend to be relatively well tolerated compared with other potential approaches to prevent cardiotoxicity such as angiotensin antagonists and beta-blockers, but there is the potential for muscle-related side effects and drug interactions.

The investigators also could not account for left ventricular ejection fraction, diastolic function, cardiac biomarkers, or biohumoral data and, thus, were unable to determine if the HF events occurred with preserved or reduced ejection fraction. Other limitations include a large proportion of missing low-density lipoprotein values and an inability to account for crossover attributable to starting or stopping statins after chemotherapy began.

Subgroup analyses were not performed based on breast cancer stage or statin lipophilicity. A recent observational study in 7.8 million adults without cancer reported that hydrophilic statins were associated with a slightly lower risk for incident HF compared with lipophilic statins.

One of the most important limitations of this study is that, even though the reduction is quite impressive, it is still an observational study," Abdel-Qadir stressed. "I have to emphasize the fact that there is still the potential that this could all be explained by confounding and, until it is proven in a randomized controlled trial, we cannot be 100% sure that it's a cause-and-effect relationship."

Commenting on the study, Tochi M. Okwuosa, DO, vice chair of the American Heart Association Council on Clinical Cardiology, CLCD & GMP Cardio-Oncology Subcommittee, said, "the main thing this study brings to the forefront is that if people have their heart health taken care of prior to treatment — and it doesn't have to be anthracycline chemotherapy but any cardiotoxic problem — they tend to do better. And a good example of that is something like COVID."

She noted that oncologists may be hesitant to add another drug to tightly controlled chemotherapy regimens for fear of drug interactions, but that patients can experience a heart attack while going through treatment. In addition, a recent study reported that mice and patients with early-stage breast cancer who experienced a myocardial infarction had a higher risk for cancer recurrence and cancer-specific death.

"We know that statins reduce the risk of heart attack and stroke, so if you put all these things together, you start to see how statins can somehow modulate the risk of issues associated with breast cancer overall," said Okwuosa, who was not associated with the study and directs the Cardio-Oncology Program at Rush University Medical Center, Chicago, Illinois. "We just need good randomized studies to show this and we don't have that yet."

Abdel-Qadir pointed out that their team is currently conducting the phase II randomized Statins for the Primary Prevention of Heart Failure in Patients Receiving Anthracycline (SPARE-AF) study comparing 40-mg daily atorvastatin vs placebo in 112 patients. Another colleague is also using a mouse model to determine the mechanisms through which statins protect against cardiotoxicity.

The study funded by the Ted Rogers Centre for Heart Research and the Canadian Cardiovascular Society. Abdel-Qadir is supported by a national new investigator award from the Heart and Stroke Foundation of Canada; he has declared no relevant financial relationships.

J Am Heart Assoc. Published online January 6, 2021. Full text.

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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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®.

PLEURAL EFFUSION REDUCES IMMUNOTHERAPY EFFICACY?

 Patients with non–small cell lung cancer (NSCLC) who have pleural effusion, especially those requiring pleural evacuation, experienced poorer survival when treated with immune checkpoint inhibitors, according to findings presented by Epaillard et al at the European Society for Medical Oncology (ESMO) Immuno-Oncology Virtual Congress 2020 (Abstract 42P).

Researchers explained that the pleura is a common site of metastatic involvement in patients with NSCLC, and the pleura also acts as a natural barrier that can limit the penetration and efficacy of immune checkpoint inhibitors. These factors led to the PLUIE study assessment of the clinical outcome of patients with NSCLC who have pleural effusion and were treated with an immune checkpoint inhibitor.

PLUIE Details

This multicenter, international, retrospective study identified 538 patients with NSCLC who were treated with an immune checkpoint inhibitor from November 2012 to November 2019. The investigators stratified this cohort by pleural effusion (n = 196) vs no pleural effusion (n = 342) as of the immunotherapy baseline.

Photo credit: Getty

Overall survival and the early death rate served as the primary endpoints, and the secondary outcomes were progression-free survival and disease control rate. The association between outcomes and pleural effusion was evaluated using logistic regression, whereas univariate and multivariate Cox models were performed for overall and progression-free survival.

The median patient age in the overall population was 62.9 years; 34.6% of patients were female; 9.5% were never smokers; and 75.7% of patients had nonsquamous NSCLC. The characteristics were similar in the pleural effusion group: the patients’ median age was 64.4 years; 31.6% were female; 12.4% were never smokers, and 77.6% had nonsquamous NSCLC. Immune checkpoint inhibitors were administered as first- or second-line therapy in 66% of patients, and 94% of patients received immune checkpoint inhibitor monotherapy.

In terms of patient characteristics, an association was found between pleural effusion and a higher number of metastatic sites: the pleural effusion cohort had a median of 3.5 metastatic sites compared with a median of 2.7 metastatic sites in the no–pleural effusion cohort. Pleural effusion was also associated with a poorer Eastern Cooperative Oncology Group performance status: 90.8% of patients with pleural effusion vs 80.5% of those without pleural effusion had a performance status of at least 2.  

Key Findings

Regarding the primary objective, the overall cohort demonstrated a median overall survival of 9.7 months (95% confidence interval [CI] = 8.1–11.8 months), whereas the pleural effusion cohort had a median overall survival of 6.3 months (95% CI = 4.0–8.6 months) compared with 11.4 months (95% CI = 9.7–13.8 months) in the no–pleural effusion cohort (P = .002). The early death rate was 31.4% in the overall cohort, whereas the early death rates in the pleural effusion compared with no–pleural effusion cohorts were 38.3% vs 27.5% (odds ratio [OR] = 1.63, 95% CI = 1.13–2.37, P = .01). 

Progression-free survival was 1.8 months (95% CI = 1.7–2.5 months) in the pleural effusion cohort compared with 2.3 months (95% CI = 2.0–3.6 months) in the no–pleural effusion group (P = .04).

Following adjustment for performance status; liver, intracranial, or bone metastasis; the immunotherapy line; and the derived neutrophil-to-lymphocyte ratio, pleural effusion remained an independent prognostic factor for overall survival (hazard ratio [HR] = 1.38, 95% CI = 1.09–1.74, P = .007) and progression-free survival (HR = 1.35, 95% CI = 1.09–1.68, P = .006). The disease control rate was 49.9% in those with pleural effusion compared with 52.3% in those without pleural effusion (OR = 1.64, 95% CI = 1.14–2.40, P = .01).

Of the 196 patients in the pleural effusion cohort, 73 (37.2%) patients required pleural evacuation, which was associated with a significantly increased early death rate of 52% in patients who had it vs 30.5% in those who did not (P = .003).

The authors concluded that pleural effusion is associated with worse prognosis and lower responses to treatment with an immune checkpoint inhibitor.

FIRST LINE IMMUNOTHERAPY BETTER FOR BRAF+ MELANOMA?

 Findings from a propensity-matched survival analysis presented by van Breeschoten et al at the European Society for Medical Oncology (ESMO) Immuno-Oncology Virtual Congress 2020 (Abstract 37P) suggest that patients with advanced melanoma and a BRAF V600 mutation derive an enhanced survival benefit from first-line treatment with anti–PD-1 monotherapy vs BRAF/MEK inhibitors.

Researchers explained that currently, data are inconclusive on whether to use anti–PD-1 monotherapy or BRAF/MEK inhibitors as first-line treatment in patients with advanced BRAF V600–mutant melanoma, prompting this propensity score-matching study, which compared the two types of agents in this patient population.  

Methods

The investigators identified patients diagnosed with unresectable stage III or IV melanoma who had a known BRAF V600 mutation and were registered in the Dutch Melanoma Treatment Registry. From 2014 to 2017, a total of 254 of these patients received first-line treatment with anti–PD-1 monotherapy and 330 received first-line treatment with BRAF/MEK inhibitors. Of these, 310 patients were matched based on their propensity scores using the nearest neighbor and the optimal matching method for inclusion in the matched cohort.

Comparison of Regimens

Comparison of these two first-line treatment strategies in the matched cohort showed that patients receiving anti–PD-1 antibodies demonstrated a higher median and 12-month overall survival compared to patients treated with first-line BRAF/MEK inhibitors.  

Median overall survival was 42.3 months (95% confidence interval [CI] = 37.3 months–not estimable) with anti–PD-1 monotherapy compared to 19.8 months (95% CI = 16.7 months–24.3 months) with BRAF/MEK inhibitors in the matched cohort. The 24-month overall survival rates were 64.0% (95% CI = 58.2%–70.4%) compared to 41.7% (95% CI = 34.2%–51.0%).

The authors concluded that these data suggest that anti–PD-1 monotherapy is the preferred first-line treatment in matched patients with BRAF V600–mutant advanced melanoma and relatively favorable patient and tumor characteristics, and added that they await results from currently ongoing randomized clinical studies to confirm this finding.

FIRST LINE PEMBROLIZUMAB FOR MSI-H COLORECTAL CANCER

 Frontline pembrolizumab (Keytruda) significantly improved progression-free survival (PFS) compared with chemotherapy among patients with microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) metastatic colorectal cancer, according to results from the KEYNOTE-177 study.

At a median follow-up of 32.4 months, PFS was 16.5 months for patients who received pembrolizumab, vs 8.2 months for the chemotherapy group.

"In the past, no medical treatment has shown such difference in terms of improvement of PFS in metastatic colorectal cancer," commented lead author Thierry André, MD, of Hôpital Saint Antoine, Paris, France, when presenting this study earlier this year at the annual meeting of the American Society of Clinical Oncology (ASCO),.

"I think this is setting a new standard of care," said Michael J. Overman, MD, of the University of Texas MD Anderson Cancer Center, Houston, Texas, who was the invited discussant at the ASCO meeting. However, he also pointed out that despite the higher overall response rate (43.8% vs 33.1% with chemotherapy), the rate of progressive disease was higher in the pembrolizumab arm than in the chemotherapy arm (29.4% vs 12.3% for patients who received chemotherapy).

The study has now been published in The New England Journal of Medicine.

Pembrolizumab is the "preferred choice" for patients with MSI-H/dMMR colorectal cancer because of "the durability of response, better safety profile, and improved quality of life associated with immunotherapy as compared with chemotherapy," comments Axel Grothey, MD, GI Cancer Research, West Cancer Center and Research Institute, Germantown, Tennessee, in an accompanying editorial.

He notes that in colorectal cancer, only 4% to 5% of metastatic cancers show the MSI-H/dMMR phenotype; the prevalence is greater in BRAF V600E–mutated cancers, in cancers originating on the right side, and among female patients.

Immune checkpoint inhibitors have already demonstrated "convincing activity" in MSI-H/dMMR colorectal cancers, and pembrolizumab as well as nivolumab (Opdivo), with or without ipilimumab (Yervoy), are approved for use as salvage therapy in colorectal cancer, he noted.

These results for use as a first-line therapy in his patient population have been "long awaited," he commented.

Study Details

The KEYNOTE-177 trial included 307 patients with confirmed, untreated MSI-H/dMMR metastatic colorectal cancer who were randomly assigned to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles (n = 153) or the investigators' choice of chemotherapy (n = 154). Chemotherapy regimens included modified FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) alone or in combination with either bevacizumab or cetuximab, or FOLFIRI (leucovorin, fluorouracil, irinotecan) alone or in combination with either bevacizumab or cetuximab. Patients in the chemotherapy group could cross over to pembrolizumab therapy after disease progression.

The study's two primary endpoints were PFS and overall survival.

At the second interim analysis, at a median follow-up (from randomization to data cutoff) of 32.4 months, pembrolizumab proved superior to chemotherapy with regard to PFS (hazard ratio, 0.60; P = .0002).

At 12 months and at 24 months, the estimated percentages of those alive without disease progression were 55.3% and 48.3%, respectively (95% CI, 39.9 – 56.2) in the pembrolizumab group and 37.3% and 18.6%, respectively, in the chemotherapy group.

The mean PFS after 24 months of follow-up was 13.7 months for patients who received pembrolizumab, vs 10.8 months for those who received chemotherapy. PFS was consistently longer with pembrolizumab across key prespecified subgroups. Complete responses were achieved in 11% of patients treated with pembrolizumab and in 4% of those treated with chemotherapy. At 24 months, 83% of patients in the pembrolizumab group had ongoing responses, as compared with 35% in the chemotherapy group.

Overall survival data continue to evolve, the authors comment. They note that 56 patients in the pembrolizumab group and 69 in the chemotherapy group have died. The independent data monitoring committee has recommended that the trial continue without any changes to the final analysis for assessment of overall survival until 190 overall deaths have occurred or until 12 months after the second interim analysis.

Crossover will be a factor when overall survival is assessed, the authors note. At the time of data cutoff, 56 of 154 patients (36%) who received chemotherapy had crossed over to the pembrolizumab group after their disease had progressed. In addition, 35 patients in the chemotherapy group received anti–PD-1 or PD-L1 therapies outside the trial. This extrapolates to a crossover rate of 59% in the intention-to-treat population.

Treatment-related adverse events of grade 3 or higher were more common in the chemotherapy group (66% vs 22%). Immune-mediated adverse events and infusion reactions were more common with pembrolizumab than with chemotherapy (31% and 13%, respectively). Adverse events that were common with chemotherapy included gastrointestinal events, fatigue, neutropenia, and peripheral sensory neuropathy.

Preferred Choice

In the accompanying editorial, Grothey points out that the results of this trial "deserve some scrutiny," because disease progression was higher in the pembrolizumab group. This is mirrored by early poorer performance among patients treated with pembrolizumab vs chemotherapy until about 6.5 months after onset of therapy, he notes. After that, the "pembrolizumab group showed protracted improvement — a phenomenon seen in various other trials with PD-1 antibodies in gastrointestinal cancers.

"It appears that a subgroup not yet clearly defined within the MSI-H–dMMR population does not have a response to immune checkpoint inhibitors," Grothey writes.

The study was funded by Merck. André has received honoraria from Amgen, GlaxoSmithKline, and Pierre Fabre Pharmaceuticals; consulting fees and travel support from Bristol-Myers Squibb; advisory board fees and honoraria from F. Hoffmann–La Roche; advisory board fees from Gritstone Oncology, Halliodx, and Tesaro; grant support, paid to Hôpitaux de Paris; advisory board fees, honoraria, and travel support from Merck Sharp and Dohme; consulting fees and honoraria from Servier; and honoraria and travel support from Ventana Medical Systems. Grothey has received grants and nonfinancial support from Bayer; grants from Boston Biomedicals; grants from OBI Pharmaceuticals, Array/Pfizer, Natera, Merck, and Bristol-Myers Squibb and grants and nonfinancial support from Roche/ Genentech outside the submitted work.

N Engl J Med. 2020;383:2207-2218, 2283-2285. Abstract, Editorial

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A NOVEL LOCAL THERAPY FOR BLADDER CANCER

 A novel intravesical gene therapy for bladder cancer has shown such promising results in clinical trials that experts are suggesting that it be considered the "new gold standard," even though it is not yet available.

The product, nadofaragene firadenovec, is being developed by FerGene Inc as a treatment for patients with high-grade bacillus Calmette-Guérin (BCG)–unresponsive non-muscle-invasive bladder cancer (NMIBC).

It is currently under consideration for approval by the US Food and Drug Administration.

The product is an adenovirus vector-based gene therapy containing the gene interferon alfa-2b. It is administered by catheter into the bladder once every 3 months. The vector enters the cells of the bladder wall, the gene turns on, and the cells then secrete high quantities of the interferon alfa-2b protein.

This approach "turns the patient's own bladder wall cells into interferon microfactories, enhancing the body's natural defenses against the cancer," the manufacturer explains.

New clinical results were published online November 27 in The Lancet Oncology.

At median follow-up of 19.7 months, a complete response (CR) was seen in about half of patients (53.4%, 55 of 103 patients) with BCG-unresponsive NMIBC in situ (with or without a high-grade Ta or T1 tumor), who received an initial dose of the investigational therapy in the single-arm, open-label, repeat-dose trial.

For 25 patients (45.5%), response was maintained at 12 months, report the investigators, led by Stephen A. Boorjian, MD, of the Mayo Clinic, Rochester, Minnesota.

These patients were among 151 treated in the trial between September 19, 2016, and May 24, 2019, and were included in a per-protocol efficacy analysis. All CRs occurred within 3 months of the initial treatment. The duration of CR was 9.69 months.

The remaining 48 patients had high-grade Ta or T1 disease. Of these patients, 35 were free of high-grade recurrence at month 3; 21 of these patients remained recurrence-free at month 12. Median follow-up in that cohort was 20.2 months, and median duration of high-grade recurrence-free survival was 12.35 months.

The most common adverse events were discharge around the catheter during placement, fatigue, bladder spasms, and micturition urgency.

In an accompanying editorial, Girish S. Kulkarni, MD, of Princess Margaret Cancer Center, the University of Toronto, Ontario, Canada, explains that BCG-unresponsive NMIBC is a "notoriously difficult to treat" condition for which nonsurgical treatment options are suboptimal. He said the findings by Boorjian and colleagues are encouraging.

"The reported efficacy, manageable adverse event profile, and straightforward dosing schedule all have the potential to make nadofaragene firadenovec the new gold standard for patients with BCG-unresponsive bladder cancer," Kulkarni writes. "At the very least, this study helps establish a new benchmark against which new therapies for this disease can be tested, thus enabling the conduct of future randomized studies."

Hope for Bladder Preservation

Kulkarni also notes that the results support "the oncological safety of an attempt at bladder preservation" in this patient population. Only 5.3% of patients experienced disease progression to muscle invasion during the study. Among those patients, salvage with cystectomy appeared feasible, he writes.

Senior study author Colin P. N. Dinney, MD, further emphasized the importance of the treatment for bladder preservation.

"Once patients with high-grade, non-muscle-invasive bladder cancer no longer benefit from their initial BCG treatments, patients often make an informed decision to decline cystectomy ― a highly complex and life-altering bladder removal surgery ― or are often medically ineligible for this complex operation, leaving them with limited options," Dinney explained in a press statement.

Treatment with this new gene therapy represents an effective alternative, he suggested.

"As a practicing urologist, I'm encouraged by these efficacy and safety data, which demonstrate the potential for a novel treatment option that fits within the urology practice and gives patients the choice of receiving treatment once every 3 months ― which may be a particularly important consideration in this evolving healthcare environment," said Gennady Bratslavsky, MD, president of the Society of Urologic Oncology Clinical Trials Consortium, which has worked with the manufacturer on the clinical trials of the product.

The study is ongoing; a 4-year treatment and monitoring phase is planned.

Boorjian has received consulting fees and personal fees from Ferring, FerGene, Sanofi, and ArTara. Dinney has used shared resources funded by a grant from the National Institutes for Health/National Cancer Institute at MD Anderson Cancer Center and has received grant and personal fees from FKD therapies. He also is a creator of intellectual property owned by UT/MDACC related to the use of genetic alterations as a predictive biomarker for response to nadofaragene firadenovec. Financial disclosures of several coauthors are available in the original article. Kulkarni has disclosed no relevant financial relationships.

Lancet Oncol. Published online November 27, 2020. Abstract, Editorial

Sharon Worcester is a reporter for MDedge News, part of the Medscape Professional Network.

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ANTI-TROP2 CHEMOTHERAPY FOR TNBC

 The antibody–drug conjugate sacituzumab govitecan (SG) (Trodelvy) appears to be effective across biomarker subgroups for women with metastatic triple-negative breast cancer (mTNBC) that has progressed after multiple lines of therapy, a biomarker evaluation from the phase 3 ASCENT trial shows.

But both an observer and the lead study author cautioned that the results were hypothesis generating.

Nonetheless, the data suggest the drug yields good survival outcomes in comparison with placebo in both BRCA1/2-positive and -negative patients and is effective even for those with low expression of the target protein, trophoblast cell surface antigen 2 (Trop-2).

The research was presented last week at the San Antonio Breast Cancer Symposium (SABCS) 2020.

Study presenter Sara Hurvitz, MD, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, urged caution in interpreting the data, given the small sample sizes in the Trop-2 low subgroup and germline BRCA1/2-positive subgroup.

Jennifer K. Litton, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, who was not involved in the research, echoed those comments.

She told Medscape Medical News that the numbers, particularly for the BRCA1/2 analysis, were "very small."

She added: "This was not a prespecified group, so it represents an interesting analysis to be hypothesis-generating for future studies but not anything applicable to current clinical practice."

Nevertheless, Litton said that the data from the primary analysis of ASCENT remain "practice changing" for women with mTNBC who have received at least two previous lines of therapy.

As to whether SG will eventually move beyond this advanced setting, she emphasized that "more trials would need to be done and reported evaluating its role in other settings, and hopefully expanding its usefulness for patients."

SG is a first-in-class drug comprising an antibody directed at Trop-2, which is highly expressed in breast cancer, and linked to SN-38, the active metabolite of irinotecan.

On the basis of positive phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with mTNBC who experience disease progression after at least two prior therapies.

As reported by Medscape Medical News, primary results from ASCENT that were presented at the 2020 annual meeting of the European Society for Medical Oncology showed that SG improved progression-free survival (PFS) by nearly 4 months and overall survival by more than 5 months for women with pretreated mTNBC compared to chemotherapy.

Study Details

At SABCS, Hurvitz presented an exploratory biomarker evaluation of data from the trial regarding the association between SG efficacy and Trop-2 expression, as well as germline BRCA1/2 mutation status.

She reminded the audience that in ASCENT, 529 patients with mTNBC who had experienced disease progression after undergong at least two chemotherapy regimens for advanced disease were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or physician's choice of treatment.

Treatment was continued until disease progression or unacceptable toxicity occurred.

For the current analysis, which focused on patients who did not have brain metastases, the team studied primary or metastatic archival biopsy or surgical specimens collected at study entry.

These were analyzed using a validated immunohistochemistry assay. Tumors were categorized as Trop-2 low, medium, or high expressers on the basis of H-score, which is a weighted summation of percent staining.

In addition, germline BRCA1/2 mutation status was determined at baseline.

Mutation status was known for 149 SG patients and 143 control patients. Of those, the majority (57% and 54%, respectively) were BRCA1/2 negative.

Among 151 SG patients for whom Trop-2 expression status was available, 56% had tumors of high expression; 26%, medium expression; and 18%, low expression.

In the control group, Trop-2 expression was known in 139 patients, of whom 52% had tumors of high expression; 25%, medium expression; and 23%, low expression.

Hurvitz reported that although median PFS among patients given SG decreased with decreasing Trop-2 expression, it remained longer than that seen with control treatment.

In patients with tumors of Trop-2 high status, median PFS was 6.9 months with SG, vs 2.5 for patients who underwent control treatment. This fell to 5.6 months vs 2.2 months in the Trop-2 medium group and 2.7 months vs 1.6 months in Trop-2 low group.

A similar pattern was seen for overall survival.

In the Trop-2 high group, median overall survival was 14.2 months with SG, vs 6.9 months with control therapy; 14.9 months vs 6.9 months in the Trop-2 medium group; and 9.3 months vs 7.6 months in the Trop-2 low group.

Again, the objective response rate fell from 44% to 38% and then to 22% with SG in the Trop-2 high, medium, and low groups, compared with 1%, 11%, and 6%, respectively, with control treatment.

There did not seem to be any interaction between Trop-2 expression and treatment-related adverse events of special interests. Rates of neutropenia, diarrhea, and anemia were consistently higher in SG-treated patients than in those given placebo.

Hurvitz said that the objective response rate was markedly higher with SG vs control treatment in both BRCA1/2-positive and -negative patients, at 19% vs 6% in the positive group and 33% vs 6% in the negative group.

This was reflected in improved median PFS with SG in both subgroups, at 4.6 months vs 2.5 months with control therapy in BRCA1/2-positive patients and 4.9 months vs 1.6 months in BRCA1/2-negative patients.

Overall survival was 15.6 months with SG, vs 4.4 months with control treatment in BRCA1/2-positive patients. In BRCA1/2-negative patients, the respective figures were 10.9 months and 7.0 months.

The study was sponsored by Immunomedics Inc. Hurvitz has financial ties to Immunomedics and multiple other pharmaceutical companies. Litton has financial ties to multiple pharmaceutical companies, including those with breast cancer therapies.

San Antonio Breast Cancer Symposium (SABCS) 2020: Abstract GS3-06. Presented December 10, 2020.

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