Κυριακή, 5 Ιουλίου 2020

FDA APPROVED MAINTENANCE AVELUMAB FOR METASTATIC UROTHELIAL CANCER

On June 30, the U.S. Food and Drug Administration (FDA) approved avelumab (Bavencio) for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma that has not progressed with first-line platinum-containing chemotherapy.

JAVELIN Bladder 100

Efficacy of avelumab for the maintenance treatment of urothelial carcinoma was investigated in the JAVELIN Bladder 100 trial, a randomized, multicenter, open-label trial that enrolled 700 patients with unresectable, locally advanced, or metastatic urothelial carcinoma that had not progressed with four to six cycles of first-line platinum-containing chemotherapy. Patients were randomly assigned 1:1 to receive either avelumab intravenously every 2 weeks plus best supportive care or best supportive care alone. Treatment was initiated within 4 to 10 weeks after last chemotherapy dose. The main efficacy outcome measures were overall survival in all patients and in patients with PD-L1–positive tumors.

The median overall survival in all patients was 21.4 months in the avelumab arm and 14.3 months in the best supportive care alone arm (hazard ratio [HR] = 0.69, 95% confidence interval [CI] = 0.56–0.86, = .001). Among patients with PD-L1–positive tumors (51%), the hazard ratio for overall survival was 0.56 (95% CI = 0.40–0.79, < .001). In an exploratory analysis of patients with PD-L1–negative tumors (39%), the overall survival hazard ratio was 0.85 (95% CI = 0.62–1.18).

The most common adverse reactions reported in > 20% of patients who were treated with avelumab were fatigue, musculoskeletal pain, urinary tract infection, and rash. One patient died from sepsis, and 28% of patients had serious adverse reactions.

The recommended avelumab dose is 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

The results from this study supported the conversion of accelerated approval of avelumab to a regular approval.

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®.

NOVEL OSTEOPOROSIS DRUG COULD INCREASE CARDIOVACULAR RISK?

New research from the University of Oxford's Big Data Institute and the Nuffield Department of Population Health suggests the anti-osteoporotic medicine, romosozumab, may lead to excess cardiovascular complications.

Previous clinical trials of the sclerostin blocker romosozumab have suggested that the medicine may increase the risk of developing serious cardiovascular complications. However, this finding was not consistently seen across all trials, which limits conclusions about the safety of romosozumab.

This study analysed genetic data from more than a million people and found that variants of the SOST gene, which codes for the negative bone regulator sclerostin, had, on average, a 41 per cent lower risk of sustaining a fracture but an 18 per cent increased risk of major adverse cardiovascular events with romosozumab, which inhibits sclerostin. The same variants were also associated with increased risk of type 2 diabetes mellitus, higher systolic blood pressure and central adiposity.

First author, Dr Jonas Bovijn, from the Big Data Institute at the University of Oxford, said the findings suggest that the cardiovascular effects seen in some trials are real.

“This emphasizes the importance of conducting further rigorous clinical studies to evaluate the cardiovascular safety of this class of medicines,” he said.

The findings suggest that inhibition of sclerostin may elevate cardiovascular risk. The results warrant rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors, the authors say.

ADJUVANT IMMUNOTHERAPY FOR STAGE III MELANOMA

mmunotherapy following surgery for stage-3 melanoma is associated with longer survival, but not all patients receive it, according to the first analysis of real-world data in the era of adjuvant immunotherapy in this patient population.

In 2015, the U.S. Food and Drug Administration (FDA) approved the immune-checkpoint inhibitor ipilimumab in patients with stage-3 melanoma when given in an adjuvant setting after surgery.

Using the National Cancer Database (NCDB), Dr. Justin Moyers of Loma Linda University in California and colleagues analyzed treatment data from melanoma cases diagnosed in 2015 and 2016 and survival data from cases diagnosed in 2015.

All patients had surgically resected stage-3 melanoma. Patients who received systemic therapies before surgery, and those who received chemotherapy after surgery were excluded.

The treatment-pattern analysis was based on 8,160 patients. Between 2015 and 2016, the percentage of patients who received immunotherapy increased from 24.8% to 30.6%.

Patients with higher Charlson-Deyo comorbidity scores (scores of 1 to 3 versus 0) and those with Medicare insurance were significantly less likely to receive immunotherapy, Dr. Moyers noted at a June 22 press briefing held in conjunction with the American Association for Cancer Research (AACR) Virtual Meeting II.

There was also a trend towards less use of immunotherapy in those with lower income and lower levels of education. This finding "highlight the negative impact of social economic background and having access to proven therapy that benefits patients, both in clinical trials and in the real world," said briefing co-moderator Dr. Antoni Ribas of the University of California, Los Angeles.

The survival analysis included 4,094 patients. When looking at survival for all stage-3 disease, there was a trend toward improved survival at 24 months in those who received immunotherapy after surgery versus those that did not (83% vs. 80%; P=0.051).

When separating by substages of disease, 24-month survival was significantly improved in patients with stage-3C disease who received immunotherapy relative to their peers who did not (70% vs. 59%; P<0.01). For stage 3A, the numbers were 94% and 91% (P=0.03), respectively, and for stage 3B, 84% and 81% (P=0.35).

"Patients with stage 3 melanoma tend to have poor prognosis even after curative-intent surgery. Based on our findings, immunotherapy after resected stage 3 melanoma appears to reveal a trend for real-world 24-month survival advantage compared with no therapy, supporting the role of adjuvant immunotherapy in the real-world setting," Dr. Moyers said in a conference statement.

The study had no commercial funding and the authors disclosed no conflicts of interest.

SOURCE: https://bit.ly/2B2pTfa American Association for Cancer Research Virtual Meeting II, presented June 22, 2020.

YOUNG ADULTS WITH CANCER SHOULD HAVE GENETIC TESTING

Young adults with early onset cancers often harbor germline mutations and would benefit from germline genetic testing, according to a new study.

"Although representing only about 4% of all cancers, young adults with cancer, defined as those diagnosed with cancer between the ages of 18 and 39, face unique challenges," Dr. Zsofia K. Stadler, of Memorial Sloan Kettering Cancer Center in New York City, said in a presentation at the American Association for Cancer Research (AACR) second virtual annual meeting.

"Identifying whether a young patient's cancer occurred in the setting of an inherited cancer predisposition syndrome is especially important in this population. Knowledge of this genetic information can significantly impact risk of second primary cancers and the need for increased cancer surveillance measures. Young adults may use genetic information to identify at-risk family members, including potentially young siblings or even children who should pursue genetic testing and have positive appropriate cancer screening or prevention measures," Dr. Stadler said.

Patients with early-onset cancer are a distinct group of young-adult cancer patients who develop cancers typically seen at older ages, including breast, colon, pancreas, kidney and ovarian cancer.

Dr. Stadler and colleagues evaluated germline mutations in 877 patients with these "early-onset" cancers and 324 patients with typical "young-adult" cancers, most commonly sarcoma, brain, testicular and thyroid cancer.

They found a "very high prevalence" of germline mutations in patients with early-onset cancers. "Indeed, 21% of these patients harbored the germline variant," Dr. Stadler reported. "On the other hand, in the remainder of young-adult cancer patients, the germline mutation prevalence was lower at 13%."

Briefing co-moderator and AACR past president Dr. Elaine R. Mardis said the "surprising" finding in this study is that the prevalence of these germline mutations is "significantly higher than we had previously thought where about 21% of the early-onset patients - those patients developing tumor types more commonly diagnosed in older adults - have germline susceptibility pathogenic or likely pathogenic variants."

The most common mutations in the early-onset group were BRCA1, BRCA2, ATM, CHEK2, and Lynch syndrome-associated genes. In the young-adult group, germline TP53 mutations were more common, which is consistent with Li-Fraumeni syndrome.

Dr. Stadler said the increased prevalence of germline mutations in adults with early-onset cancer "supports a role for genetic testing irrespective of tumor type."

This study had funding from Memorial Sloan Kettering Cancer Center. The authors have no relevant disclosures.

SOURCE: https://bit.ly/2B2pTfa Association for Cancer Research Virtual Annual Meeting II, presented June 22, 2020.

FGFR INHIBITORS FOR CHOLANGIOCARCINOMA

At the European Society for Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer 2020 Virtual, Javle et al reported that third- and later-line treatment with the selective fibroblast growth factor receptor (FGFR) 1–3 inhibitor infigratinib resulted in a progression-free survival and overall response rate benefit for patients with cholangiocarcinoma and FGFR2 fusions (Abstract SO-5).

The authors also reported that outcomes with second-line chemotherapy in patients with cholangiocarcinoma and FGFR2 fusions were similar to those reported in the literature for all patients with cholangiocarcinoma—regardless of genomic status—and remain “dismal”.

According to the study team, chemotherapy is the most common second-line treatment in patients with cholangiocarcinoma. FGFR2 fusions occur in 13% to 17% of patients with cholangiocarcinoma, and several targeted tyrosine kinase inhibitors are in development for this patient population. However, the outcome of patients with cholangiocarcinoma and FGFR2 fusions receiving standard second-line chemotherapy is unknown.

Phase II Trial

Seventy-one patients with advanced cholangiocarcinoma and FGFR2 fusions who had undergone prior treatment with gemcitabine-based chemotherapy were enrolled in a single-arm phase II study. Patients received infigratinib (previously known as BGJ398) at 125 mg orally once daily on days 1 through 21. Cycles were repeated every 28 days until unacceptable toxicity, disease progression, investigator discretion, or withdrawal of consent.

A retrospective analysis of a subset of patients who received infigratinib as third- or later-line treatment was performed. Investigator-assessed progression-free survival and overall response rate per Response Evaluation Criteria in Solid Tumors version 1.1 following second-line chemotherapy (pre-infigratinib) and third-line or later-line therapy with infigratinib were calculated.

Of the 71 patients, 44 were women; the median patient age was 53 years. Of patients with FGFR2 fusions who were enrolled at the time of analysis, 37 patients (52%) were included in this retrospective analysis.

Results

Median progression-free survival with standard second-line chemotherapy was 4.63 months (95% confidence interval [CI] = 2.69–7.16) compared with 6.77 months (95% CI = 3.94–7.79) with third- and later-line infigratinib.

The overall response rate for second-line chemotherapy was 5.4% (95% CI = 0.7–18.2) compared with 21.6% (95% CI = 9.8–38.2) for third- and later-line infigratinib.

According to the authors, infigratinib administered as third- and later-line treatment resulted in a meaningful benefit.

Disclosure: This study was funded by QED Therapeutics, Inc.

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®.

ASCO 2020-TUMOR MARKERS FOR INTRACRANIAL GERM CELL TUMORS

Tumor markers can be used to detect relapse with a high degree of sensitivity in patients with central nervous system nongerminomatous germ cell tumors (CNS-NGGCTs), according to a pooled analysis of cooperative group trials.

The findings suggest a role for the routine use of tumor markers for surveillance in CNS-NGGCT patients, said Adriana Fonseca, MD, a pediatric neuro-oncology fellow at the Hospital for Sick Children in Toronto.

She presented these findings as part of the American Society of Clinical Oncology virtual scientific program.

This pooled analysis represents the largest prospective cohort to date of relapsed intracranial germ cell tumors, Dr. Fonseca said. The analysis included 483 patients enrolled in five prospective CNS-NGGCT trials between 1989 and 2016. There were 106 patients who relapsed after the end of therapy; the relapsed patients had a median age of 13 years (range, 1-30 years) at diagnosis and 82% were male.

Tumor Marker Utility

There were 86 patients with tumor marker assessments at diagnosis, and 83 had tumor marker elevations in serum, cerebrospinal fluid (CSF), or both.

The three patients without tumor marker elevations at diagnosis had mixed GCT, choriocarcinoma, and yolk sac tumor, which are usually associated with tumor marker elevation, so this will be investigated further, Dr. Fonseca said.

The sensitivity of tumor markers at diagnosis was 94% for serum, 83% for CSF, and 97% for either serum or CSF.

The median time to relapse was 15.5 months. Relapses were local in 45 patients (44%), distant in 32 (33%), and combined in 22 (21%). Three intracranial relapses were located outside of the radiation field and were classified as distant.

Only two patients presented with isolated tumor marker elevations as the sole evidence of relapse, and the elevations usually preceded the presence of macroscopic disease, Dr. Fonseca said.

At the time of relapse, 88% of patients (n = 73) had tumor marker elevations. The sensitivity of tumor markers was 82% in serum, 85% in CSF, and 88% in either.

To better understand if tumor markers can be used for surveillance, the researchers analyzed data from patients who had either serum or CSF tumor marker levels available at both diagnosis and relapse.

Of the 74 evaluable patients who had elevated tumor markers at diagnosis, 68 had elevated tumor markers at relapse as well. This means 92% of relapsed patients were detectable by tumor markers, Dr. Fonseca said.

"Only six patients had tumor marker–negative relapses, and interestingly, one patient who was tumor marker negative at diagnosis relapsed with tumor markers positive," she added.

Rationale and Next Steps

CNS-NGGCTs are rare and heterogeneous tumors that respond best when treated using multimodal approaches, including surgical resection, chemotherapy, and radiation, according to Dr. Fonseca. The 5-year event-free and overall survival rates range from 72%-84% and 82%-93% respectively.

"GCTs are unique as they express tumor markers, such as AFP and beta-HCG, which we know are sensitive and specific and used for diagnostic and monitoring purposes," Dr. Fonseca said.

Current surveillance strategies use a combination of brain and spine MRI and serum tumor markers with declining frequency over time.

"CSF tumor markers are not performed during follow-up, and they are usually obtained only at the time of relapse," Dr. Fonseca said. "But what is the best surveillance strategy? We have to remember that some of our patients require sedation to undergo MRI, and recurrent sedations in children have been recently associated with potential detrimental neurocognitive effects."

Similarly, the administration of gadolinium used for MRI has been associated with an increased risk of renal fibrosis and negative neurological outcomes.

"Additionally, nonspecific areas of enhancement are commonly encountered and can lead to unnecessary further investigations," Dr. Fonseca said, adding that this can contribute to patients' and parents' anxiety and to increased overall health care costs and resource utilization.

Recent Children's Oncology Group data showed that 98% of patients with extracranial germ cell tumors who relapsed were detectable by tumor markers alone, and this led to a change in surveillance guidelines for those patients. This raised the question as to whether a similar approach could be used in CNS-NCCGTs, Dr. Fonseca explained.

"We hypothesized that tumor markers alone may be sufficient for relapse detection in children and adolescents treated for CNS-NGGCT, and hence, the frequency and associated risk with serial MRIs could be safely avoided," she said.

Though this study was limited by missing data in some cases, the inclusion of trials from different eras, and the use of different detection techniques across trials, the findings confirm the sensitivity of tumor markers in this setting.

"Tumor markers represent a valuable surveillance strategy with the potential to reduce MRI frequency in these patients," Dr. Fonseca said. "Additionally, the higher proportion of tumor marker–negative relapses, compared to extracranial GCTs, suggests a different biological behavior. Further studies to investigate the biology of the primary versus relapsed samples in GCTs are currently needed."

Dr. Fonseca and colleagues are "currently undertaking some correlative outcomes analyses to try to understand if the elevation or nonelevation to tumor markers is correlated with survival. We also would like to elucidate the optimal MRI frequency required for surveillance," she said.

Dr. Fonseca reported having no disclosures, and the researchers disclosed no funding for the study.

SOURCE: Fonseca A et al. ASCO 2020, Abstract 2503.

Τετάρτη, 1 Ιουλίου 2020

TRIPLE THERAPY FOR METASTATIC BRAF+ MELANOMA

As reported in The Lancet by Gutzmer et al, the phase III IMspire150 trial has shown that the addition of atezolizumab to BRAF and MEK inhibitor therapy with vemurafenib and cobimetinib improved progression-free survival in first-line treatment of patients with unresectable BRAF V600–mutant melanoma.

Study Details 

In the double-blind trial, 514 patients with unresectable stage IIIC to IV disease from sites in 20 countries were randomly assigned between January 2017 and April 2018 to receive 28-day cycles of atezolizumab, vemurafenib, and cobimetinib (n = 256) or atezolizumab placebo, vemurafenib, and cobimetinib (n = 258). Randomization was stratified by lactate dehydrogenase (LDH) concentration and geographical region.

In cycle 1, all patients received twice-daily vemurafenib at 960 mg for 21 days plus once-daily cobimetinib at 60 mg, followed by either twice-daily vemurafenib at 720 mg in the atezolizumab group or at 960 mg for 7 days in the control group. Starting with cycle 2, patients in the atezolizumab group received atezolizumab at 840 mg on days 1 and 15, twice-daily vemurafenib at 720 mg, and once-daily cobimetinib at 60 mg on a 21 days on/7 days off schedule. Patients in the control group received placebo on days 1 and 15, twice-daily vemurafenib at 960 mg, and once-daily cobimetinib at 60 mg on a 21 days on/7 days off schedule. The primary endpoint was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1.

In the atezolizumab vs control groups:

  • Median age was 54.0 vs 53.5 years (24% vs 23% ≥ 65 years)
  • 59% vs 58% were male
  • 95% vs 95% were non-Hispanic white
  • Geographic region was North America for 5% vs 5%, Europe for 79% vs 79%, and Australia, New Zealand, or other for 16% vs 16%
  • Eastern Cooperative Oncology Group performance status was 0 for 76% vs 77% and 1 for 24% vs 22%
  • Disease stage was IV for 95% vs 93%
  • 33% vs 33% had elevated LDH
  • 57% vs 63% had M1C disease
  • 16% vs 12% had taken prior adjuvant therapy
  • 63% vs 61% had PD-L1–positive disease (≥ 1% immune cells).

Progression-Free Survival

Median follow-up was 18.9 months. Median progression-free survival was 15.1 months (95% confidence interval [CI] = 11.4–18.4 months) in the atezolizumab group vs 10.6 months (95% CI = 9.3–12.7 months) in the control group (hazard ratio [HR] = 0.78, 95% CI = 0.63–0.97, = .025).

Progression-free survival benefit was consistent among patient subgroups examined. With regard to stratification factors, hazard ratios were: 0.85 (95% CI = 0.32–2.27) for patients in North America, 0.79 (95% CI = 0.62–1.00) for Europe, and 0.69 (95% CI = 0.37–1.27) for Australia, New Zealand, or other. Hazard ratios were 0.81 (95% CI = 0.58–1.14) for those with elevated LDH and 0.76 (95% CI = 0.57–1.01) for those with normal LDH, and 0.80 (95% CI = 0.60–1.06) for patients with PD-L1–positive disease and 0.76 (95% CI = 0.53–1.10) for PD-L1–negative disease.

Median progression-free survival as assessed by independent review committee was also prolonged in the atezolizumab group (median = 16.1 months vs 12.3 months, HR = 0.85, 95% CI = 0.67–1.07, = .16), although the difference not achieve statistical significance.

At interim analysis of overall survival, death had occurred in 36% of patients in the atezolizumab group vs 43% of patients in the control group (HR = 0.85, 95% CI = 0.64–1.11, P = .23). Estimated 2-year overall survival was 60% vs 53%. Investigator-assessed confirmed objective response was observed in 66.3% of patients vs 65.0% of patients, with complete response observed in 15.7% vs 17.1%. Median duration of response was 21.0 months (95% CI = 15.1 months–not estimable) vs 12.6 months (95% CI = 10.5–16.6 months).

Adverse Events

Common treatment-related adverse events of any grade (> 30% of patients) in the atezolizumab and control groups were increased creatine phosphokinase (51.3% vs 44.8%), diarrhea (42.2% vs 46.6%), rash (40.9% in both groups), arthralgia (39.1% vs 28.1%), pyrexia (38.7% vs 26.0%), increased alanine aminotransferase (33.9% vs 22.8%), and increased lipase (32.2% vs 27.4%).

Treatment-related grade 3 or 4 adverse events occurred in 79% vs 73% of patients, with the most common in the atezolizumab group being increased lipase (20% vs 21% in control group), increased creatine phosphokinase (20% vs 15%), increased alanine or aspartate aminotransferase (13% vs 9%), and maculopapular rash (13% vs 10%).

Treatment-related serious adverse events occurred in 33% vs 29% of patients. Adverse events led to discontinuation of all treatment in 13% vs 16% of patients. Adverse events led to death in seven patients in each group. Causes of death in the atezolizumab group consisted of sepsis in two patients and cardiac arrest, pneumonia, septic shock, hepatic failure, and fulminant hepatitis in one patient each; causes in the control group consisted of cardiac arrest, cardiac failure, left ventricular failure, cerebrovascular accident, hydrocephalus, gastrointestinal hemorrhage, and pulmonary hemorrhage in one patient each.

Immune-mediated adverse events occurred in 63% vs 51% of patients, with those occurring more commonly in the atezolizumab group (≥ 2% difference) consisting of increased aspartate aminotransferase, increased alanine aminotransferase, pneumonitis, increased amylase, dermatitis-acneiform, uveitis, hyperthyroidism, and acne.

The investigators concluded, “The addition of atezolizumab to targeted therapy with vemurafenib and cobimetinib was safe and tolerable and significantly increased progression-free survival in patients with BRAF V600 mutation–positive advanced melanoma.”

Ralf Gutzmer, MD, of Medizinische Hochschule Hannover, Germany, is the corresponding author for The Lancet article.

Disclosure: The study was funded by F. Hoffmann–La Roche and Genentech. 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®.

Τρίτη, 30 Ιουνίου 2020

FEWER CARDIOVASCULAR ADVERSE EVENTS WITH GnRH ANTAGONISTS

Men with prostate cancer on androgen-deprivation therapy are usually treated with leuprolide, a long-acting injectable luteinizing hormone-releasing hormone (LHRH) agonist requiring an every-3-month injection, but it may be possible for ADT to be delivered by a daily oral treatment, pending regulatory approval. In the phase III HERO study, oral relugolix, given daily, was superior to leuprolide for achieving testosterone suppression in men with advanced prostate cancer who required androgen-deprivation therapy, as reported during the ASCO20 Virtual Scientific Program by Neal D. Shore, MD, FACS, of Carolina Urologic Research Center, Myrtle Beach, South Carolina, and published online in The New England Journal of Medicine to coincide with the presentation.1,2

Neal D. Shore, MD, FACS

Neal D. Shore, MD, FACS

The study met the primary endpoint of sustained castration levels of testosterone at 48 weeks. Almost all men treated with relugolix (96.7%) maintained castration levels of testosterone through 48 weeks vs 88% of men treated with leuprolide (P < .001 for superiority). In addition, the risk of developing a major adverse cardiovascular event was 54% lower with relugolix.

“Prescribing information for leuprolide and other LHRH agonists already contains warnings about increased risk of myocardial infarction, sudden cardiac death, and stroke. In the HERO trial, the oral GnRH antagonist relugolix showed sustained testosterone suppression superior to that of leuprolide [an LHRH agonist],” stated Dr. Shore.

“Relugolix is a novel, oral GnRH antagonist that has the potential to become a new standard for androgen-deprivation therapy in advanced prostate cancer,” he added.

Practice-Changing Results?

This abstract was one of three prostate cancer abstracts selected for the Genitourinary Highlights session at this year’s ASCO meeting. David Wise, MD, of Perlmutter Cancer Center at NYU Langone Health in New York, who discussed the highlights, agreed that relugolix is a new standard of care. “Is this practice-changing? Yes, for a subset of patients with a history of significant cardiovascular disease and without gastrointestinal malabsorption problems,” Dr. Wise stated. “I will use this drug to avoid injection-site reactions commonly experienced with degarelix [another GnRH antagonist]. The concern for noncompliance with an oral drug will necessitate more frequent serum testosterone checks, particularly for monotherapy,” he added.

Relugolix is practice-changing for a subset of patients with a history of significant cardiovascular disease and without gastrointestinal malabsorption problems. 
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Dr. Shore explained that the reduced incidence of major adverse cardiovascular events with relugolix is noteworthy, because men with prostate cancer have an increased risk of cardiovascular events. “Cardiovascular events are the leading cause of death in men with prostate cancer, now accounting for up to one-third of deaths. Approximately 30% of men with prostate cancer have known cardiovascular disease, and many more have risk factors such as obesity, diabetes, hypertension, and hyperlipidemia. In the HERO trial, more than 90% of men had cardiovascular risk factors.”

Study Details

The global trial randomly assigned 930 men with advanced prostate cancer in a 2:1 ratio to receive oral relugolix at 120 mg/d (n = 622) or leuprolide injections (n = 308) every 3 months, for a total of 48 weeks. To be eligible for the trial, men had to be 18 years or older, have histologically confirmed adenocarcinoma of the prostate, and be candidates for at least 1 year of continuous androgen-deprivation therapy. Eligible patients had to have one of the following: evidence of biochemical or clinical relapse after primary therapy with curative intent, newly diagnosed hormone-sensitive metastatic disease, or advanced localized disease unlikely to be cured. Patients who experienced major adverse cardiovascular events within 6 months of enrollment were excluded.

At baseline, the median patient age was 71 years, and 28.6% were older than age 75. About 31% had metastatic disease, 43% had Gleason 8 to 10 disease, 11.9% had previous androgen-deprivation therapy, and 30.3% had previous radiotherapy. The median prostate-specific antigen (PSA) level at baseline was 10.8 ng/mL. The mean testosterone level at baseline was 427.5 ng/dL. More than 90% of men had at least one cardiovascular risk factor, and the percentage of men with risk factors was well balanced in the two arms. Treatment adherence was more than 99% in both groups. The median time to follow-up, including safety, was 52 weeks.

Key Results

In addition to superiority for the primary endpoint of maintained castration levels of testosterone over 48 weeks, relugolix was superior to leuprolide for all key secondary endpoints (P < .001). These endpoints included the cumulative probability of castrate levels on day 4 (56% vs 0%) and on day 15 (98.7% vs 12%) and of testosterone suppression to profound levels (ie, < 20 ng/dL). The percentage of patients with a confirmed PSA response at day 15 was 79.4% with relugolix and 19.8% with leuprolide (< .001).

Men treated with relugolix achieved castration levels of testosterone more rapidly than leuprolide, and this response was maintained throughout treatment. On the other hand, patients who discontinued relugolix treatment had faster testosterone recovery to normal levels.

“Another clinical advantage of oral relugolix over leuprolide is a higher percentage of men achieved testosterone recovery to normal levels within 90 days after treatment discontinuation (54% vs 3%),” Dr. Shore noted. “This should be particularly relevant for men receiving intermittent androgen-deprivation therapy, short-course androgen-deprivation therapy, or stopping treatment to recover from serious and debilitating testosterone suppression adverse effects,” he explained.

Safety

The overall incidence of adverse events was consistent across the two treatment arms. Hot flash was the most common adverse event in both arms: 54.3% for relugolix and 51.6% for leuprolide. Moderate or mild diarrhea was reported in more patients in the relugolix group (12.2%) than in the leuprolide group (6.8%). There were no treatment withdrawals due to diarrhea.

Fatal events occurred in 1.1% of the relugolix group and 2.9% of the leuprolide group. A prespecified analysis after 48 weeks of treatment found the incidence of major adverse cardiovascular events was 2.9% with relugolix compared with 6.2% with leuprolide—a rate 54% lower with the oral androgen-deprivation therapy.

In a subgroup of patients with a reported history of major adverse cardiovascular events, the incidence of such events during treatment was 3.6% for relugolix and 17.8% for leuprolide. “The odds ratio was 5.8 times higher with leuprolide in comparison to relugolix in men with a history of major adverse cardiovascular events,” Dr. Shore stated. 

DISCLOSURE: The HERO study was funded by Myovant Sciences. Dr. Shore has reported consulting relationships with Myovant Sciences, Amgen, Astellas Pharma, AstraZeneca, Bayer, BMS, Dendreon, Ferring, Genentech/Roche, Janssen, Medivation/Astellas, Merck, Pfizer, and Tolmar. Dr. Wise has received honoraria from OncLive; consulting fees from AlphaSights, Foundation Medicine, GLG Pharma, Guidant Global, Leap Therapeutics, Pfizer, and Silverlight; and reimbursement for travel expenses from Pfizer.

REFERENCES

1. Shore ND, George DJ, Saad F, et al: HERO phase III trial: Results comparing relugolix, an oral GnRH receptor antagonist, versus leuprolide acetate for advanced prostate cancer. ASCO20 Virtual Scientific Program. Abstract 5602.

2. Shore ND, Saad F, Cookson MS, et al: Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N Engl J Med 382:2187-2196, 2020.

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®.

FDA APPROVED HER-PER sc COMBINATION

On June 29, the U.S. Food and Drug Administration (FDA) approved a new fixed-dose combination of pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo) for subcutaneous injection in the following indications: 

  • Use in combination with chemotherapy as: 
    • Neoadjuvant treatment for patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either greater than 2 cm in diameter or node-positive) as part of a complete treatment regimen for early breast cancer
    • Adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence.
  • Use in combination with docetaxel for treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

“Currently, most patients with HER2-positive breast cancer receive trastuzumab and pertuzumab at infusion centers. With a new administration route, [this triplet] offers an outpatient option for patients to receive trastuzumab and pertuzumab,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence and Acting Director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research.

Richard Pazdur, MD

Richard Pazdur, MD

FeDeriCa Trial

Efficacy was investigated in FeDeriCa, an open-label, multicenter, randomized trial that enrolled 500 patients with operable or locally advanced HER2-positive breast cancer. Patients were randomly assigned to receive neoadjuvant chemotherapy with concurrent administration of either the triplet combination or intravenous pertuzumab and intravenous trastuzumab during the neoadjuvant and adjuvant therapies.

The primary endpoint of FeDeriCa was noninferiority of cycle 7 pertuzumab serum trough concentration comparing pertuzumab/trastuzumab/hyaluronidase-zzxf to intravenous pertuzumab. Secondary endpoints included cycle 7 trastuzumab serum trough concentration, pathologic complete response, and safety.

Pertuzumab/trastuzumab/hyaluronidase-zzxf showed noninferior pertuzumab and trastuzumab serum trough concentrations compared to intravenous pertuzumab and trastuzumab. The pathologic complete response rate was 59.7% (95% confidence interval [CI] = 53.3%–65.8%) in the pertuzumab/trastuzumab/hyaluronidase-zzxf arm and 59.5% (95% CI = 53.2%–65.6%) in the intravenous pertuzumab and intravenous trastuzumab arm. 

The safety profile of pertuzumab/trastuzumab/hyaluronidase-zzxf is comparable to intravenous pertuzumab and trastuzumab, except for increased administration-related reactions. The most common adverse reactions in > 30% patients receiving the triplet combination were alopecia, nausea, diarrhea, anemia, and asthenia.

The recommended initial dose of pertuzumab/trastuzumab/hyaluronidase-zzxf is 1,200 mg of pertuzumab, 600 mg of trastuzumab, and 30,000 units of hyaluronidase administered subcutaneously over approximately 8 minutes, followed every 3 weeks by a dose of 600 mg of pertuzumab, 600 mg of trastuzumab, and 20,000 units of hyaluronidase administered subcutaneously over approximately 5 minutes.

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®.

Κυριακή, 28 Ιουνίου 2020

COVID-19 ANTIBODIES CAN DISAPPEAR AFTER 2-3 MONTHS

People who develop antibodies after becoming infected with the coronavirus may not keep them more than a few months, especially if they showed no symptoms to begin with, a Chinese study shows.

Previous studies had found that most people who became infected developed antibodies. Health departments around the world give antibody tests as a way to prove a person has already had the coronavirus.

Scientists in the Wanzhou district of China studied 37 people who became infected with the coronavirus and showed symptoms and 37 people who became infected and showed no symptoms, according to the study published in the online journal Nature Medicine

Eight weeks after recovery, antibody levels fell to undetectable levels in 40% of asymptomatic people and 13% of symptomatic people, Nature Medicine said.

The researchers noted that only a small group of people were studied and that the human body can also use T cells to kill the virus and B cells to produce new antibodies, Business Insider reported. Neither T cells nor B cells were measured in the new study.

Business Insider reported that the researchers tested for two types of antibodies: immunoglobulin G (IgG) and immunoglobulin M (IgM). IgG usually develops over a longer time period, meaning it's a better indicator of long-term immunity, Business Insider said.

The decrease in detectable antibodies was sharp after 8 weeks, with a 71% median drop for IgG levels in the asymptomatic group and a 76% median drop in the symptomatic group, the study said.

The findings call into question the idea of "immunity passports," which some countries want to issue to people who test positive for antibodies. These people would be allowed to go back to work and travel because they're supposedly immune to the virus.

"Together, these data might indicate the risks of using COVID-19 'immunity passports' and support the prolongation of public health interventions, including social distancing, hygiene, isolation of high-risk groups and widespread testing," the authors wrote.

CONDITIONS THAT INCREASE COVID19 MORTALITY

Obesity poses a greater risk as an underlying condition when someone develops COVID-19, whereas newer evidence suggests hypertension poses a lower risk compared with the reports at the beginning of the pandemic in the United States, officials with the Centers for Disease Control and Prevention (CDC) announced today in a press briefing.

CDC Director Robert Redfield, MD, also told reporters on the briefing that the number of people infected with the novel coronavirus might be 10 times higher than reported.

Among those who are infected, the connection between obesity and more severe COVID-19 outcomes — defined as hospitalization, ICU admission, and/or death — early on was "most obvious among people with a BMI over 40," said Jay C. Butler, MD, CDC deputy director of infectious diseases and COVID-19 response incident manager.

"Now with more data, it appears that even obesity at a BMI over 30 may increase the risk as well," he said.

The potential contribution of hypertension to elevated risk shifted over time as well, Butler added during the briefing. He explained that high blood pressure is a risk factor for a number of conditions, and more recent studies helped CDC officials better tease out the individual risk associated with COVID-19.

The agency expanded its list of underlying conditions associated with the more severe COVID-19 outcomes. For example, in addition to a BMI of 30 or more, evidence suggests serious heart conditions, sickle cell diseasetype 2 diabetesand other conditions elevate the risk for severe illness. Joining hypertension in the "might be at increased risk" category are people with moderate-to-severe asthma, dementia, and cystic fibrosis.

"We are talking about the strength of evidence rather than upgrading or downgrading the level of risk" for each of these conditions, Butler said.

No More Specific Age Distinction

The CDC also removed an age cutoff associated with elevated risk for more serious COVID-19, previously set at older than 65 years. Instead, it's more of a continuum. "As you get older, your risk for hospitalization, intensive care, and death increases," said Redfield.

Although increased age is an independent risk factor, the agency acknowledged that older Americans tend to have more underlying conditions as well. 

Pregnancy Risks Linked to COVID-19

Pregnant women with COVID-19 appear to be at elevated risk for hospitalization, intensive care unit admission, and use of mechanical ventilation, according to research published online today in Morbidity and Mortality Weekly Report(MMWR). At the same time, however, this study of 8207 pregnant women with confirmed COVID-19 infection had no significantly increased risk of death.

"The good news is that the data we have so far is that pregnant women are not at increased risk of death," Dana Meaney-Delman, MD, MPH, COVID-19 deputy incident manager at the CDC, said during the briefing."But we do see increased risk of ICU admission and mechanical ventilation," she added. So it remains "important to get the message out there that pregnant women need to take precautions."

Of 91,412 (28%) women with laboratory-confirmed infections reported to the CDC between January 22 and June 7, 9% were pregnant.

Among the women with COVID-19, almost 32% of pregnant women were hospitalized compared with 6% of women who were not pregnant. Furthermore, the pregnant women were 50% more likely to be admitted to an ICU (adjusted relative risk [aRR], 1.5; 95% confidence interval, 1.2 - 1.8) and 70% more likely to be placed on mechanical ventilation (aRR, 1.7; 95% CI, 1.2 - 2.4). These analyses adjusted for age, underlying conditions, and race/ethnicity.

Multiply Confirmed Cases By 10

Addressing a recent increasing number of cases in the United States, Redfield said "there are a number of states, particularly in the Southeast and the Southwest, that are seeing increases in COVID-19 cases."

Many factors are driving the increase, he added, including outbreaks in particularly challenging settings, increased testing, and community transmission.

"This virus causes so much asymptomatic infection, we don't know the exact number," Redfield said.

More data are coming in from antibody testing and public health surveillance. "We probably recognized about 10% of the outbreak during March, April, and May," he said. The agency is working now to enhance detection closer to real time, he added.

"The best estimate for now is, for everyone diagnosed there were 10 other cases," Redfield said. Although data will be refined in next few weeks, "that is a good rough estimate for now."

At the same time that the number of positive cases is increasing, data is pointing to a higher infection rate among younger people, as reported byWebMD Health News.

"Obviously we are seeing infections that are targeting younger individuals, as in Florida or the Southeast and Southwest of the country," Redfield said. "In the past, I don't think we diagnosed these infections."

Redfield "remains concerned" about the public health messaging for people under age 45 or even under 30. "The impact of COVID-19 on them may not be associated with hospitalization and death, but they do act as transmission connectors to individuals who could be at higher risk."

"Everyone needs to understand there is some risk of severe illness, including among young people," he added.

Future Concerns

"It's clear that many individuals in this nation are still susceptible," Redfield said. The risk will vary with different prevalence rates in different states.

He estimated that between 5% to 8% of Americans have experienced COVID-19 infection so far, "whether they recognize it or not." This also means that greater than 90% of the public has not experienced the virus, although they are susceptible.

"This outbreak is not over, this pandemic is not over, and we need to continue to take steps we know are effective at limiting COVID-19," he said. The most powerful tool we have is social distancing. He emphasized the need to maintain 6 feet of distance with others, wearing a face covering "when we cannot maintain social distancing," and continuing frequent hand hygiene practices.

"As we go into the fall and winter, these will be important defense mechanisms," Redfield said. 

Follow Damian McNamara on Twitter: @MedReporter.

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PREVENTION OF TYPE 2 DIABETES

Adults at high risk for type 2 diabetes who had received either lifestyle intervention or metformin in the 3-year Diabetes Prevention Program (DPP) and continued in the Diabetes Prevention Program Outcomes Study (DPPOS) were less likely to develop diabetes than patients in the placebo group over an average 22-year follow-up.  

DPPOS chair David M. Nathan, MD, and other study investigators presented findings last week during the virtual American Diabetes Association (ADA) 80th Scientific Sessions.

At the end of the DPP, conducted in 1996-2001, patients in the lifestyle-intervention or metformin group were 58% and 31% less likely to have incident diabetes, respectively, than patients in the placebo group.

Now, 22 years after they enrolled in the DPP, patients were on average 72 years old and those in the original lifestyle intervention or metformin group were 25% and 18% less likely to have diabetes, respectively.

And participants who did not develop diabetes had significantly lower rates of eye, kidney, and major cardiovascular disease, at 57%, 37%, and 39%, respectively, according to a statement from the ADA.

"What we have shown is that diabetes prevention is possible," Nathan, from Massachusetts General Hospital and Harvard Medical School, Boston, told Medscape Medical News in an interview.

Unique Long-Term Study 

The DPP participants were at very high risk for diabetes, Nathan stressed.

"Their glucose levels were rising. They were overweight, if not obese, and we also overrecruited in ethnic and racial groups that are at particularly high risk — African Americans, Hispanic Americans, American Indians, and Asian Americans."

This unique, long-term study showed "a pretty remarkable — and not unexpected, some may say — reduction in eye disease, kidney disease, and major cardiovascular disease in people who did not develop diabetes," he noted.

"I think it is important for providers and patients with prediabetes to know that even after 22 years, adults at high risk for diabetes have continued to benefit from metformin or prior intensive lifestyle modification in preventing or delaying" diabetes, Christine Lee, MD, told Medscape Medical News in an email.

Lee is program director of the Division of Diabetes, Endocrinology, and Metabolic Diseases, at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Lifestyle Modification Better for Prevention in Adults > 60 Years

In the DPP, 3234 patients at high risk of developing diabetes were randomized to receive placebo or metformin (850 mg twice a day) or an intensive lifestyle counseling program that aimed for 7% weight loss and 150 minutes of moderate exercise per week.

At the end of the DPP, 88% of participants (including those who had developed diabetes) entered the DPPOS; those who were taking metformin stayed on it and all three groups received less intensive lifestyle counseling.As reported earlier, 15 years after enrolling in the DPP, 55% of participants in the lifestyle group and 56% of those in the metformin group had developed diabetes, compared with 62% of those in the placebo group.

At 22 years, 75% of patients from the DPP who were still alive were still participating in the DPPOS.

"The new findings did not show that taking metformin can prevent cancer, cardiovascular disease, or diseases of the eyes and kidney caused by diabetes," Lee pointed out.

However, "the data suggest that there may be some preventive effects of metformin for these outcomes in adults younger than 45 years [eg, a trend to less stroke], but these outcomes were more infrequent in this younger age group and further studies are needed before conclusions can be made for this age group."

"Conversely, there appeared to be a greater risk for kidney disease with metformin in older adults," she continued.

Therefore, "when balancing that risk [from metformin]" with prior, and newer, results that respectively show lifestyle modification works better than metformin for preventing diabetes in older adults, and can also decrease the risk of frailty in this same group, "patients ages 60 and older at high risk for diabetes should focus on intensive lifestyle modification for diabetes prevention," according to Lee.

Metformin is not approved for diabetes prevention in the United States, and it is unlikely that any of the several manufacturers of generic metformin would file a new drug application for this use with the US Food and Drug Administration, according to Nathan.

Widespread Prediabetes, Few Referrals for Community DPPs

In the United States, an estimated 30 million people have diabetes (mostly type 2), including about 7 million not yet diagnosed, Nathen said, and another 90 million have prediabetes.

More research is needed to be able to identify which patients with prediabetes are most vulnerable to developing diabetes and would benefit most from prevention interventions, he stated.

Similarly, Lee said that the current findings "highlight the importance of trying to further understand differences in how metformin or lifestyle modification work in adults at high risk for diabetes."

"Research to better identify who can benefit most from metformin or lifestyle will help providers offer patient-centered approaches for diabetes prevention," she said.

In the meantime, and as previously reported, the US Preventive Services Task Force and the ADA recommend screening and lifestyle counseling to achieve weight loss and reduce diabetes risk in high-risk adults, and diabetes prevention programs are covered by Medicare, many commercial health plans, and some Medicaid and state employee health plans.

About 2 years ago, the Center for Medicare and Medicaid Services began funding the diabetes prevention lifestyle program for qualifying Medicare beneficiaries at high risk of diabetes, said Nathan, and the program is available in many US communities.

And as previously reported, the turnkey lifestyle program to prevent diabetes by the US Centers for Disease Control and Prevention (CDC) replicates the DPP intervention and is offered by 244 YMCAs at more than 1100 locations.

Patients receive coaching from trained individuals about making long-term dietary changes, increasing physical activity, and overcoming challenges to maintaining weight loss and a healthy lifestyle. Counseling is given in 22 sessions over 1 year.

However, few physicians are referring patients with prediabetes to the program. According to a 2019 CDC study, only 5% of individuals with prediabetes and 0.4% of those with an elevated risk of diabetes had been told by their physician to participate in a diabetes prevention program (JAMA Netw Open2019;2:E193160).

DPPOS is supported by the NIDDK, National Cancer Institute, National Heart, Lung, and Blood Institute, National Institute on Aging, National Eye Institute, Office of Research on Women's Health, and CDC. Merck supplied the metformin.  

ADA 2020 Scientific Sessions. June 16, 2020.   

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