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.

IMMUNOTHERAPY FOR UVEAL MELANOMA

In a single-institution phase II trial reported in the Journal of Clinical Oncology, Pelster et al found that nivolumab plus ipilimumab produced durable responses and improved survival outcomes in patients with metastatic uveal melanoma.

Study Details

The trial enrolled 35 patients at The University of Texas MD Anderson Cancer Center between July 2015 and March 2018. Patients received nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg every 3 weeks for a total of four doses, followed by nivolumab maintenance for up to 2 years; nivolumab maintenance was initially given at 3 mg/kg every 2 weeks, with dosing subsequently changed to 480 mg every 4 weeks. In total, 43% of patients had received one or more prior line(s) of therapy. The primary outcome measure was overall response rate on Response Evaluation Criteria in Solid Tumors version 1.1.

Responses

Median follow-up was 13.0 months (range = 1.3­­–43.5 months). Among 33 patients evaluable for response, confirmed responses were observed in 6 patients (18%), including complete response in 1 patient. Stable disease was observed in an additional 11 patients (33%). The median duration of response was 12.1 months (range = 2.8­–43.0 months), with three responses ongoing at data cutoff.

Among 27 evaluable patients with liver metastases, 5 (19%) had a partial response and 3 (11%) had stable disease for 6 months or longer. Among six patients with only extrahepatic metastases, one (17%) had complete response and three (50%) had stable disease for six months or longer.

Among all 35 patients, median progression-free survival was 5.5 months (95% confidence interval [CI] = 3.4­–9.5 months). Median progression-free survival among patients with liver metastases vs those with only extrahepatic metastases was 12.0 vs 5.5 months (P = .0918).

KEY POINTS

• Treatment with nivolumab/ipilimumab produced response in 18% of patients, with a median response duration of 12.1 months.
• Median overall survival was 19.1 months.

Median overall survival was 19.1 months (95% CI = 9.6 months–not reached), with a 1-year rate of 56%. No significant difference in overall survival was observed between patients with liver metastases vs those with only extrahepatic metastases.

The investigators noted, “The overall survival with nivolumab and ipilimumab of 19.1 months is notably longer than the 6.8 to 9.6 months reported with single-agent checkpoint inhibition.”

Adverse Events

Grade 3 or 4 adverse events occurred in 57% of patients (treatment-related in 40%), with the most common being increased alanine transaminase (ALT; 17%), increased aspartate transaminase (AST; 11%), and diarrhea (9%). The most common adverse events of any grade were diarrhea (60%), increased ALT (49%), increased AST (40%), pruritus (40%), and hypothyroidism (37%). Adverse events led to discontinuation of treatment in 29% of patients. No treatment-related deaths were observed.

The investigators concluded, “The combination regimen of nivolumab plus ipilimumab demonstrates activity in metastatic uveal melanoma, with deep and sustained confirmed responses.”

Meredith S. Pelster, MD, of The University of Texas MD Anderson Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Bristol Myers Squibb and The University of Texas MD Anderson High Impact Clinical Research Support Program. For full disclosures of the study authors, visit ascopubs.org.

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®.

NO BENEFIT OF TRIPLE THERAPY FOR BRAF+ MELANOMA

Patients with unresectable or metastatic melanoma harboring BRAF V600 mutations did not benefit from the addition of the anti–PD-1 antibody spartalizumab to dabrafenib and trametinib in the COMBI-i trial, which was presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.1

“The triplet of spartalizumab, dabrafenib, and trametinib did not significantly improve investigator-assessed progression-free survival, compared with the doublet of dabrafenib and trametinib with placebo,” said Paul D. Nathan, MBBS, PhD, of Mount Vernon Cancer Centre in Northwood, United Kingdom, during his presentation. “Additional analyses are ongoing and planned to better understand these results, and further overall survival follow-up may provide additional insights.”

According to Dr. Nathan, preclinical data suggest that the combination of an anti–PD-1 antibody with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib may enhance antitumor activity compared with the doublet alone. Additionally, in phase II and phase III trials, the use of immune checkpoint inhibitors with targeted therapy have been shown to improve outcomes. Early clinical findings also showed that the triplet of spartalizumab, dabrafenib, and trametinib may boost durable responses. These findings led to the COMBI-i study.

COMBI-i Details

The global phase III COMBI-i trial enrolled 532 patients, randomly assigning them to spartalizumab at 400 mg intravenously every 4 weeks plus dabrafenib at 150 mg orally twice daily and trametinib at 2 mg orally once daily, or placebo plus dabrafenib and trametinib. All patients had untreated BRAF V600–mutant melanoma that was unresectable or metastatic. Approximately 60% of patients had stage IV M1c disease, about 40% had an elevated lactate dehydrogenase (LDH) level, and 45% had disease at three or more organ sites.

The primary endpoint was investigator-assessed progression-free survival. This analysis was based on a minimum follow-up of 24 months, with 312 events occurring; the statistical threshold was P = .02497 (1-sided).

At a median follow-up of 27.2 months, the addition of spartalizumab to dabrafenib and trametinib did not significantly improve progression-free survival, which was 16.2 months with the triplet and 12.0 months in the placebo arm (hazard ratio [HR] = 0.82; P = .042). At 24 months, 44% of the spartalizumab arm was progression-free compared with 36% of the control arm.

Of note, Dr. Nathan said, “The performance of patients receiving the doublet was superior to that which we have seen historically with the COMBI-d and COMBI-v studies.”

He added: “In the preplanned subset analysis, there were some interesting trends in favor of the immunotherapy-containing triplet.” He singled out benefits with the triplet as opposed to the doublet in terms of higher LDH levels (HR = 0.72), more sites of metastasis (HR = 0.63), increasing bulk of disease (HR = 0.52), and higher tumor mutational burden (HR = 0.70).

Overall survival was not formally tested because the primary endpoint was not statistically significant. That said, median survival was not reached across treatment arms (HR = 0.785, 95% confidence interval [CI] = 0.589–1.047).

Objective responses were achieved in 68.5% of the spartalizumab arm, of which 19.9% were complete responses vs 64.2% of the placebo arm, of which 17.7% were complete responses. Median duration of response was not reached with spartalizumab and was 20.7 months without spartalizumab.

Treatment-related adverse events of grade ≥ 3 occurred in 54.7% of patients receiving the triplet and 33.3% of those treated with the doublet. Adverse events leading to discontinuation of all study drugs were seen in 12.4% and 8.0%, respectively. The greater use of dose interruptions and reductions among patients treated with spartalizumab resulted in a slightly lower relative dose intensity. 

DISCLOSURE: COMBI-i was funded by Novartis Pharmaceuticals Corporation. Dr. Nathan has served in a consulting or advisory role for 4SC, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Immunocore, Ipsen, Merck, MSD, Novartis, Pfizer, and Pierre Fabre; has participated in a speakers bureau for Bristol Myers Squibb, Merck, MSD, and Novartis; and has been reimbursed for travel, accommodations, or other expenses by Bristol Myers Squibb and MSD.

REFERENCE

1. Nathan P, Dummer R, Long GV, et al: Spartalizumab plus dabrafenib and trametinib in patients with previously untreated BRAF V600-mutant unresectable or metastatic melanoma: Results from the randomized part 3 of the phase III COMBI-i trial. ESMO Virtual Congress 2020. Abstract LBA43. Presented September 19, 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®

LENVATINIB CAN OVERCOME IMMUNOTHERAPY RESISTANCE IN MELANOMA

Patients with advanced melanoma who have progressed on anti-programmed death (PD)-1/PD ligand 1 (PD-L1) immunotherapy could substantially extend their overall survival (OS) with a combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and pembrolizumab (Keytruda), suggests an open-label, single arm study.

The research was presented September 19 at the European Society for Medical Oncology Virtual Congress 2020.

In LEAP-004 trial, over 100 patients with stage 3 or 4 melanoma who had progressed after immunotherapy were given lenvatinib plus pembrolizumab, which yielded a median progression-free survival (PFS) of more than 4 months and a median OS of more than a year. Median follow-up was 12 months.

Presenting the findings, Ana Maria Arance Fernandez, MD, PhD, Hospital Clínic de Barcelona, Spain, said lenvatinib plus pembrolizumab has "promising" antitumor activity in patients with advanced melanoma with confirmed progression on a PD-1 inhibitor given alone or in combination. "These results are encouraging given the stringent definition of progression on prior anti-PD-1 therapy and the enrollment of poor-risk patients."

Arance Fernandez added that "these data support lenvatinib plus pembrolizumab as a potential treatment regimen for this population of high unmet medical need."

Bartosz Chmielowski, MD, PhD, Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, who was not involved in the study, discussed the findings.

He highlighted that the patients were not randomly assigned in LEAP-004, with all of them receiving the same therapy.

Nevertheless, the response rate was "quite impressive for this patient population."

He also drew comparison with previous data with nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) in a similar population, noting that the overall survival was less than half that seen in the current trial, "which makes these results even more important."

"It tells us that this combination might be an option with disease progression on anti-PD-1," Chmielowski noted.

Investigator Arance Fernandez pointed out that patients with advanced melanoma who progress on standard-of-care treatment with anti-PD-1 therapy or a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor plus anti-PD-1 "have very limited therapeutic options available and there is no approved regimen in this indication."

Response Rate, PFS, and OS

Previous studies have indicated that adding an anti-PD-1 drug to lenvatinib achieves superior antitumor activity than either treatment alone, with promising results in phase 1/2b data in pretreated metastatic melanoma.

LEAP-004 therefore enrolled patients with unresectable stage 3 or 4 melanoma, who had disease progression within 12 weeks of their last dose of anti-PD-(L)1 therapy either alone or with a CTLA-4 inhibitor. There was no limit on the number of prior treatments.

The patients received pembrolizumab 200 mg IV for up to 35 cycles plus lenvatinib 20 mg daily until progression, unacceptable toxicity, or patient or physician decision.

They were imaged at baseline and every 9 weeks through to week 54, then every 12 weeks until week 102, and then every 24 weeks.

From February to September 2019, 103 patients were enrolled, all of whom received at least one dose of lenvatinib plus pembrolizumab. The median age of the patients was 63 years, and 53.4% were male.

Arance Fernandez pointed out that this was a high-risk population, with 20.4% having a lactate dehydrogenase level twice the upper limit of normal and 14.6% brain metastasis, while the median sum of target lesions was 100 mm.

A BRAFv600 mutation was identified in 36.9% of patients and 64.1% were PD-L1 positive.

Nearly one third (28.2%) had received a prior anti-CTLA-4 plus anti-PD-(L)1 combination, and 19.5% had undergone four or more prior lines of therapy.

The overall response rate to lenvatinib plus pembrolizumab was 21.4%, with 1.9% having a complete response, and 19.4% a partial response. This was seen across subgroups, including by age and disease stage.

Arance Fernandez said that the overall response rate was even higher in patients who had previously been treated with an anti-CTLA-4 plus anti-PD-(L)1 combination, at 31%.

However, Chmielowski warned that "we must interpret this result with caution since only 29 patients were in this subpopulation."

The median duration of blinded independent committee review-confirmed response across the study population was 6.3 months, with 72.6% still responding at 6 months.

The median PFS was 4.2 months with the combination therapy, with 41.7% of patients progression-free at 6 months, and 26.2% at 9 months.

Median overall survival was 13.9 months, with 77.3% of patients still alive at 6 months, and 65.4% alive at 9 months.

Although 96.1% of patients experienced at least one treatment-related adverse event of any grade, only 44.7% had grade 3 or higher events, and only in 7.8% of cases did that lead to treatment discontinuation.

The most common adverse events were hypertension (56.3%), diarrhea (35.9%), nausea (34%), and hypothyroidism (33%), although in the vast majority of cases these were grade 1 or 2.

LEAP Presents Challenges

UCLA's Chmielowski would like to see treatment in this setting individualized somehow.

"It will be also important to come up with personalized immunotherapy, so that based on the mechanism of resistance in patient populations, we would be able to choose the subsequent treatments," he commented.

Investigator Arance Fernandez explained that lenvatinib inhibits multiple tyrosine kinases involved in angiogenesis, cell proliferation, and immune modulation, and has demonstrated immunomodulatory activity in the tumor microenvironment.

However, Arance Fernandez noted that, as resistance to immunotherapy is "multifactorial," it may be that a combination treatment will be more effective in these patients.

The study was funded by Merck. Arance Fernandez has financial ties to Merck and multiple other drug companies. Chmielowski has financial ties to Merck Serono and multiple other companies.  

ESMO Virtual Congress 2020: Abstract LBA44. Presented September 19, 2020.

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ADJUVANT THERAPY FOR MELANOMA

Adjuvant therapy for patients with high-risk resected melanomas is now a standard of care, but the durability of the benefit gained from this treatment is still unclear.

New data show that the benefit is maintained over the longer term.  

At 5 years, just over half of patients (52%) with advanced melanoma who had received a year of adjuvant therapy with two targeted agents were still alive and remained relapse-free, compared with 36% of patients who received placebo.

The combination of dabrafenib (Tafinlar) and trametinib (Mekinist)  conferred a durable long-term, relapse-free survival benefit for patients with resected stage III melanoma with BRAF V600E or V600K mutations, the investigators concluded.

These data come from the COMBI-AD phase 3 trial and were published onlinetoday in the New England Journal of Medicine.

"The treatment duration of this adjuvant therapy was 12 months; however, we do not know whether this is the optimal treatment duration," said lead author Reinhard Dummer, MD, vice-chairman, Department of Dermatology, University of Zurich Hospital, Switzerland. "Early biomarker results suggest that in a subgroup, longer treatment durations might be necessary. In other patients, a shorter treatment could be sufficient."

Approached to comment on the study, Richard Carvajal, MD, director of Melanoma Service at NewYork-Presbyterian Hospital and Columbia University Medical Center in New York City, said the new data "address prior concerns that any benefit achieved with targeted therapy in the adjuvant setting may be limited in duration."

"Indeed, with active therapy, over 50% of patients are alive without relapse and 65% of patients are alive without the development of distant metastasis," he said. "Although overall survival data remain immature, numerical improvement in survival is also reported."

Carvajal told Medscape Medical News that the plateaus observed with relapse and distant metastasis-free survival suggest that true disease cures are being achieved with treatment. "Based upon these results, the discussion of adjuvant therapeutic options should include a 12-month course of adjuvant dabrafenib and trametinib, as well as the option of adjuvant anti-PD1 therapy," he said.

As for how the MEK-BRAF inhibitor combination compares to immunotherapy in this setting, he pointed out that since there has been no head-to-head comparison of adjuvant targeted therapy and adjuvant nivolumab (Opdivo) or pembrolizumab (Keytruda), it is not possible to conclusively state that one regimen is more effective than another.

"For patients with resected BRAF-mutant melanoma at high risk of disease recurrence, we now have data demonstrating the clinical benefit for a course of adjuvant dabrafenib and trametinib, adjuvant nivolumab and adjuvant pembrolizumab," said Carvajal"Although the efficacy of adjuvant ipilimumab [Yervoy] as well as adjuvant interferon have also been previously demonstrated, these agents are now appropriate for consideration in extremely rare clinical circumstances given the clinical efficacy and improved toxicity profile of single agent anti-PD1 therapy."

"The selection of the most appropriate adjuvant therapy should take into account the preferences of individual patients in terms of toxicity profile and drug administration considerations," he added. 

Study Details

The COMBI-AD was a randomized, double-blind, placebo-controlled, phase 3 study conducted in 870 patients with high-risk, stage III, BRAF-V600E/K-mutant melanoma who were treatment naive. Participating patients had undergone surgical resection and had been disease free for ≤12 weeks.

Interim results from this study, reported in 2017, showed 1 year of oral adjuvant therapy with dabrafenib and trametinib provided a 53% lower risk for 3-year recurrence compared with placebo.

Now, the investigators report on the 5-year results for relapse-free survival and survival without distant metastasis. They note that they were unable to analyze overall survival since the required number of events had not been reached.

Patients had been randomly assigned to receive 12 months of oral dabrafenib (at a dose of 150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. Patients were followed for 60 months (5 years) for dabrafenib plus trametinib and 58 months for placebo.

At 5 years, the median relapse-free survival was not reached for patients who received the combination therapy group vs 16.6 months in the placebo group (hazard ratio [HR] for relapse or death, 0.51).

The percentage of patients who were alive without distant metastasis at 5 years was 65% in the dabrafenib plus trametinib group and 54% in the placebo arm (HR for distant metastasis or death, 0.55).

The hazard ratio for relapse-free survival favored dabrafenib plus trametinib across all patient subgroups that were evaluated in the study, and survival without distant metastasis showed a similar benefit for the combination regardless of disease stage.

Subsequent therapy was needed in 40% of patients who received dabrafenib + trametinib and by 54% of those in the placebo group, with the most common treatments being immunotherapy in the combination-therapy group [26%] and small-molecule targeted therapy in the placebo group (35%).

A Viable Option

Dummer noted that when this clinical trial was designed, all patients had to undergo aggressive surgery that involved lymph node dissection. "Nowadays, based on the lack of improvement on progression-free survival and overall survival, the surgical procedures are less aggressive and today we do not recommend aggressive lymph node dissection in patients that qualify for adjuvant therapy," he said. "In patients that do not have the BRAF mutation, there is the possibility of giving immunotherapy."

He added that there is an urgent need for biomarkers that can identify early progression during adjuvant therapy. "Potentially, these patients would profit from immunotherapy alone or from combination using targeted therapy and immunotherapy," Dummer said.

The study was funded by GlaxoSmithKline and Novartis. Dummer has declared multiple relationships with industry as noted in the original article.

N Eng J Med. Published online September 2, 2020. Abstract

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MELANOMA NO ROUTINE USE OF GENE PROFILING

An international panel of 49 melanoma specialists has come out against routine gene expression profile (GEP) testing for cutaneous melanoma, pending solid proof of clinical benefit.

"The currently published evidence is insufficient to establish that routine use of GEP testing provides additional clinical value for melanoma staging and prognostication beyond available clinicopathologic variables," they argue.

Patients must be protected "from potentially inaccurate testing that may provide a false sense of security or perceived increased risk," leading to the wrong decisions, they said in a consensus statement from the United States' national Melanoma Prevention Working Group.

The statement was published on July 29 in JAMA Dermatology.

The GEP test for melanoma that is available in the US — DecisionDx-Melanoma from Castle Biosciences — checks the expression levels of 31 genes reported to be associated with melanoma metastasis and recurrence. It uses quantitative reverse transcriptase and polymerase chain reaction on RNA from formalin-fixed, paraffin-embedded biopsy specimens.

The test stratifies patients as being at low, intermediate, or high risk.

It is marketed as a guide to whether to perform sentinel lymph node biopsies (SLNB) on patients age 55 years or older with tumors less than 2 mm deep, and to decide what levels of follow-up, imaging, and adjuvant treatment are appropriate for tumors at least 0.3 mm deep.

Medicare reimburses at $7,193 per test for SLNB-eligible patients.

However, this test is not endorsed by the American Academy of Dermatology or National Comprehensive Cancer Network outside of studies because the evidence of benefit is not strong enough, the consensus authors note.

Even so, use of the test is growing, with up to 10% of cutaneous melanomas now being tested in the United States.

Company Welcomes "Further Discussion"

"To date, thousands of clinicians — over 4200 US clinicians in the last 12 months — have utilized our GEP test for cutaneous melanoma in their patients after reviewing our clinical data and determining that our test provides clinically actionable information that complements current melanoma staging," said Castle Biosciences Vice President of Research and Development Bob Cook, PhD, when asked for comment.

Citing company-funded studies, he said that "the strength of the existing evidence in support of these claims has undergone rigorous evaluation to obtain Medicare reimbursement."

"We believe that the application of the test to help guide [the] decision to pursue SLNB has the potential to realize significant cost savings by reducing unnecessary SLNB procedures, particularly in the T1 population."

Asked for a reaction to the consensus statement, Cook told Medscape Medical News: "We recently launched two prospective studies with multiple centers nationwide that will involve thousands of patients and provide additional data relating our tests to patient outcomes.… We welcome further discussions to promote collaborative efforts with centers that are part of the [Melanoma Prevention Working Group] to improve patient outcomes."

Cart Before the Horse

Medicare, although it reimburses the test, has its doubts. Due to the "low strength of evidence," the Centers for Medicare & Medicaid Services said in their local coverage determination that continued reimbursement depends on demonstration of 95% or greater distant-metastasis-free survival and melanoma-specific survival at 3 years "in patients directed to no SLNB by the test compared to standard of care, and...evidence of higher SLNB positivity in patients selected for this procedure by the test compared to standard of care."

The statement hints at the Achilles' heel of GEP in melanoma — ie, the lack of evidence that test results improve outcomes. This was the main concern of the consensus statement; the cart is before the horse.

One of the consensus authors, David Polsky, MD, PhD, a professor of dermatologic oncology at New York University, Manhattan, said that "most of the data for this test come from retrospectively collected patient groups." The prospective studies have been generally small, with no comparator group. "While they have shown some promise in intermediate thickness melanoma, they have not yet demonstrated utility for thin, stage I melanomas."

First, Do No Harm

A new meta-analysis of over 800 patients with cutaneous melanoma tested by DecisionDx-Melanoma, published in JAMA Dermatology alongside the consensus statement, shows how the tests perform.

Among patients with a recurrence, DecisionDx-Melanoma correctly classified 82% with stage II disease but only 29% with stage I disease as high risk. Among those without recurrence, the test correctly classified 90% of stage I patients but only 44% with stage II disease as low risk.

Similar results were seen with the melanoma GEP test available in Europe, MelaGenix (NeraCare GmbH). This test was developed from a panel that was narrowed to seven protective genes and one high-risk gene using a training cohort of 125 cutaneous melanomas.

"The prognostic ability of GEP tests...appeared to be poor at correctly identifying recurrence in patients with stage I disease, suggesting limited potential for clinical utility in these patients," comment the meta-analysis authors, led by Michael Marchetti, MD, an assistant professor of dermatology at Weill Cornell Medical College in New York City.

"Unknown are the harms associated with a false-positive result, which were 10-fold more frequent than true-positive results in patients with stage I disease," they point out.

"Further research is needed to define the incremental improvement in risk predictions provided by the test beyond...all other known clinicopathologic factors," which include patient sex, age, tumor location and thickness, ulceration, mitotic rate, lymphovascular invasion, microsatellites, and other factors proven to be linked to outcomes, they said.

Studies so far suggesting benefit have incorporated a few of those factors, but not all of them. For now, "it is not clear which patients should be tested or how to act on the results," Marchetti and colleagues conclude.

Breast Cancer Standard of Proof 

Larger, prospective studies are needed to address whether GEP testing can replace SLNB to predict relapse "and [can identify] patients who could be spared surveillance imaging and/or benefit from adjuvant therapy," say the consensus authors. Follow-up also needs to be long enough to detect delayed recurrence of thin melanomas, they add.

With more research, there is reason to hope that gene expression profiling will help in melanoma; it's already standard of care in breast cancer, they point out.

On the hope front, one cohort study evaluated whether DecisionDx-Melanoma could identify patients at low risk for positive lymph nodes in T1/T2 disease who were eligible for biopsy. Only 1.6% of subjects who were age 65 years or older and pegged by the test as low risk had a positive node.

"This is a promising direction of investigation...in a narrow, defined population," said authors led by Carrie Kovarik, MD, associate professor of dermatology at the University of Pennsylvania, Philadelphia, in an opinion piece last springBut still, until there's "clear evidence that [DecisionDx-Melanoma] results affect patient outcomes, we should not use it to influence care decisions in patients with thin" melanomas. Dermatology "should expect the same standards" of proof as breast cancer, they said.

What to do Right Now? 

Despite the marketing, "think twice before ordering GEP tests for" T1a melanomas is the message in an editorial that accompanies the consensus statement. The 5- and 10-year melanoma-specific survival rates are 99% and 98%, respectively. "GEP tests will unlikely change these estimates significantly. In fact, the new meta-analysis indicates "that there may be an approximately 12% misassignment rate in this population," write editorialists Warren Chan, a medical student at Baylor College of Medicine, Houston, and Hensin Tsao, MD, PhD, director of the melanoma genetics program at Massachusetts General Hospital, Boston.

"Even if you use GEP testing and discover a low-risk class assignment for a 2 mm thick melanoma, avoid the urge to bypass the sentinel lymph node discussion…. Nodal sampling, for good reasons, remains part of all major guidelines and determines eligibility for adjuvant treatments.... Many of us engaged in genomics research believe that accurate [melanoma] GEP will be developed in time, but better tools and greater tenacity are needed," they wrote.

There was no industry funding for the consensus statement and meta-analysis. Authors on the consensus statement reported numerous ties to pharmaceutical and other companies, as listed in the paper.

M. Alexander Otto is a physician assistant and award-winning medical journalist who has worked previously for several major news outlets, including McClatchy and Bloomberg BNA. He is an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com.

JAMA Dermatol. Published online July 29, 2020. Consensus Statement Abstract, Meta-analysis Abstract, Editorial; and 2020;156:837-838. Opinion Piece Abstract

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ADJUVANT IMMUNOTHERAPY FOR MELANOMA

In an interim analysis of the German phase II IMMUNED trial reported in The Lancet, Lisa Zimmer, MD, of University Hospital Essen, and colleagues found that adjuvant nivolumab plus ipilimumab and nivolumab alone significantly prolonged recurrence-free survival vs placebo in patients with resected stage IV melanoma and no evidence of disease.1 Severe treatment-related toxicity and treatment discontinuations were substantially more common with combination vs nivolumab treatment. Study Details In the multicenter, double-blind trial, 167 patients with no evidence of disease after surgery or radiotherapy were randomly assigned 1:1:1 between September 2015 and November 2018 to receive nivolumab at 1 mg/kg every 3 weeks plus ipilimumab at 3 mg/kg every 3 weeks for 4 doses, followed by nivolumab at 3 mg/kg every 2 weeks (n = 56), nivolumab at 3 mg/kg every 2 weeks plus placebo (n = 59), or double placebo (n = 52). Treatment continued for up to 1 year or until disease recurrence or unacceptable toxicity. Patients with uveal or mucosal melanoma and those who had received prior immune checkpoint inhibitors or any previous immunosuppressive therapy within 30 days before study drug administration were not eligible for the trial. The primary endpoint was recurrence-free survival in the intention-to-treat population. The results in the current report are from a prespecified interim analysis of recurrence-free survival after 90 events had been reported. Among all patients, the median age was 55 years (26% ≥ 65 years); 57% were male; metastasis status was M1a in 40%, M1b in 29%, and M1c (including a history of brain metastasis) in 31%; all had an Eastern Cooperative Oncology Group performance status of 0 (93%) or 1; 76% had undergone surgery, 13% had had radiotherapy, and 11% had both; 98% had fewer than three organ sites with disease; 32% had received prior adjuvant systemic therapy, and 2% had received systemic therapy in the metastatic setting; 45% had BRAF-mutant disease; and programmed cell death ligand 1 (PD-L1) expression was at least 5% in 49%. Recurrence-Free Survival The median follow-up was 28.4 months at the time of analysis. The median number of doses received was eight in the nivolumab-plus-ipilimumab group, 18 in the nivolumab group, and 19 in the placebo group; the median time on treatment was 6.5 weeks, 21.9 weeks, and 24.1 weeks, respectively. Median recurrence-free survival was not reached in the nivolumab-plus-ipilimumab group (hazard ratio [HR] vs placebo = 0.23, 97.5% confidence interval [CI] = 0.12–0.45, P < .0001), 12.4 months (95% CI = 5.3–33.3 months) in the nivolumab group (HR vs placebo = 0.56, 97.5% CI = 0.33–0.94, P = .011), and 6.4 months (95% CI = 3.3–9.6 months) in the placebo group. Recurrence-free survival was 75% and 52% vs 32% at 1 year and 70% and 42% vs 14% at 2 years. Exploratory analysis indicated a hazard ratio of 0.40 (97.5% CI = 0.20–0.79) for the combination vs nivolumab alone. Benefits of nivolumab plus ipilimumab and nivolumab vs placebo were consistent across the subgroups examined. Hazard ratios vs placebo were 0.07 (95% CI = 0.02–0.23) for the combination and 0.39 (95% CI = 0.19–0.78) for nivolumab among patients with BRAF-mutant disease and 0.44 (95% CI = 0.22–0.88) and 0.71 (95% CI = 0.39–1.28), respectively, among patients with wild-type BRAF. Hazard ratios vs placebo were 0.21 (95% CI = 0.10–0.48) for the combination and 0.55 (95% CI = 0.30–1.02) for nivolumab for PD-L1 expression up to 5% and 0.24 (95% CI = 0.10–0.57) and 0.57 (95% CI = 0.29–1.11, respectively, for PD-L1 expression of at least 5%. For M1a, M1b, and M1c disease, hazard ratios vs placebo were 0.13, 0.46, and 0.19 for the combination and 0.39, 0.65, and 0.77 for nivolumab alone. Relapse occurred in 26.8% of the combination group, 55.9% of the nivolumab group, and 80.8% of the placebo group. Relapse rates were 9%, 11.9%, and 25.0% for local relapse; 1.8%, 3.4%, and 7.6% for local and distant relapses; 14.3%, 39.0%, and 44.2% for distant relapse; and 0%, 1.7%, and 1.9% for new primary melanoma. Overall survival outcomes are to be assessed when the last patient off treatment has been followed for 2 years. Adverse Events Treatment-related grade 3 or 4 adverse events were reported in 71% of the nivolumab-plus-ipilimumab group, 27% of the nivolumab group, and 6% of the placebo group. The most common adverse events in the combination group were increased alanine transaminase (24% vs 11% in the nivolumab group), autoimmune disorder (22% vs 2%), increased aspartate transaminase (15% vs 5%), increased lipase (15% vs 5%), and autoimmune hepatitis (11% vs 4%). Treatment-related serious adverse events occurred in 58%, 20%, and 4% of patients. Treatment-related adverse events of any grade led to treatment discontinuation in 62%, 13%, and 2% of patients. Three deaths due to adverse events were reported, consisting of one in the nivolumab/ipilimumab group due to pneumonia and two in the nivolumab group due to pneumonia and liver abscess. None of the deaths were considered related to treatment. The investigators noted: “High toxicity but substantial efficacy of combined nivolumab plus ipilimumab treatment has also been described in two small trials in the adjuvant and neoadjuvant setting in stages III and IV melanoma…. Data from IMMUNED as well as other trials … suggest that short but intense immune checkpoint inhibition with nivolumab plus ipilimumab might be sufficient to achieve long-lasting tumour control in a substantial subset of patients with melanoma with no or small tumor burden disease. Whether ipilimumab is required in the standard dose of 3 mg/kg needs further investigation. The risk-benefit profile and alternative dosing regimens of the immunotherapy combination will be further clarified by data from the ongoing double-blind, randomized, phase III CheckMate-915 trial (ClinicalTrials.gov identifier NCT03068455), which investigates two weekly, 240-mg flat-dose nivolumab plus ipilimumab (1 mg/kg, every 6 weeks) as an experimental group in resected stage IIIB/C/D or IV melanoma, compared with four weekly nivolumab (480-mg flat dose).” They concluded: “Adjuvant therapy with nivolumab alone or in combination with ipilimumab increased recurrence-free survival significantly compared with placebo in patients with stage IV melanoma with no evidence of disease. The rates of grade 3/4 treatment-related adverse events in both active treatment groups were higher than the rates reported in previous pivotal trials done in advanced melanoma with measurable disease.” DISCLOSURE: The study was funded by Bristol Myers

TRIPLE DRUG COMBINATION APPROVED BY FDA FOR MELANOMA

The US Food and Drug Administration (FDA) has approved the triple-therapy combination of atezolizumab (Tecentriq) plus cobimetinib (Cotellic) and vemurafenib (Zelboraf) for the treatment of BRAF V600 mutation-positive advanced melanoma, according to a press statement from Genentech, which owns all three drugs.

This is the first melanoma indication for the PD-L1 inhibitor atezolizumab; the other two drugs, cobimetinib and vemurafenib, are a MEK- plus BRAF-inhibitor combination previously approved for BRAF-mutated melanoma.

The new approval is based on safety and efficacy results from the randomized, phase 3 IMspire150 study from patients with previously untreated BRAF V600 mutation-positive metastatic or unresectable locally advanced melanoma.

Progression-free survival (PFS), the primary endpoint, was improved by 4.5 months with the triple therapy compared to the doublet.

The addition of atezolizumab to cobimetinib and vemurafenib led to a longer median PFS of 15.1 months, compared to 10.6 months with placebo plus cobimetinib and vemurafenib (hazard ratio, 0.78; 95% CI, 0.63 – 0.97; P = .025).

The most common adverse reactions (rate ≥20%) in patients who received the triple combination were rash (75%), musculoskeletal pain (62%), fatigue (51%), hepatotoxicity (50%), pyrexia (49%), nausea (30%), pruritus (26%), edema (26%), stomatitis (23%), hypothyroidism (22%), and photosensitivity reaction (21%).

The review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence that facilitates concurrent submission and review of oncology products among international partners.

TREATMENT OF MELANOMA PATIENTS AFTER PDL1 FAILURE

I'd like to report on an interesting article in the Journal of Clinical Oncology by Allison Betof Warner and colleagues, describing a single-institution experience, from the outstanding Memorial Sloan Kettering Cancer Center, of patients with metastatic melanoma who received single-agent programmed death-1 (PD-1) blockade. The article describes the outcome in those mostly nonprotocol patients and, importantly, also talks about what happens when a significant proportion of them progressed and went on to receive subsequent therapy.

A very important question for academicians and practicing oncologists is: What do you do if a patient has had single-agent PD-1 blockade and does well for a period of time but then progresses and requires second-line therapy? What is the best choice? The natural history of this disease after PD-1 blockade is a very important issue, and that is what this article addressed.

There were 396 patients in total; 69% of them were not on a trial, so this was a reasonable, real-world experience. Twenty-five percent had a complete response (CR), of which about 70% were subsequently confirmed on independent radiologic review. (These were called by the investigator; many of them had trivial disease and, in the real world, were probably complete responders.) Something like 14% had CNS metastases and 40% had M1b disease. Overall survival was excellent. The median survival was 39 months, which is about what you would see in frontline therapy in clinical trials of PD-1 blockade alone. The majority had pembrolizumab, but a significant minority had nivolumab — very similar drugs. The likelihood of remaining in remission at 3 years was over 70% if you had a CR, and the [estimated] survival of the complete responders at 3 years was 83%. Something like 73% of the complete responders did not require any further therapy by year 3. The median duration of therapy [of the complete responders] was 9.4 months, so a lot of them stopped before then. The majority of patients who went on to other therapy stopped because of toxicity or progression.

Tumor mutational burden was definitely associated with CR in a multivariable analysis. Stage M1b compared with M1c was associated with complete response. (There were very few M1a's.) For negative associations, high lactate dehydrogenase was associated with a poor outcome and not achieving a CR, as was having mucosal or acral lentiginous melanoma. Interestingly, in contrast to prior reports of the importance of body mass index (BMI), there was no association in men or women between BMI and outcome.

Of the 102 complete responders, 23 did progress and presumably required further therapy.

A total of 78 patients were described who did require further therapy after PD-1 blockade failed. Of the 34 patients who [received further therapy with] single-agent PD-1 blockade alone, there were only five responders (15% response rate). Not very impressive. Of those who then went on to receive combination ipilimumab and nivolumab, there was only a 25% response rate (11 out of 44 patients). So again, disappointing but not a surprise. In the 78 patients who were re-treated, 13 patients had stable disease and 37 patients had progressive disease. This is different from prior reports discussing how patients do well after having a CR or a partial response and then get re-treated. Here, it's not just the complete responders who were re-treated; it was those who had stable disease or progressed. The average amount of time between treatments was 6.3 months.

What does this tell us? To recap, it suggests that those patients who get to CR (again, not on a protocol setting) do very well. Eighty-two percent of them are alive at 3 years, and about 73% of them at 3 years did not require other therapy. But again, if patients progress or are progressing on single-agent PD-1 blockade, the likelihood of re-responding to PD-1 blockade is not high. In my view, it sets us up to think that combination checkpoint blockade may be the best way to go subsequently.

This is Dr Jeffrey Weber. Thank you for your attention.

Jeffrey S. Weber, MD, PhD, is deputy director of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center and co-director of its Melanoma Research Program.

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ADVANCES IN MELANOMA SURVIVAL

Advances that emerged from 2007 – 2016 in the treatment of melanoma, including targeted agents, immunotherapy, and new radiotherapy techniques, led to significant improvement in overall survival for patients with melanoma and brain metastases, according to findings from a large population-based cohort study.

The 2-year survival rate doubled during that period, the researchers note: it was 13.8% for patients treated from 2013 – 2016, compared to 6.4% for patients treated from 2007 – 2009 (adjusted hazard ratio for the 2-year survival comparison, 0.65).

The study included 1096 melanoma patients who underwent radiotherapy, surgical excision, or both for brain metastases in Ontario, Canada, between January 1, 2007, and June 30, 2016.

During the study period, there was "a substantial increase in the use of new therapeutic agents," the authors note.

In initial period, from 2007 – 2009, only eight patients (2.5%) received BRAF and MEK inhibitors or immunotherapies, compared with 247 patients (53.7%) in the period from 2013 – 2016.

The study also showed that use of whole-brain radiotherapy (WBRT) decreased from 75.5% the period 2007 – 2009 to 52.0% in the period 2013 – 2016 (P < .001).

At the same time, the percentage of patients who initially received partial-brain radiotherapy techniques, such as gamma knife stereotactic radiosurgery, three-field intensity-modulated radiotherapy, or volumetric modulated radiotherapy, increased from 3.4% to 21.3% during those respective periods.

The study was published online July 6 in JAMA Network Open.

The findings suggest that innovations in systemic therapy and radiotherapy during the past decade were associated with improvements in clinical outcomes, the researchers conclude.

"This is good news for people affected by melanoma brain metastasis, a group with historically a very poor prognosis," lead author Timothy Hanna, MD, PhD, of the Cancer Research Institute at Queen's University, Kingston, Ontario, said in an interview.

Despite the advances, more than half of the patients with melanoma brain metastasis continued to receive WBRT in routine practice in the latter period of the analysis. This could be related to substantial disease burden at the time the brain metastasis was first detected or to geographic accessibility to focal brain therapies, the authors speculate.

In addition, during the period 2013 – 2016, many patients did not receive targeted therapeutic agents or immunotherapies.

Although the findings suggest that recent treatment advances have important benefits for people with melanoma brain metastasis, they also highlight "opportunities to further improve outcomes by optimizing the use of these novel treatments," Hanna told Medscape Medical News.

The study was supported by a grant from the Canadian Institutes of Health Research and by funding from the Institute for Clinical Evaluative Sciences and the Ontario Ministry of Health and Long-Term Care. Hanna has received grants from Roche and pilot funding from the Ontario Institute for Cancer Research outside the submitted work. Two coauthors report relationships with pharmaceutical companies, as listed in the original article.

JAMA Netw Open. Published online July 6, 2020. Full text

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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.

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, P = .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, P = .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®.

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