April is the month when clinical researchers usually gather for the annual American Association of Cancer Research (AACR) meeting to share cutting edge data in basic, translational and clinical cancer research. However, due to the COVID-19 virus pandemic, meeting in person was not possible this year and therefore organizers transformed the meeting into two virtual meetings, the first of which was held on April 27-28, 2020. This approach enabled the dissemination of important advances in cancer diagnosis and treatment, and insights into the impact of COVID-19 on cancer care. During the opening clinical plenary session, two randomized clinical trials in advanced BRAF-mutant melanoma were presented.

The introduction of targeted therapy with BRAF and MEK inhibitors and immune checkpoint inhibitors (ICIs) have substantially improved outcomes in patients with advanced melanoma; however, both therapeutic approaches have their limitations. While different combinations of BRAF and MEK inhibitors can yield high overall response rates (ORR) in patients with BRAF-mutated melanoma, the responses are usually short-lived, and the majority of patients develop resistance to therapy. In contrast, response rates are lower with ICIs but are more durable. As these treatments have distinct mechanisms of action and complementary strengths and limitations, there has been interest in combining targeted therapy and immunotherapy, and results from early trials have been promising. In addition, preclinical data indicate that intermittent dosing of targeted therapy may overcome acquired resistance to BRAF inhibitors and extend disease control in BRAF-mutated melanoma.

Results from the randomized phase III IMspire 150 trial that evaluated the efficacy and safety of a combination of vemurafenib (BRAF inhibitor), cobimetinib (MEK inhibitor) and atezolizumab (ICI) as first-line treatment for patients with previously untreated BRAF-mutated advanced melanoma, were presented by Grant McArthur, MBBS, PhD (The Peter MacCallum Cancer Centre in Melbourne, Australia). Patients (n = 514) were randomized to one of two treatment arms: vemurafenib and cobimetinib plus atezolizumab, or plus placebo. Patients assigned to the atezolizumab arm received a 4 weeks run-in with targeted therapy alone. The primary endpoint of the study was investigator assessed progression-free survival (PFS) and secondary endpoints were independent review committee (IRC) assessed PFS, ORR, duration of response (DOR), and overall survival (OS). A statistically significant improvement in median PFS was achieved in patients in the atezolizumab arm versus placebo (15.1 months versus 10.6 months; P = 0.0249). The PFS benefit with the triplet combination was seen across all prognostic subgroups. Interestingly, the IRC assessed PFS favored the atezolizumab arm (16.1 months) versus the placebo arm (12.3 months) although it was not statistically significant (log-rank P = 0.1607). Response rates were very similar between the treatment arms (66.3% versus 65%); however, the triple combination led to a clinically meaningful improvement in DOR at 12 months (21.0 months versus 12.6 months). An interim analysis showed no difference in OS at 12 months but by 24 months OS favored the atezolizumab arm (60.4% versus 53.1%). Importantly, there were no new treatment-related adverse events (TRAEs) recorded; however, pyrexia, elevated liver transaminases and thyroid dysfunction were more common in the atezolizumab arm. Treatment discontinuation and death were similar in both arms. These data indicate that the addition of atezolizumab to BRAF and MEK inhibitors produces a clinically meaningful improvement in DOR and PFS and represents a viable treatment option for patients with advanced BRAF mutated melanoma.

The results were discussed by Charles Sawyer, MD (Memorial Sloan Kettering Cancer Center, New York), who highlighted that the study confirms the superiority of triple therapy over BRAF/MEK inhibition alone, but questioned whether a BRAF/MEK inhibitor comparator arm is still relevant based on standard of care with combined checkpoint blockade. He pointed out that the ongoing phase III trial, DREAMSeq that compares the sequencing of a combination of BRAF and MEK inhibitors with ICIs, may address this question.

The second trial, presented by Alain Algazi, MD (University of California, San Francisco), was a randomized phase II SWOG S1320 study comparing the efficacy of continuous versus intermittent dosing of BRAF and MEK inhibitors in patients with advanced BRAF-mutated melanoma. Patients (n = 206) who responded, or had stable disease, after the first eight weeks of continuous dosing of BRAF and MEK inhibitors, dabrafenib and trametinib, were randomly assigned to an intermittent or continuous dosing arm. Patients in the intermittent dosing arm received treatment on a three weeks off/five weeks on schedule. In contrast to preclinical studies, results from this trial showed that patients in the continuous dosing arm had a significantly higher post-randomization median PFS compared with those in the intermittent arm (9.0 months versus 5.5 months; HR = 1.36; P = 0.063). Dr Algazi noted that this “negative” result for intermittent dosing could be due to differences between preclinical animal models and humans, the longer half-life of trametinib precluding the rapid withdrawal of the drug levels, as well as non-MAPK resistance mechanisms. At the time of data analysis, median OS was the same in both arms (29.2 months). However, after disease progression, OS favored the intermittent dosing arm, although post-study treatments were similar. Dr. Algezi highlighted that the study was not adequately powered to detect differences in survival and therefore the data should be considered as hypothesis generating. While the results of this study generate more questions than answers, findings support current practice of continuous dosing of targeted therapy.

References

McArthur GA, et al. 2020 AACR: Abstract CT012

Algazi A, et al. 2020 AACR: Abstract CT013