Atezolizumab combination extends PFS in BRAF V600-mutant advanced melanoma
The addition of atezolizumab to cobimetinib and vemurafenib significantly prolonged PFS and conferred durable responses among patients with BRAF V600 mutation-positive advanced melanoma, according to results of the randomized phase 3 IMspire150 study presented at the virtual American Association for Cancer Research Annual Meeting.
The treatment also appeared tolerable, researchers noted.
“Overall, the addition of atezolizumab led to a clinically meaningful benefit compared with cobimetinib and vemurafenib alone,” Grant A. McArthur, MBBS, PhD, FRACP, executive director of Victorian Comprehensive Cancer Centre, head of the molecular oncology laboratory and senior consultant medical oncologist at Peter MacCallum Cancer Centre in Australia, said during the presentation. “The safety profile was consistent with the known risks for each individual drug. There were no new safety signals observed.”
Current systemic treatments for advanced melanoma include immune checkpoint inhibitors and targeted therapy with BRAF and MEK inhibitors for BRAF V600E- or V600K-mutant melanoma. Response rates generally are lower with checkpoint inhibitors than with targeted therapy, but responses tend to be more durable.
Previous studies have suggested that checkpoint inhibitors and BRAF plus MEK inhibitors could work well together.
“Collectively, these data led to the hypothesis that combining checkpoint inhibitors with BRAF and MEK inhibitors may overcome the clinical limitations of individual classes of therapy and potentially lead to more durable responses,” McArthur said.
The study included 514 treatment-naive patients with unresectable stage IIIc or stage IV melanoma and BRAF V600 mutations.
McArthur and colleagues randomly assigned 256 patients to a combination of the anti-PD-L1 antibody atezolizumab (Tecentriq, Genentech/Roche), the MEK inhibitor cobimetinib (Cotellic, Genentech) and the BRAF inhibitor vemurafenib (Zelboraf, Genentech). The other 258 patients received placebo plus cobimetinib and vemurafenib.
Treatment continued until disease progression or unacceptable toxicity. PFS served as the primary endpoint.
Median follow-up was 18.9 months.
Results showed superior PFS in the atezolizumab group (15.1 months vs. 10.6 months; HR = 0.78; 95% CI, 0.63-0.97).
Researchers observed similar objective response rates in both groups; however, median duration of response was longer with atezolizumab than placebo (21 months vs. 12.6 months).
Common treatment-related adverse events in the atezolizumab combination and placebo combination groups included blood creatinine phosphokinase increase (51.3% vs. 44.8%), diarrhea (42.2% vs. 46.6%), rash (40.9% in both), arthralgia (39.1% vs. 28.1%), pyrexia (38.7% vs. 26%), alanine aminotransferase increase (33.9% vs. 22.8%) and lipase increase (32.2% vs. 27.4%).
Common grade 3 and grade 4 adverse events in both groups included lipase increase (20.4% vs. 20.6%), blood creatinine phosphokinase increase (20% vs. 14.9%), alanine aminotransferase increase (13% vs. 8.9%) and maculopapular rash (12.6% vs. 9.6%). Both groups had similar incidence of serious treatment-related adverse events (33.5% vs 28.8%).
About 12.6% of patients in the atezolizumab group and 15.7% of patients in the placebo group stopped treatment because of adverse events.
“The OS data are not yet mature, but it does favor the atezolizumab group so far,” McArthur said. “That will be something that will be followed up with.”– by John DeRosier
Reference:
McArthur GA, et al. Abstract CT012. Presented at: AACR Annual Meeting; April 27-28, 2020 (virtual meeting).
Disclosures: McArthur reports reimbursement of costs for clinical trials to his institution from Array BioPharma and Genentech/Roche. Please see the abstract for all other researchers’ relevant financial disclosures.
Perspective
Back to TopThe combination of kinase inhibitors and checkpoint inhibitors could be a fantastic idea, because kinase inhibitors would liberate the gold mine of tumor antigens present in the tumor cells so that the immune system can see them if enabled by a checkpoint inhibitor.
As we have seen in trials presented at AACR, triple therapy with immunotherapy plus kinase inhibitors is superior to kinase inhibitors alone.
The most impressive part of the result is the durability of response and the tail on the PFS curve. This is perhaps an expected result based on the tails we see with checkpoint blockade alone.
Another big point is that, since these trials started, the standard of care for these patients has changed. That’s based on the remarkable benefit of giving combined checkpoint blockade with checkpoint inhibitors targeting PD-1.
The real reason this abstract is interesting for a translational scientist is that is offers an opportunity to answer whether MEK-plus-BRAF inhibition releases a gold mine of tumor antigens. The answer is, we don’t know for sure. But, we have hints that it could. One is the T-cell infiltrate is known to increase in patients who get just the kinase inhibitors, so they are going from “warm” to “hot” tumors. Furthermore, there is a side benefit of MEK inhibition — it can increase the expression of HLA class 1 molecules in tumor cells. So, in theory, it could improve antigen presentation to T cells.
I am quite excited by the development of technology that allows us to obtain tumor samples in a trial like this and study them much more accurately using single-cell RNA sequencing and spatial transcriptomics.
Another possible explanation for the benefit seen here is the hypothesis of patient-to patient variability, which shows some patients benefit because they respond better to drug A and others respond better to drug B without there being any synergy. Time will tell whether that is true or not.
Immuno-oncology combinations with kinase inhibitors have already spread to kidney cancers, and there is the possibility this will work in prostate cancer.
Perspective
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These results appear to confirm an important and favorable immunomodulatory interaction between double MAPK inhibition and immune checkpoint blockade. A previous trial that used a similar design showed comparable results in a smaller, randomized phase 2 design with dabrafenib (Tafinlar, Novartis) and trametinib (Mekinist, Novartis) plus pembrolizumab (Keytruda, Merck) or placebo, but that trial was insufficiently powered to demonstrate significant benefits for the combination. In the current trial, what is most interesting and may lead to statistically significant survival benefit for the combination is the late separation of the OS curves, suggesting that after a period in which the molecularly targeted therapies are the primary drivers of benefit, the immunotherapy effect kicks in and predominates.
Lacking in these studies was a cohort of patients randomly assigned to the immunotherapy alone, either single agent PD-1 blockade or the currently best available immunotherapy for melanoma, which is a combination of ipilimumab (Yervoy, Bristol-Myers Squibb) and nivolumab (Opdivo, Bristol-Myers Squibb) either at standard or reversed doses that are associated with comparable activity and less toxicity. It also will be very important to understand sequence questions because OS benefit can only occur if patients who progress on the protocol regimen do not achieve equal benefit from whatever therapy they receive after progression. Conversely, it would be important to know whether sequences rather than combinations can provide similar or greater benefits at the cost of less toxicity, as well as better ability to identify and manage toxicities.
The data have been reported for both the investigator-assessed outcomes and those of an independent review committee, which essentially always comes up with slightly less favorable results in all cohorts compared with the investigator assessments. It doesn’t mean the investigators are biased or dishonest but may simply mean that the investigators know the clinical picture and may exercise their judgment in the interpretation of questionable lesions that may arise on tumor assessments. This is particularly important for reactive inflammatory nodes that occur frequently in patients on immunotherapy regimens or for transient abnormalities that turn out to be infectious or otherwise nonmalignant.
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