Welcome to your weekly roundup of approaching clinical readouts. The treatment of Braf-driven melanoma has been transformed by Braf and Mek inhibitors, which produce dramatic responses. Most patients relapse within a year, however, and a big question is whether adding anti-PD-(L)1 to the mix could help more people live longer.
Two phase III trials, being run by Roche and Novartis, are due to yield results before the end of the year, and promise to provide the first robust look at a triple combination strategy in this setting. Earlier studies have hinted at additional benefits with substantially greater toxicity, and clear survival benefits will need to be seen to drive another big step forward.
Still, the success of Opdivo plus Yervoy, a very toxic regimen that has also been responsible for transforming melanoma treatment, shows that some patients are willing to bear substantial risks if a durable response – or perhaps a cure – is possible. Not everyone responds to immunotherapies, however, and this is also likely to be seen in Roche and Novartis's triple studies.
Roche first up
Roche is likely to be first to report. Its study involves Tecentriq, and completed recruitment in the second quarter of 2018; the company tells Vantage that it hopes to file next year.
Meanwhile, Novartis’s Combi-I study is still recruiting, according to clinicaltrials.gov, although that company has said it intends to release results before the end of the year. A spokesperson told Vantage that it was difficult to pin down a more exact timeline given that this is an event-driven study.
This will be the first phase III data seen with Novartis's still-experimental PDR001, or spartalizumab. The drug is something of an unknown quantity and this trial represents a big test of the anti-PD1 antibody.
Both studies have progression-free survival as the primary endpoint, but duration of response and overall survival will be crucial measures of immunotherapy’s contribution.
|Adding to targeted therapy? The numbers to beat|
|Novartis: Tafinlar + Mekinist (n=211)||
Roche: Cotellic + Zelboraf (n=247)
|Progression-free survival (months)||9.3||12.3|
|Overall response rate||66%||70%|
|Median duration of response (months)||9.2||13|
|Overall survival (months)||25.1||22.3|
|Source: US drug labels.|
Another key question is whether these trials can generate a sufficient number of durable responses in a patient group that is likely to see a high drop-out rate. Prior studies in this setting suggest that some very convincing individual results will be seen, but that a statistically significant outcome is not a foregone conclusion.
So far, the most rigorous test of a triple combo in Braf-driven melanoma has been done by Merck & Co. The phase II Keynote-022 study tested Keytruda in combination with Novartis’s Tafinlar and Mekinist, against the double therapy, in 120 Braf-mutant stage III/IV subjects.
At a median follow-up of 9.6 months median PFS was 16.0 months for the triple arm, versus 10.3 for the doublet. Statistically this was a failure, however, as the 0.66 hazard ratio (p=0.042870) did not meet the prespecified significance parameter of a hazard ratio of at most 0.62.
Still, the study was widely considered to contain encouraging signals: on most measures the triple was clearly numerically superior. Median duration of response, for example, was 18.7 months for the triple against 12.5 for the doublet, despite a melanoma severity imbalance.
Notably, however, 40% of patients in the Keytruda arm dropped out because of treatment-related adverse events, against 20% in the doublet. Rates of grade 3-4 adverse events came in at 58% and 27% respectively.
|The triple quest – key studies in Braf-driven, advanced melanoma|
|Roche||Zelboraf + Cotellic +/- Tecentriq||Completed enrolling 513 subjects in Q2 2018||NCT02908672|
|Novartis||Taflinar + Mekinist +/- PDR001||Still enrolling 538 subjects||NCT02967692|
|Merck & Co||Taflinar + Mekinist +/- Keytruda||Phase II study of 120 subjects; failed to hit primary endpoint||NCT02130466|
Source: Clinical trial entries.
Whatever the topline results, these studies will not be the end of the story. Other factors to watch include the order in which these agents are given, which could affect side effects and improve responses. And then of course there is the ever-present issue with immunotherapy: how to find the patients that do respond well.
This becomes particularly relevant to manufacturers that want to persuade physicians and patients to try regimens that carry significant toxicities, and many will hope that these studies help in the search for viable biomarkers.