During the opening clinical plenary of the American Association for Cancer Research (AACR) virtual annual meeting I on Monday, April 27, Memorial Sloan Kettering’s Charles Sawyers, MD served as a discussant and featured thought leader on two phase III BRAF-mutant melanoma trials, providing commentary and a broader outlook on the highlighted clinical trials.
As Chair of MSK’s Human Oncology and Pathogenesis Program, Dr. Sawyers develops molecularly targeted cancer therapy.
Combination Therapy with Checkpoint Blockade
The first clinical trial, led by the Peter MacCallum Cancer Centre, Melbourne, Australia, focuses on triple combination therapy with checkpoint blockade. Dr. Sawyers shared in his discussion that the trial is promising and shows that triple therapy with immune-oncology and kinase inhibitors is superior to kinase inhibitors alone. Regarding these findings Dr. Sawyers said, “I think the most impressive part of that result is the durability of the response: the tail that we are starting to see on the progression free survival (PFS) curve. [This is] perhaps is an expected result based on the tails that we see with checkpoint blockade alone.” However, he did note that difference in PFS seen was based on the investigative review and not the control review, so the investigators will need to reconcile these discrepancies. Since the time this trial was initiated, the standard of care has changed, and patients now receive combined checkpoint blockade.
Continuous vs. Intermittent Therapy
The second clinical trial, led the University of California, San Francisco, CA, focuses on continuous versus intermittent BRAF/MEK therapy. Intermittent therapy is standard with most chemotherapy because continuous therapy can be too toxic. However, Dr. Sawyers clarified that targeted therapy makes continuous 24/7 therapy a viable option because it spares normal tissue from these toxicities. The experts working on this particular study based their rationale on two previous papers in Cancer Cell and Nature. Both papers concluded that continuous BRAF inhibition selects for subclones with mutations that lead to higher ERK output. If you acutely withdraw the inhibitor, you see a rebound in ERK activity that leads to toxicity. The trial highlighted in the discussion was designed to test this hypothesis, and while the preclinical data was compelling, it ultimately failed. Dr. Sawyers contemplated that the right patients might not have been enrolled and that there needs to be a much larger trial to capture more data. He also said that the drug withdrawal schedule may not have tested the preclinical hypothesis adequately and that the long half-life of the MEK inhibitor used in the trial may have been a problem.
According to Dr. Sawyers, there are two key takeaways that we can learn from these trials. The first is that combination immune-oncology plus targeted therapy clearly works in certain contexts (e.g. melanoma, kidney cancer), but we don’t know why yet. The second is that there are several promising preclinical examples to support intermittent or pulsatile therapy, but little clinical evidence. More research will need to be done.