Today we learned the long-awaited results of a phase III trial of a combination of two checkpoint inhibitors for the treatment of advanced melanoma, as well as some promising results from early phase studies of immunotherapies for brain cancer.
A New Standard for Melanoma
Two years ago at ASCO, Jedd D. Wolchok, M.D., Ph.D., chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center and CRI’s clinical director, presented data from a phase I trial of a combination of two checkpoint inhibitors, ipilimumab (Yervoy®) and nivolumab (Opdivo®), in advanced melanoma. The impressive results showing rapid and deep regression of patient tumors generated a lot of buzz among oncologists. At the time, the idea of combining these drugs was relatively new—supported by studies in mice, but not yet tested in humans. Today, these two drugs seem poised to set a new standard of care for this deadly disease.
As part of the plenary session today, Dr. Wolchok presented the results of a large phase III trial of the ipi + nivo combination in advanced melanoma. Called CheckMate 067, the trial accrued 945 patients to receive one of three possible treatments: ipi + nivo in combination; nivo alone; or ipi alone. The results showed that the ipi + nivo combination had a “highly statistically significant impact on progression-free survival” compared to nivo or ipi alone, Dr. Wolchok said. Progression-free survival (PFS) means the length of time that patients experienced no worsening of their disease. For the combo, nivo, and ipi arms, the PFS was 11.5 months, 6.9 months, and 2.9 months, respectively. The objective response rate was 57.6%, 43.7%, and 19%, respectively. And the rate of complete responses was 11.5%, 8.9%, and 2.2%. Data on overall survival are not yet available since the study is new.
In some ways, these results were expected, given the effectiveness of the combination demonstrated in earlier phase I and II trials. However, the previous trials were relatively small, and did not directly compare each treatment in a head-to-head manner as this trial did. This large phase III trial provides hefty support to the value of the combination as a treatment for advanced melanoma, and sets the stage for review by the FDA for approval.
The combination is not without toxicities. A higher number of grade 3 and 4 adverse events occurred in the combo group than in the nivo or ipi groups. But the toxicities were manageable with treatments like steroids, and importantly there were no treatment-related deaths in the combo group. A paper describing these results more fully was published today in the New England Journal of Medicine.
So will ipi + nivo become the new standard of care for advanced melanoma? According to Michael Atkins, M.D., of the Lombardi Comprehensive Cancer Center at Georgetown University, who provided commentary on the results that Dr. Wolchok presented, that possibility seems likely—with one caveat. He thinks it’s likely that the combo will be the preferred choice when patients are well enough to endure the associated toxicities of this approach; when a patient is too frail or toxicity is a concern, then nivolumab alone (or another PD-1-blocking antibody, such as pembrolizumab [Keytruda®]) would be recommended.
One aspect of the trial remains a bit controversial: whether a patient’s PD-L1 status can usefully inform treatment decisions. As Dr. Wolchok pointed out, the combination of ipi + nivo seems to work well for both PD-L1-positive and PD-L1-negative patients. (This was shown in a phase II trial, the results of which were presented in April at the annual meeting of the American Association for Cancer Research and updated here at ASCO yesterday.) However, the results of the phase III study suggest—though they do not prove—that patients who are PD-L1-positive may benefit equally well from nivo alone as from the ipi + nivo combination. Stated another way, the combo might do the most good for patients who are PD-L1-negative, whereas treatment with nivo monotherapy might be sufficient for patients who are PD-L1-positive. And since nivo alone has far fewer side effects than the combination, this could be a reasonable decision for a patient and his or her doctor to make. But as Dr. Atkins pointed out, we won’t know this for sure until we see the data on long-term survival to see if the two treatments really are comparable for patients who are PD-L1 negative.
Nevertheless, Dr. Atkins drew a clear conclusion from the study results: ipilimumab alone can no longer be considered standard of care for advanced melanoma. In his words, we’ve reached “a new standard for melanoma.”
As for which PD-1-blocking drug is the better choice—nivolumab (made by Bristol-Myers Squibb) or pembrolizumab (made by Merck)—Dr. Atkins said the two medications are very similar in terms of efficacy and side effects. Given that, the decision to use one or the other drug would likely come down to other considerations, such as, for example, cost.
Immunotherapy for Brain Cancer
While melanoma took center stage today, there were also some important developments in immunotherapy for glioblastoma multiforme (GBM), a deadly type of brain cancer. Newly diagnosed GBM patients live, on average, just 15 months with current standard of care therapies, which may include surgery, radiation, chemotherapy, and targeted therapy. More and more, oncologists are pinning their hopes on immunotherapies to help improve these grim survival odds.
David Reardon, M.D., clinical director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute and a member of CRI’s clinical trials network, presented data from a phase II trial of a cancer vaccine called rindopepimut (Rintega®) given along with the standard-of-care drug bevacizumab (Avastin®) to patients with recurrent GBM. The study showed that rindopepimut + bevacizumab improved overall survival compared to bevacizumab alone (45% vs. 31% of patients alive at 12 months). As Dr. Reardon pointed out, rindopepimut is the first immunotherapy to show an improvement in overall survival for patients with GBM.
The particular GBM patients treated in this study have a genetic mutation in their tumors called EGFRvIII. This is a mutated version of the epidermal growth factor receptor (EGFR), which as a result of the mutation remains permanently stuck in the “on” position and leads to more aggressive tumor growth and a worse prognosis in patients. About 30% of GBM patients have the EGFRvIII mutation. Rindopepimut, made by the pharmaceutical company Celldex Therapeutics, is a 14 amino acid peptide coupled to an adjuvant molecule called keyhole limpet hemocyanin that binds to EGFRvIII and sparks an immune response against it. Since EGFRvIII is only found in GBM cells, it can be safely targeted with the vaccine without causing toxicity to normal tissues. The FDA granted rindopepimut “Breakthrough Therapy” status in February of this year, based in large part on earlier results from this phase II study, called ReACT. A large phase III trial of rindopepimut for patients with GMB has finished accrual and results are currently being analyzed.
While rindopepimut appears to be a promising treatment option for patients with EGFRvIII-positive GBM, there is still a great need for immunotherapy options for other GBM patients. To that end, one approach that researchers are exploring is another form of cancer vaccine that targets a broader set of tumor-associated antigens. Orin Bloch, M.D., from the Feinberg School of Medicine at Northwestern, presented results from a phase II trial of a vaccine called HSPPC-96 (Prophage) given to patients with newly diagnosed GBM following surgery and radiation. Prophage is a heat shock protein (HSP)-based vaccine, an approach to cancer vaccines that was developed by former CRI postdoctoral fellow and now Scientific Advisory Council member Pramod Srivastava, M.D., Ph.D. HSPs are proteins, found in all cells in the body, that act as shuttles and chaperones for other proteins. They can be used to package the entire suite of antigens from a cancer cell into a vaccine. They also have the added benefit of serving as their own adjuvant by interacting with Toll-like receptors on immune cells. The results of this trial showed that patients treated with the HSP vaccine had an overall survival of 23.8 months, as compared to about 16 months for patients treated with standard of care therapy including surgery, radiation, and chemotherapy.
The study investigators then looked more closely at distinct subsets of patients to see if any responded better or worse to the vaccine. They found that patients whose circulating immune cells had high levels of a protein called PD-L1 lived less long than patients with low levels of PD-L1. As discussed in my blog post yesterday, PD-L1 is a binding partner for the PD-1 checkpoint on immune cells. PD-L1 engages the brake on immune cells and shuts down the immune response against cancer. The fact that patients with high PD-L1 expression did worse than those with low PD-L1 suggests that there could be a role for combining PD-1/PD-L1 checkpoint inhibitors with vaccines for patients with GBM. And in fact, the Cancer Research Institute is funding a phase II clinical trial of the PD-L1 checkpoint inhibitor MEDI4736, made by MedImmune/AstraZeneca, in patients with GBM. Preliminary results of that trial will be presented by Dr. Reardon, of Dana-Farber, tomorrow afternoon.
Finally, it seems fitting to report today that James P. Allison, Ph.D., the person who can justly be considered the father of checkpoint blockade therapy, was given this year’s Science of Oncology Award from the American Society of Clinical Oncology. In his award lecture given this morning, Dr. Allison described the research that led to a paradigm shift in cancer immunotherapy. Rather than trying to “turn on” the immune response to fight cancer, perhaps what was needed was to “release the brakes” on the immune system, to unleash a pre-existing immune response against cancer. This approach, known as checkpoint blockade, has become the foundation of a new and powerful way to treat cancer, one that is bringing the word “cure” into reach for more and more patients. Dr. Allison is chair of the Immunology Department at The University of Texas MD Anderson Cancer Center and also the director of the Scientific Advisory Council of the Cancer Research Institute, and we are happy to have him.
Check back tomorrow for more updates from ASCO.