On day 2 of the 2015 AACR annual meeting we learned the results of some long-awaited clinical trials for immunotherapies, and got to hear several high-profile members of CRI’s leadership give plenary talks to a packed-to-overflowing crowd in the massive Philadelphia Convention Center.
Antoni Ribas, M.D., Ph.D., of UCLA’s Jonsson Cancer Center, and a member of our Clinical Trials Network as well as a CRI-SU2C Dream Team grantee, unveiled the results of a phase III clinical trial with Merck’s anti-PD-1 drug pembrolizumab (Keytruda) in patients with advanced melanoma. As I reported in a previous post, the trial directly tested the efficacy of pembro versus ipilimumab—the current standard of care for this condition. The trial was stopped early, last month, because the study endpoints were met. Today, the final results are in, and the upshot is that pembrolizumab conferred better overall survival, with less toxicity, than ipilimumab. Risk of death was reduced by about 35% for patients being treated with pembro compared to ipi. Superior performance of pembro over ipi was shown for all patient subgroups (except for patients with PD-L1 negative tumors, where sample sizes were small). According to Ribas, the results support the use of pembrolizumab for advanced melanoma regardless of whether patients have received prior ipilimumab treatment. Pembrolizumab is currently FDA-approved for the treatment of advanced melanoma that has failed prior treatment with ipilimumab.
These results were discussed by Jedd D. Wolchok, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center, who is also CRI’s clinical director. Wolchok praised the study's careful design and impressive results, while noting the interesting finding that PD-L1-negative patients can still respond to anti-PD-1 therapy in many cases. He added that it is perhaps too soon to predict how these results will change standard of care for advanced melanoma. After all, as he noted, results of a clinical trial directly comparing the combination of nivolumab and ipilimumab (both made by the drug company Bristol-Myers Squibb) to ipilimumab alone, will be unveiled tomorrow here at AACR, and so far the combination has performed quite well. Wolchok is one of the principal investigators on that trial. Both clinical efficacy and safety/toxicity are likely to be important considerations when evaluating these various drugs and drug combinations.
Today we also learned the results of other trials testing pembrolizumab in two additional cancer types: mesothelioma and non-small cell lung cancer (NSCLC). Evan W. Alley, M.D., Ph.D., of the University of Pennsylvania, presented data from a phase Ib study showing that pembro was well tolerated in patients with mesothelioma and was associated with response rates that were better than historical response rates with second-line chemotherapy. As Alley pointed out, there is currently no FDA-approved therapy for mesothelioma patients who fail standard chemo, besides more chemo, so these results were welcome news.
The results of the pembro lung cancer trial were presented by Edward B. Garon, M.D., of UCLA. This was a phase Ib study, the early results of which led to pembrolizumab being given “Breakthrough Therapy” status by the FDA last year. Based on those promising results, the study investigators expanded the trial to include a total of 495 patients with NSCLC. In addition to testing the efficacy of the drug, the investigators also wished to draw conclusions about the role of PD-L1 expression as a biomarker of response. PD-L1 is the binding partner of the PD-1 receptor. PD-L1 is often found on cancer cells that are under immune attack, and represents an attempt on cancer’s part to evade immune destruction. Results of the trial indicate that those patients with high levels of PD-L1 expression were more likely to respond to pembro. The overall response for all patients was 19.4%, while the response for those patients with high PD-L1 expression was 45.2%. D. Ross Camidge, M.D., of the University of Colorado, noted that these findings could be used to help make treatment decisions for patients. By taking a patient’s PD-L1 expression into account, for example, one could decide whether pembro or a targeted therapy might make sense as first- or second-line treatment. Whether PD-L1 expression is an adequate predictor of which cancer patients are likely to respond to PD-1/PD-L1-targeting therapies is an ongoing question in the field, and the verdict is not yet in.
The other big news of the day, on the immunotherapy front, was the report of results of a phase I clinical trial of mesothelin-targeted chimeric antigen receptor (CAR) T cells. Janos L. Tanyi, M.D., Ph.D., of the University of Pennsylvania School of Medicine, presented results for his team, which also includes CRI-funded scientists Gregory Beatty, M.D., Ph.D., and CRI Scientific Advisory Council member Carl June, M.D. As our CEO and director of scientific affairs Jill O’Donnell-Tormey, Ph.D., pointed out in a previous blog post, this study is one of the first to look at the safety and efficacy of CAR T cell therapy against a new antigen in a new context—mesothelin, in the context of solid tumors. The results of the study presented today were clear: mesothelin-targeted CAR T cells did not induce any severe side effects and the methods employed to make and administer the CAR T cells were 100% feasible. According to Michel Sadelain, M.D., Ph.D., of Memorial Sloan Kettering and CRI's clinical trials network, who was not involved in the trial, the results gave him “cautious optimism for CAR therapy in (some) solid tumors.” Several other trials using mesothelin-targeted CAR T cells are under way at Penn, the National Cancer Institute, and Memorial Sloan Kettering.
As I mentioned in my post yesterday, a big question in the field right now is which antigens in cancer represent good targets for immunotherapy. Mesothelin is a normal body protein that is often upregulated in cancer. Since it is not absolutely specific to cancer, there is a danger for off-target immunotoxicity. Another approach is to use antigens that are truly specific to cancers—so-called neoantigens, the product of mutation. CRI Scientific Advisory Council associate director Robert Schreiber, Ph.D., gave a plenary lecture on the subject of using neoantigens to create a truly “personalized immunotherapy.” For a description of the approach, check out this previous blog post we wrote about Schreiber’s groundbreaking work.
The evening concluded with an AACR Cancer Immunology (CIMM) Working Group Town Hall Meeting and Reception, which CRI co-sponsored this year. The standing-room-only hall was full of AACR attendees eager to learn more about the field of cancer immunology. Outgoing chairperson, Nina Bhardwaj, M.D., Ph.D., a member of CRI’s Scientific Advisory Council and clinical trials network, described the intensifying interest the scientific community has in cancer immunology, as shown through both a steady increase in CIMM Working Group membership and the broad diversification of specializations represented in the membership, with bioinformatics and cancer biology as leading growth segments. Incoming chairperson, Pamela S. Ohashi, Ph.D., FRSC, honored Dr. Bhardwaj with a plaque of recognition for her contributions to the cancer immunotherapy community. CRI associate director Glenn Dranoff, M.D., formerly of the Dana-Farber Cancer Institute and now at Novartis, who was also editor-in-chief of the joint CRI-AACR scientific journal Cancer Immunology Research, gave an overview of the publication’s offerings, with particular emphasis on the journal’s high quality of primary research articles and educational primers on leading concepts in cancer immunology. CRI CEO and director of scientific affairs, Jill O’Donnell-Tormey, Ph.D., presented an overview of CRI’s mission, history, programs, and impact, and chaired the remainder of the meeting, introducing the scientific portion of the evening, featuring: E. John Wherry, Ph.D., of the University of Pennsylvania, a former CRI-funded investigator who described molecular mechanisms of T cell exhaustion, a key consideration in developing immunotherapeutic strategies; Ana C. Anderson, Ph.D., of Harvard Medical School, who described the growing landscape of immune checkpoint receptors as therapeutic targets and who also touched on growing attention to agonists that stimulate immune activity, such as OX40 and GITR (both targets that CRI is currently studying in its Clinical Accelerator program); and Holbrook E. Kohrt, M.D., Ph.D., of Stanford University, who discussed intratumoral environment and strategies to unlock systemic anti-tumor immune responses.
Besides all the great data that demonstrate the power of immunotherapy, one other thing has become increasingly clear at AACR: if you plan to attend an immunotherapy session, you’d better get there early or you won’t find a seat.
Check back tomorrow for updates from Day 3 of AACR.