If you were milling about at this year’s American Society for Clinical Oncology (ASCO) conference, held in Chicago from May 30-June 2, you would have heard an endless stream of comments such as: “Can you believe the explosion of immunotherapy?” and “I never thought this was possible.” Nearly every immunotherapy session was standing-room-only and poster presentations had crowds peering to get a look.
Not surprisingly, the biggest news at this year’s conference was the clinical progress being made with checkpoint inhibitors targeting the PD-1 pathway. PD-1, which stands for programmed cell death 1, is the second immune checkpoint pathway currently being targeted with immunotherapies. Like its older sibling CTLA-4, PD-1 is an immune checkpoint on T cells that, when activated, puts the brakes on the immune response. Cancer cells can hijack this checkpoint by binding to the PD-1 receptor on T cells with a ligand called PD-L1, thereby escaping immune destruction. A number of different PD-1 and PD-L1 antibodies, made by several different companies, are currently being evaluated in clinical trials.
Merck’s anti-PD-1 drug pembrolizumab (MK-3475) is currently being investigated in a large a phase I trial for patients with metastatic melanoma and lung cancer. For the 411 melanoma patients enrolled, the 1-year overall survival rate was 69%. Given that the average 1-year survival rate of patients with metastatic melanoma is less than 25%, this represents a nearly triple-fold improvement.
"These are early data, but they tell us we are on to something really important," said Antoni Ribas, M.D., Ph.D., of UCLA (left), who is principal investigator for the study and also a member of CRI’s clinical trials network.
On the basis of these promising early results, pembrolizumab was recently granted a "Breakthrough Therapy" designation by the FDA, which means that the drug will benefit from a faster, more expedited review by the FDA, and could be approved for use as early as October, 2014 as a second-line treatment for melanoma patients who fail frontline treatment with ipilimumab (Yervoy®).
"These are early data, but they tell us we are on to something really important."
The other big melanoma success story came from a trial of Bristol-Myers Squibb’s anti-PD-1 drug, nivolumab, given in combination with ipilimumab. In this trial, which is being led by CRI’s clinical director Jedd Wolchok, M.D., Ph.D., the 2-year overall survival rate for all dose cohorts was 79%. At the most promising dose level (nivolumab 1 mg/kg and ipilimumab 3 mg/kg), the 2-year survival rate was even more impressive—88%. As Jeffrey S. Weber, M.D., Ph.D., of Moffitt Cancer Center noted in his discussion of the presentation, "It doesn’t get better than that in metastatic melanoma."
If there was a theme to take away from this year’s ASCO, it was the expansion of immunotherapy into new and previously unchartered cancer types. A good example was a presentation by Sylvia Adams, M.D., of NYU, showing that triple negative breast cancer (TNBC)—long thought to be an improbable candidate for immunotherapy—is immunogenic after all. Adams found that the number of tumor infiltrating lymphocytes (TILs) correlated with outcome: the more TILs, the longer the survival. These results raise the hope that immune modulation may be enlisted in the treatment of this deadly disease.
Similarly, a wide range of cancers, beyond melanoma, are now being treated in clinical trials with a variety of PD-1 and PD-L1 inhibitors. Robert Motzer, M.D., of Memorial Sloan Kettering Cancer Center, presented results from a phase 2 trial of nivolumab in renal cell carcinoma (RCC), commonly known as kidney cancer. Approximately 20% of a total of 160 patients responded to the treatment, with a 1-year survival rate of about 70%. As Motzer pointed out, those results are better than the results of phase 3 trials for the existing drugs approved for the treatment of RCC.
Also impressive were the results of Genentech’s anti-PD-L1 antibody, MPDL3280A, in patients with urinary bladder cancer (UBC). In a phase 1 trial, this checkpoint inhibitor reduced the size of tumors in 43% of 67 patients with metastatic UBC, according to Thomas Powles, M.D., of the Barts Cancer Institute at the Queen Mary University in London. Based in part on these promising findings, the FDA granted MPDL3280A a “Breakthrough Therapy” designation.
"In a phase 1 study, 80% (28 out of 35) patients showed tumor shrinkage on scans."
Tanguy Seiwert, M.D., of The University of Chicago, presented results of a phase 1b trial of Merck’s pembrolizumab in a cohort of patients with advanced head and neck cancer. The overall response rate was 20%, meaning that 11 out of 56 patients showed either a complete or partial response to the drug. Based on these promising results, an additional 110 patients with advanced head and neck cancer are being recruited to the study.
Naiyer Rizvi, M.D., of Memorial Sloan Kettering, presented results of pembrolizumab in lung cancer. In a phase 1 study, 80% (28 out of 35) patients showed tumor shrinkage on scans. Rizvi called pembrolizumab a "promising new approach" for the treatment of non-small cell lung cancer.
Merck has high hopes for pembrolizumab, which is currently being evaluated in more than 30 different tumor types. If approved by the FDA in October for the treatment of refractory melanoma, pembrolizumab would be the first PD-1 checkpoint inhibitor approved in its class, beating out BMS’s nivolumab in the race to the finish line—or starting line, really, since both drugs will likely have multiple future uses.
While checkpoint inhibitors got most of the attention at ASCO, there were also several exciting presentations on other areas of immunotherapy. In one eye-opening review of recent research, Charles Drake, M.D., Ph.D., of Johns Hopkins, who is also a member of CRI’s clinical trials network, discussed several cancer vaccines that are making progress, including coxsackievirus A21, an oncolytic virus vaccine being studied in late stage melanoma, and NewLink’s algenpantucel-L in pancreatic cancer (HyperAcute® pancreas). The promising findings led him to predict, "Vaccines will rise again." Somewhere, CRI's founding scientific director Lloyd J. Old, M.D., is smiling.