ASCO 2015: Report from Day 4

Today, on day 4, the litany of cancers being treated successfully with PD-1/PD-L1 checkpoint blockade therapy grew longer, with kidney, bladder, and ovarian cancer added to the list.

Immunotherapy for Genitourinary Tumors

Progress in treating genitourinary cancers including kidney and bladder cancer was the subject of a large morning session. As on other days, the talks devoted to immunotherapies garnered the most attention and largest crowds.

Toni Choueiri, MD, of Dana-Farber Cancer Institute, presented results from a study looking at the anti-PD-1 checkpoint inhibitor nivolumab (Opdivo^®) in metastatic kidney cancer. As I discussed in my blog post on day 1, kidney cancer has long been known to be immunogenic—or able to trigger an immune response. But not all bladder cancer patients respond to immunotherapy. Dr. Choueiri and his team wanted to know whether they could detect differences in biological markers between patients on the study who responded to the nivolumab versus those who did not. To do this, they took biopsy samples from patients while they were being treated and then measured levels of a panel of different genes. They found the responders to treatment had distinct changes in gene expression levels indicative of an immune response. Also significant was the finding that patients treated with nivolumab showed an increase in expression of immune checkpoints, such as CTLA-4 and PD-1, while on nivo treatment. This was true even among patients who showed reduction in the size of their tumors. As Dr. Choueiri pointed out, this suggests that a CTLA-4-blocking antibody such as ipilimumab could be combined with nivolumab for even better responses in metastatic kidney cancer, much as has been done with melanoma, as we saw yesterday.

Next up was Daniel Petrylak, MD, of Yale Cancer Center, who discussed results of a Phase Ia trial of the anti-PD-L1 antibody atezolizumab (formerly known as MPDL3280A), made by Genentech/Roche, in patients with relapsed bladder cancer. As Dr. Petrylak pointed out, there are no FDA-approved treatments for patients who relapse after platinum-based chemotherapy, and therefore there is a great need to develop new therapies. Immunotherapies are a very promising approach. Bladder cancer is one of the main cancers, along with lung cancer, for which smoking is a known cause, and as a result tends to have a high ‘mutational load.’ (Smoking damages DNA and causes mutations, or changes in the DNA sequence.) This means the tumors are more likely to be recognized by the immune system as foreign. And in fact, the first immunotherapy to be FDA approved for any cancer—BCG—was approved for bladder cancer, and is still considered standard therapy for this condition. Patients on this trial were separated into two groups: those with higher levels of PD-L1 expression on immune cells in their tumors and those with lower PD-L1 expression on these cells. The trial investigators then looked at which group responded better to anti-PD-L1 therapy. On this trial, patients with high PD-L1 had a response rate of 50%, while those with low PD-L1 had a response rate of 17%. The 1-year survival rate for these two groups was 57% and 38%, respectively. The conclusions were that atezolizumab was well tolerated and had durable activity in bladder cancer. The number of patients in the trial (85 total) was small, so it is impossible to say for sure whether the difference in response between the two groups is statistically significant. However, both groups showed better responses than historical controls with standard chemotherapy. Another bladder cancer trial, this one with pembrolizumab, also showed a favorable response to treatment, including a response rate of 28% (8 of 33 patients).

Noah M. Hahn, MD, of Johns Hopkins, who discussed the three trials of PD-1/PD-L1-blocking antibodies in urogenital cancers, confidently pronounced that the era of chemotherapy for bladder cancer was officially over. “We can’t even see it in the rearview mirror anymore,” he said.

Immunotherapy for Ovarian Cancer

The theme of mutations and PD-1/PD-L1 therapy continued into the afternoon sessions, including one focused on ovarian cancer—the leading cause of death from gynecological cancer in the U.S. The session was co-chaired by Kunle Odunsi, MD, PhD, an oncologist at the Roswell Park Cancer Center, and a member of CRI’s Scientific Advisory Council. Four separate talks were given.

First up was Mary Disis, MD, of the University of Washington, who discussed the results of a Phase IIb trial of the anti-PD-L1 antibody avelumab, made by Merck KGaA/Pfizer, in patients with recurrent or refractory ovarian cancer who had been treated with several lines of prior chemotherapy. The response rate in this heavily pre-treated patient population was 11%.

Andrea Varga, MD, of Gustave Roussy Institute, discussed result of a Phase Ib trial of the PD-1-blocking antibody pembrolizumab (Keytruda^®) in women with advanced ovarian cancer. Similarly, in this trial, the response rate was 11.5%.

The second two talks focused on types of endometrial and ovarian cancers with specific genetic mutations (called POLE and BRCA1/2). The results of both trials showed a clear link between mutational load in the tumors, presence of tumor-infiltrating immune cells, and PD-L1 expression on immune cells in tumors suggesting that these subsets of gynecological cancer could be susceptible to treatment with PD-1/PD-L1-blocking therapy.

Are you detecting a theme here?

Ovarian cancer is one of the hardest cancers to cure with standard approaches. While many women respond well to chemotherapy, and experience rapid and complete remissions with these treatments, the tumors tend to come back. And when they do, they are largely resistant to chemotherapy. Effective immunotherapies for these women are badly needed, and these early trials showing efficacy of PD-1/PD-L1 checkpoint blockade therapies are a promising start.

News for Cancer Patients

The day also featured a panel discussion on the latest news from ASCO that is most relevant for cancer patients. Panelists included ASCO keynote speaker Jedd D. Wolchok, MD, PhD, director of CRI’s clinical program and chief, melanoma and immunotherapeutics services, and Jae Park, MD, a hemotologic oncologist, both at Memorial Sloan Kettering Cancer Center, and Naiyer Rizvi, MD, director of thoracic oncology and director of immunotherapeutics at Columbia University Medical Center. Jill O’Donnell-Tormey, PhD, CEO and director of scientific affairs at the Cancer Research Institute, moderated the discussion, which featured the latest in immunotherapy for melanoma, lung, and blood cancers. We will publish a recording of the panel later this month, so check back for that soon.

Come back tomorrow for updates from the final day of ASCO.