ASCO Preview: Bristol PD-1 Data Spur Hopes For Double Immunotherapy

Immune checkpoint antibodies feature prominently in American Society of Clinical Oncology annual meeting program, showing promise in a range of cancers. Bristol showcases data for Yervoy in combination with its anti-PD-1 nivolumab in melanoma, while Roche unveils extensive early results for its anti-PD-L1 MPDL3280A.

Early data supporting combination use of Bristol-Myers Squibb Co.’s anti-CTLA-4 drug Yervoy (ipilimumab) with the firm’s investigational anti-PD-1 antibody nivolumab is spurring talk of yet another paradigm change in treatment in advanced melanoma.

Nivolumab (BMS-936558) is one of the most advanced members of a new class of biologics targeting PD-1, or programmed death-1, which is one of a series of immune checkpoints that can be manipulated to affect mutations that drive cancer (Also see "Immune Checkpoint Blockade: The New Big Idea In Cancer" - Pink Sheet, 29 Apr, 2013.). CTLA-4 is part of the same family of checkpoint molecules.

PD-1 regulates activity of T-cells, switching cancer-killing activity on and off as needed. But cancer cells can adapt through the expression of the protein PD-L1, which binds to PD-1, so the T-cells are not able to do their job. A range of drugs have been developed to block this process by targeting either PD-1 or PD-L1 and are being positioned to play an important role in treating a range of cancers, including melanoma.

The first Phase I data for nivolumab was eagerly received at ASCO in 2012 (Also see "Bristol’s New Anti-PD-1 Immunotherapy An ASCO High Point" - Pink Sheet, 11 Jun, 2012.). Since then, Bristol has moved aggressively to advance the program.

The firm is betting that anti-CTLA4 and anti-PD-1 are complementary immunotherapy mechanisms, and is set to start the Phase III CheckMate-067 trial of the combination in first-line advanced melanoma in June. The pivotal trial has three arms, allowing comparison of the combination (nivolumab 1 mg/kg with Yervoy 3 mg/kg) to nivolumab/placebo and Yervoy/placebo. Success with the combination could position Yervoy as a partner for other oncologics in addition to its own nivolumab.

The American Society of Clinical Oncology selected Phase I results for the Yervoy/nivolumab combination in a Phase I melanoma study, as well as Phase I data forRoche/Genentech Inc.’s engineered anti-PD-L1 antibody MPDL3280A in a range of cancers, as highlights out of thousands of abstracts to be presented at its annual meeting from May 31 to June 4.

Melanoma has already undergone a revolution in care triggered by the 2011 approvals of Bristol’s Yervoy and Roche’s BRAF inhibitor Zelboraf (vemurafenib), not to mention combinations of MEK with BRAF inhibitors on the way, but ASCO President Sandra Swain is expecting another change in the standard of care.

“The study is clearly proof of principle that concurrent use of two immune checkpoint antibodies can change the treatment paradigm for advanced melanoma,” Swain said during a May 15 press briefing ahead of the meeting, commenting that the rapid, lasting responses for the Yervoy/nivolumab combination were “truly remarkable” and the best seen with immunotherapy..

Bristol’s study tested a variety of regimens in 86 patients previously treated with up to three therapies, including different doses and concurrent vs. sequential treatment regimens.

The objective response rate for 17 patients treated with the dosing regimen being tested in the CheckMate trial (1 mg/kg nivolumab and 3 mg/kg Yervoy) was 53% with a complete response rate of 17%, investigator Jedd Wolchok reported during the ASCO briefing. In comparison, Yervoy and nivolumab as single agents in other trials had shown objective response rates of 11% and 41% respectively, with complete response rates of under 3%.

“What was unique in our experience was that most of these responding patients had rapid and deep regressions, with many showing more than 80% tumor regression by the time of the first scans,” said Wolchok, an oncologist at Memorial-Sloan Kettering.

The ORR rate for the optimal dose was lower than investors’ expectations of 60%, while the CR rate was in line or better than expectations, ISI Group analyst Marck Schoenebaum observed in a May 15 research note.

However, the analyst highlighted the importance of details in the results, such as the impressive 41% of patients (7 of 17) in the optimal dose that achieved more than 80% tumor regression, which is close to a complete response. The depth of the response is “pretty incredible,” he concluded.

Overall, in all concurrent cohorts, the ORR rate was 40% – similar to what has been seen with nivolumab alone – with a complete response rate of about 10%. And 90% in the concurrent arms continued to respond as of follow-up in February. The combination also showed activity in patients who had received Yervoy prior to the study.

As for safety, adverse events were in line with what has been known about the drugs as single agents and were manageable with standard protocols, Wolchok reported. Wary of additional toxicities for the combination, the trial was designed for dosing to be slowly scaled up. The adverse event rate for patients in the concurrent arms (n=53) was 53% and mainly consisted of asymptomatic liver and lipase abnormalities. For the 33 who had sequential dosing, the rate of Grade 3-4 adverse events was 18%, again with the most common being asymptomatic lab abnormalities.

The nivolumab/Yervoy combination is also being tested in earlier-stage trials in cancers of the kidney and lung.

Roche Advances Anti-PDL1 In Lung

Safety and efficacy of Roche’s engineered anti-PD-L1 antibody MPDL3280A were also highlighted during the ASCO press briefing.

Investigator Roy Herbst presented results for the drug in a large Phase I study of multiple tumor types – melanoma, lung cancer, kidney cancer, colorectal and gastric cancer – in patients who had progressed after other treatments. Efficacy data was presented for 140 patients and safety results for 171.

MPDL3280A was administered intravenously every three weeks. Overall, the response rate was 21%. Further analysis showed that in those who tested positive for PD-L1, the overall response rate was higher at 36% vs. to 13% for those who were negative for PD-L1. Of the responders, the majority had lasting effects – with 26 of 29 continuing to have a response as of the last follow-up.

“The fact that this drug was active in such a variety of tumors suggests that PD-L1 is part of a universally or generally important immune mechanism,” ASCO said in a statement about the trial results.

Overall, Grade 3-4 adverse events from all causes occurred in 43% of patients. But in further analysis to be presented in Chicago, investigators determined that only 13% of those reports were due to the test drug. Furthermore, the immune related adverse event rate was only 2%, said Herbst, chief of oncology at Yale-New Haven’s Smilow Cancer Center.

“We could keep going higher and higher on dose and there were no dose limiting toxicities or treatment related deaths. This is good news,” Herbst said.

Roche will be presenting several oral presentations on MPDL3280A at the ASCO meeting all from the same Phase I trial, with breakdowns by tumor type as well as biomarker data that could help determine eligibility for treatment.

Based on the results, Roche intends to begin a program of pivotal studies in non-small cell lung cancer that will include development of a companion diagnostic.