PD-1 BLOCKADE FOR NSCLC

SYDNEY — Early promising results with immunotherapy are making these "exciting times" in the treatment of non-small cell lung cancer (NSCLC), several experts commented here at the 15th World Conference on Lung Cancer.

"Harnessing the immune system holds considerable promise in the treatment of this disease," said Peter Ellis, MBBS, MMed, PhD, from McMaster University in Hamilton, Ontario, Canada.

Dr. Ellis was discussing abstracts on 3 investigational immunotherapeutics: nivolumab (under development by Bristol-Myers Squibb); MK-3475 (also known as lambrolizumab, Merck & Co); and MPDL-3280A (Genentech/Roche). All 3 products act on the programmed death (PD) pathway, but at slightly different points — nivolumab and MK-3475 are both anti-PD1, whereas MPDL-3280A is anti-PDL1.

Clinical results from early phase 1 trials with these drugs have been so promising that all 3 products went immediately into large phase 2/3 trials, some of which are testing each agent alone vs docetaxel.

There are high hopes that immunotherapy in NSCLC will make an impact that echoes the success of immunotherapy in melanoma. That was achieved with a different immune checkpoint blocker ipilimumab (Yervoy, Bristol-Myers Squibb), a CTLA-4 inhibitor. The latest data with this agent show that some patients with metastatic melanoma patients are living for 10 years, and it appears that treatment with ipilimumab had apparently reset their immune system.

Nivolumab: Durable Responses, Landmark Survival

The most data in NSCLC so far has been accumulated for nivolumab, which has shown long-lasting responses and "landmark" survival, said Julie Brahmer, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore.

She presented further details from an expanded phase 1 dose-ranging trial in 129 advanced pretreated NSCLC patients, which was previously reported this year at the annual American Society of Clinical Oncology meeting.

Across all the nivolumab doses tested, responses were seen in 17% of patients (22 of 129), but the best responses (24%) were seen with the 3 mg/kg dose, and this has been selected for further study.

The responses were rapid, Dr. Brahmer said; 50% of patients (11 of 22) demonstrated response at first tumor assessment (8 weeks).

The responses were also durable, with an estimated median response duration of 74 weeks, and about half of these responses are still ongoing (12 of 22 patients). Three patients who stopped therapy continue to have a response more than 24 weeks after discontinuation, and none have progressed, Dr. Brahmer said.

Survival benefit was demonstrated by "landmark" overall survival rates of 42% at 1 year and 24% at 2 years, Dr. Brahmer commented. Median overall survival was 14.9 months with the 3 mg/kg dose, and was similar across all histologies.

Drug-related adverse events affected skin (reported by 16% patients), gastrointestinal (12%), and the pulmonary system (7%). Drug-related pneumonitis occurred in 6% of patients (8 of 129), and this was severe (grade 3/4) in 3 patients, resulting in 2 deaths early in the trial. Since then, early management strategies were introduced to deal with this adverse event.

MK-3475: Patients Continuing to Respond

Data on MK-3475 come from a phase 1 study of 38 patients with advanced NSCLC who had been treated with at least 2 prior therapies, and were presented by Edward Garon, MD, from the David Geffen School of Medicine at UCLA in Los Angeles.

Responses were seen in 24% of patients, and were seen early, he said. Most of the responses were seen by the 9 week assessment. One patient had a partial response after 1 dose, Dr. Garon reported. At a median follow-up of 9 months, the median duration of response has not been reached, and 7 of the 9 responding patients are continuing on therapy.

The median overall survival was 51 weeks, Dr. Garon reported. Median progression-free survival has not been reached and will be at least 52 weeks, he said.

The most common drug-related adverse events were fatigue, rash, and pruritus (16% each), and diarrhea (13%). There was 1 case of grade 2 pneumonitis, 1 case of grade 3 pulmonary edema, and there were no drug-related fatalities, he reported.

Phase 1 results with MK-3475 in melanoma were published recently (N Engl J Med. 2013;369:134-144).

MPDL3289A: "Game Changer" in NSCLC?

Data on MPDL3289A were reported recently at the European Cancer Congress by Jean-Charles Soria, MD, from the Institut Gustave Roussy in Villejuif, France, who suggested this drug could be a "game changer" in NSCLC.

The results come from a phase 1 study in 52 patients with advanced pretreated NSCLC, and here an update was presented by Leora Horn, MD, from Vanderbilt University Medical Center in Nashville, Tennessee, who reported on 41 patients evaluable for efficacy.

Responses were seen in 22% of patients, and all responses were ongoing or improving at data cutoff, she said. The 24-week progression-free survival was 46%.

There was a better response seen in smokers (23%; 8 of 35 patients) than in never smokers (17%; 1 of 6 patients), she noted.

Treatment-related grade 3/4 adverse events occurred in 12% of patients, including fatigue (4%) and hypoxia (4%), and there was 1 case of an immune-related hyperglycemia in a patient who developed diabetes mellitus. There were no cases of grade 3 to 5 pneumonitis or diarrhea, she said.

Response Rate Consistent Across the Studies

Discussing all 3 abstracts after their presentation here, Dr. Ellis said the response rate of more than 20% was seen consistently across all these trials. The responses are seen early and are durable, and continue after treatment discontinuation.

The toxicity seen in all of these studies was "acceptable," he commented, although he noted that there are unique immunological toxicities with these agents.

There is some indication that responses are better in patients who have higher PD1 or PDL1 expression, and this intriguing observation merits further study, he said.

Going forward, questions to be addressed include how long these agents should be used for, and should they be used alone or in combinations with other therapies, he said. There is also a question of when in the treatment of NSCLC they should be used, he said. At present, they are being investigated mostly as a last line of therapy in heavily pretreated patients.

New Treatment Paradigm?

These data were discussed further at the meeting at a satellite symposium sponsored by Bristol-Myers Squibb, which drew a packed audience. The company is a leader in the field of immunotherapy, with ipilimumab already on the market for melanoma, and nivolumab now placed as the most advanced immunotherapeutic for NSCLC.

These 2 agents have also been tested together in melanoma (N Engl J Med. 2013;369:122-133), and produced what were described as "truly remarkable responses." A further study of the combination in melanoma is underway, and the combination is now being investigated in NSCLC. In addition, ipilimumab alone is being tested in a phase 3 trial in NSCLC.

Having clinical experience in treating both melanoma and NSCLC, Michael Millward, MD, professor of clinical cancer research at the University of Western Australia in Perth, noted that the pattern of responses to immunotherapy is "different to what we're used to seeing with chemotherapy and targeted agents."

"We need to be aware of that when treating patients and when designing clinical trials," he said, adding that overall survival should be the end point.

Dispel Myth of Slow Action

Some of the responses seen in melanoma "have been extremely good responses," Dr. Millward said. In addition, many of the responses have been rapid, particularly with the combination of immunotherapies.

"One of the notions that we need to dispel is that immunotherapy is slow-acting," he said. "If you think about it, we wouldn't survive if the immune system took weeks or months to defeat a particular pathogenic invader, and think of acute transplant rejection, when the immune system can destroy an organ within a matter of hours."

"The immune system can act very rapidly, if we know have to manipulate it," he said.

"We need to know more about the immune system, both peripherally and at the interface with the tumor in cancer patients," he said. "And we need to know the influence on the immune system of prior therapies" and not only chemotherapy, but also the effects of targeted therapy, radiation, and surgery.

"We also need to work out when to use immunotherapy in the course of lung cancer," he said. "It may be preferable to use it as early as possible, particularly as we know the outcome for even early-stage lung cancer is not always that good."

The combination of ipilimumab and nivolumab in melanoma has produced some "responses that are rapid, durable, and curative, and we hope that will also be the case in lung cancer, too," he said.

Each of the 3 trials was supported by the company developing the drug under investigation. Dr. Ellis reports serving on the speaker's bureau for Roche. Dr. Brahmer reports consultancy (uncompensated) for Bristol-Myers Squibb and Merck. Dr. Horn reports serving as a consultant to Squibb, and receiving grant/research support from Astellas and Clovis Oncology. Dr. Millward reports consultancy and receiving grant/research support from Roche, Boehringer Ingelheim, and AstraZeneca, and also consultancy for Eli Lilly.

15th World Conference on Lung Cancer (WCLC). Abstracts M18.01 (MPL-3280A), M18.02 (MK-3475), and M18.03 (nivolumab). Presented October 29, 2013.