Zosia Chustecka

May 29, 2015

CHICAGO, IL — The immunotherapy nivolumab (Opdivo, Bristol-Myers Squibb) has beaten chemotherapy in another subset of patients with lung cancer in the second phase 3 trial to show an improvement in survival compared with docetaxel.

The results were hailed as practice-changing here at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting.

Nivolumab is the new standard of care in patients with previously treated squamous nonsmall cell lung cancer (NSCLC), declared Roy Herbst, MD, PhD, chief of medical oncology at the Yale Cancer Center in New Haven, Connecticut, who acted as discussant for the study. Overall survival was significantly improved, and nivolumab showed significantly less toxicity than docetaxel, he said.

"We now need to move this to frontline therapy in lung cancer," Dr Herbst said.

The latest results come from the CheckMate 057 study, Results released today from the CheckMate 057 study, conducted in 582 patients with advanced nonsquamous NSCLCnonsmall cell lung cancer (NSCLC) who who had progressed on platinum-doublet chemotherapy, . The overall results show that treatment with nivolumab extended median overall survival by 3 months compared with docetaxel (12.2 vs 9.4 months; hazard ratio, 0.73; P = .00155).

However, a subset of patients with high levels of expression of programmed death ligand 1 (PDL-1) showed even great benefit; here the median overall survival was 17.2 to 19.4 months. This is unprecedented in this type of patient population, commented lead author Luis Paz-Ares MD, PhD, from the Hospital Universitario Virgen Del Roccio in Seville, Spain. Usually, patients who are treated with second-line docetaxel have a median overall survival of 8 to 10.4 months, he added.

He noted that although the responses and survival were much lower in the patients who had low PDL-1 expression, some of these patients did respond, so this biomarker is useful as a positive predictor of patients who are likely to respond, but not so useful as a negative predictor of those who are unlikely to respond.

In his discussion of the results, Dr Herbst said the PDL-I biomarker is not yet ready for clinical use.

Response rates were higher in the nivolumab group compared with in the docetaxel group (19.2% vs 12.4%). Responses also lasted significantly longer in the nivolumab group (17.1 vs 5.6 months, on average).

Dr Paz-Ares said he was hopeful that longer follow-up will show that the responses to immunotherapy in lung cancer are long-lasting, as they have shown to be in melanoma.

Already Approved for NSCLC

This is the second phase 3 trial to show a survival benefit with nivolumab. The other was CheckMate 017, which was conducted in patients with advanced squamous NSCLC. This trial has already resulted in the approval of nivolumab for squamous NSCLC in the United States; this indication was also recently recommended for approval in Europe.

These latest results should result in an approval for the nonsquamous subset of NSCLC as well, predicts Dr Paz-Ares. He noted that nonsquamous subset is the larger of the two, accounting for around 60% of all patients with lung cancer, whereas the squamous subset accounts for some 25%. The remainder is made up of SCLC, he commented, which is a different disease.

Immunotherapy has the potential to shift the treatment paradigm of lung cancer, Dr Paz-Ares suggested. Some of the responses that have been seen with nivolumab are unprecendented, he told Medscape Medical News.

In addition, in the other trial in squamous NSCLC, the PDL-1 biomarker appeared to be irrelevant: it was not associated with better responses rates in Checkmate 017.

Nivolumab was well tolerated, and treatment-related adverse events leading to discontinuation were reported in only 5% of patients compared with 15% of those receiving docetaxel.

The adverse effects seen with these immunotherapies are unique: They are immune-related adverse events, and they are much less significant than traditionally used chemotherapy, commented ASCO expert Lynn Schuschter, MD, a medical oncologist at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia.

The durability of these responses is astounding. Dr Ben Creelan

Immunotherapy is a "game changer" in lung cancer, commented Ben Creelan MD, assistant faculty in thoracic oncology at the Moffitt Cancer Center, Tampa, Florida.

Immunotherapy is a leap forward even when compared with targeted therapy, he added, because it can benefit more patients. The results so far suggest that in an unselected population of patients with NSCLC, about 20% will see tumor shrinkage, but about 20% will have stable disease, so the overall clinical benefit is seen in about 40% of patients.

In addition, the responses are long-lasting, whereas a big drawback with the targeted therapies is that the tumor becomes resistant, often within 6 months or so.

"We have been treating lung cancer patients with nivolumab and drugs like it since 2010, and we [have seen] patients since then who are still in remission 5 years later," Dr Creelan said. "The durability of these responses is astounding," he told Medscape Medical News. These patients were participating in early clinical trials and took nivolumab for 2 years only, and yet they remain in remission even though they are no longer taking the drug. "It has really changed the way we talk to our patients about their expectations," he added.

It has really changed the way we talk to our patients about their expectations. Dr Ben Creelan

Docetaxel is the gold standard in second-line treatment of lung cancer, having been approved for that indication in 1999, and nothing has ever beaten it in NSCLC until nivolumab, he said.

And nivuolumab has now done it twice, in two separate phase 3 studies, in both squamous and nonsquamous subtypes of NSCLC.

Nivolumab is also much better tolerated than chemotherapy, he added. "Docetaxel can cause alopecia, nail problems, diarrhea, neuropathy, neutropenia, and fatigue, whereas nivolumab has comparatively fewer side effects," Dr Creelan said.

Patients can get on with their lives and can return to work, and they say they feel and look like normal human beings, he commented. "They aren't defined by their disease anymore as much."

"And the attractive thing is, that they are doing this themselves," he added. Their immune system is holding the tumor in check, having been reset by the immunotherapy.

The CheckMate studies were funded by Bristol-Myers Squibb. Dr Paz-Ares reports receiving honoraria from Roche/Genentech, Lilly, Pfizer, Boehringer Ingelheim, Clovis Oncology, Bristol-Myers Squibb, and MSD. Some coauthors are company employees. Dr Creelan reports receiving research funding from Boehringer Ingelheim and serving as a speaker for Bristol-Myers Squibb.

American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstract LBA109, presented May 30, 2015; abstract 8009, presented May 31, 2015.


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