Alexander M. Castellino and Zosia Chustecka

June 18, 2015

Immunotherapies like nivolumab (Opdivo) can make a difference of "epic proportions" in lung cancer and, in the near future, immunotherapy could become the backbone onto which all other therapies are added, said Roy S. Herbst, MD, PhD, from Yale Comprehensive Cancer Center in New Haven, Connecticut.

Dr Herbst, who is chief of medical oncology and director of the thoracic oncology research program at Yale, was commenting in an interview with Medscape Medical News after the recent American Society of Clinical Oncology (ASCO) 2015 Annual Meeting in Chicago.

At the meeting, Dr Herbst acted as discussant for CheckMate 057 — the phase 3 study that showed better survival with nivolumab, a PD-1 immune checkpoint inhibitor, than with docetaxel in the treatment of nonsquamous non-small cell lung carcinoma (NSCLC), as reported by Medscape Medical News.

"Unprecedented" and "practice-changing," is how he referred to the data with nivolumab in NSCLC from CheckMate 057. "This is a positive trial in patients with refractory, nonsquamous advanced NSCLC, the number 1 cause of cancer deaths worldwide," he explained.

The number 1 cause of cancer deaths worldwide.

Approximately nine of 10 cases of lung cancer can be categorized as NSCLC, and nonsquamous NSCLC comprise up to 70% of these cases. There will be 1.8 million new cases of lung cancer each year, and 1.6 million deaths.

"That is why immunotherapies like nivolumab can make a difference of epic proportions in the lives of many more patients with lung cancer, compared with melanoma," he said. CheckMate 057 was featured in a special session on immunotherapy with other late-breaking abstracts at the ASCO meeting.

The data on nivolumab in nonsquamous NSCLC were particularly impressive at 1 year, Dr Herbst commented. "Early on, there appears to be benefit for chemotherapy, whereas later on, immunotherapy is significantly better," he indicated.

The crossing on the Kaplan–Meier survival curve indicates that there could be populations of treatable patients, and reliable biomarkers might define patient populations that will benefit from immunotherapy.

There is a lot of interest in identifying such a biomarker, and some of this has fallen on PD-L1 expression in tumors.

A CheckMate 057 analysis demonstrated that clinical response to nivolumab — overall survival, progression-free survival, and objective response rate — was better in patients with tumors that expressed any level of PD-L1.

However, some patients with low levels of PD-L1 expression responded to nivolumab, so the researchers advise that level of expression not be used as a reason to forego immunotherapy.

"Expression of PD-L1 is heterogeneous — patchy vs diffuse, intratumoral vs peripheral, tumor cell vs stromal — and varies with the antibody used," Dr Herbst explained.

"More work needs to be done on biomarkers that predict response in NSCLC, he added."

"I will be comfortable using nivolumab in most patients in the second-line setting of refractory, advanced NSCLC," he noted. in the front-line setting, the use of immunotherapy might require appropriate patient selection with validated biomarkers, he indicated.

Dr Herbst is optimistic that immunotherapy will benefit a greater number of patients in the future. He predicts that drugs such as nivolumab will become front-line therapy in advanced disease, and will subsequently move into the adjuvant setting. In addition, he predicts that immunotherapy will be explored in lung cancers that are currently treated with targeted agents, such as tumors with ALK and EGFR mutations in which initial results are still not promising.

"I conceive that there will come a day when immunotherapy will be the standard of care and backbone therapy on which other treatment modalities will be added, especially for patients with no long-term benefits," Dr Herbst told Medscape Medical News.

"Targeted therapies will still be there for patients with tumors having a target. For patients developing resistance to targeted therapies or those with tumors without a target, immunotherapy will be the treatment of choice," he added.

Dr Herbst addressed the skepticism about immunotherapy that has been expressed by some clinicians: "They should review the data and then use their clinical judgment." In CheckMate 057, even patients on nivolumab who were biomarker-negative did as well as patients on docetaxel, and experienced fewer toxicities, he added.

"Although we still have work to do on our endgame, we are making progress, and lung cancer patients are better off today than they were 1 month ago," he told Medscape Medical News.

This vision of the future was supported by Neil H. Segal, MD, PhD, from the Immunotherapeutics Group at Memorial Sloan Kettering Cancer Center in New York City, who introduced the special session at the ASCO meeting entitled Immunotherapy for Every Patient: Check Your Enthusiasm.

Since 2011, patients around the world have had unprecedented access to clinical studies evaluating immunotherapy, he pointed out. And in 2015, one of every 22 studies registered on involved immunotherapy.

However, some clinicians have become skeptical about immunotherapy being portrayed as the latest advance, and point out that although responses are dramatic, overall, only 20% to 40% of patients respond to immunotherapy. "The key will be to use science to identify who the patients are in advance," Dr Herbst explained.

There will be a role for other treatments for some time yet, clinicians argue. Plus, there is the problem of cost; the new immunotherapies have huge price tags, and will be unaffordable for many patients with copays, as previously reported by Medscape Medical News.

Dr Herbst reports receiving research support and honoraria from several companies. Dr Segal has disclosed no relevant financial relationships.


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