The Lynx Group

NCCN Lung Cancer Guidelines: Combinations May Be the Future of Immunotherapy

June 2017, Vol 8, No 3

Orlando, FL—Immunotherapy is now an established option for patients with non–small-cell lung cancer (NSCLC) in the second-line setting and in selected patients in the first-line setting.

Even with the exciting advances in the treatment of NSCLC made possible by immunotherapy, only about 20% of patients will respond to a checkpoint inhibitor as second-line treatment, and only 45% of patients who qualify for immunotherapy in the first line will have a response. Therefore, immunotherapy combinations may be the way forward, and may provide the best value in treating NSCLC, according to Matthew A. Gubens, MD, MS, Assistant Clinical Professor, Thoracic Oncology, University of California, San Francisco.

“I would argue that they are expensive drugs, but if we could optimize them, the right combinations in the right patients for the right duration, we actually may yield superior value by meaningfully improving survival in our patients,” said Dr Gubens at the 2017 National Comprehensive Cancer Network (NCCN) annual conference.

He reviewed the landscape of current NCCN recommendations for immunotherapy in NSCLC and previewed the future.

The most recent NCCN guideline (version 5.2017) for NSCLC recommends PD ligand 1 (PD-L1) be used as a biomarker to direct immunotherapy. In patients with PD-L1 expression and negative or unknown EGFR, ALK, or ROS1 mutation status, pembrolizumab (Keytruda) is recommended as first-line treatment (Category 1 recommendation).

The rationale for use of pembrolizu­mab as first line came from the KEYNOTE-024 trial, in which patients with NSCLC had to have PD-L1 expression of >50% to be eligible for enrollment. Patients with activating EGFR or ALK mutations were not considered.

“Even if you see those high [PD-L1] expressions come through on your multiplex testing, this is not the right study approach or the right treatment approach for standard of care for EGFR or ALK patients,” said Dr Gubens.

He added that the subpopulation of patients with NSCLC and high PD-L1 expression was so small that it took screening of 1934 patients to find 500 with PD-L1 expression of >50%.

In KEYNOTE-024, pembrolizumab improved progression-free survival (PFS) by 4 months compared with platinum doublet chemotherapy. Notably, 44% of patients crossed over from the chemotherapy arm to pembrolizumab. The objective response rate was 45% in the pembrolizumab arm, which was vastly superior to the response rate in the chemotherapy arm. The median duration of response in the pembroliz­umab arm had not yet been reached.

When the trial was repeated with nivolumab (Opdivo) as first-line therapy in patients with PD-L1 expression of >5%, it failed to show an overall survival advantage with the immunotherapy.

The take-home message for second-line use of the checkpoint inhibitors is that although the study designs were different, nivolumab, pembroliz­umab, and atezolizumab (Tecentriq) all showed similar PFS benefit compared with standard chemotherapy.

After disease progression with pembrolizumab, the NCCN guideline recommends nivolumab or atezolizumab as second-line options; pembrolizumab is approved specifically as a second-line option for patients with PD-L1 expression of ≥1%. Systemic chemotherapy is also an option with a checkpoint inhibitor as the next line of treatment at disease progression.

The Future May Lie in Combinations

“Going forward, there are a lot more savvy approaches to thinking about biomarkers,” said Dr Gubens. “None of us think that PD-L1 is the end all, be all. There’s only a 45% response rate for the high expressers, and there are nonexpressers who benefit from the drug as well. Over time, we’re probably going to get more savvy in terms of patient selection, but also patient surveillance on treatment, by looking at a whole bevy of other aspects of the immune function, and using immunoassays that can be biopsy-driven and also blood-based to answer these questions.”

Immunotherapy plus Chemotherapy

The use of immunotherapy combinations may be the next step, Dr Gubens said. The most mature data are from the use of PD-1 inhibitors with chemotherapy. Chemotherapy induces cancer-cell death, but by releasing antigens in the course of cell death, the hope is that it may prime the immune system, and that may enhance the activity of PD-1 inhibitors.

Caveats to this combination are the need for steroids with some chemotherapies, which may attenuate the effectiveness. Also, the immunosuppressive state postchemotherapy may make the body less amenable to immunotherapy.

Early data with chemotherapy plus immunotherapy combinations are “quite tantalizing,” Dr Gubens said, with a response rate of 55% and 13-month PFS compared with 29% and 8.9-month PFS for carboplatin plus pemetrexed, respectively, in one series. Phase 3 data of this combination may be available in the next year, Dr Gubens said.

Two Immunotherapies Combined

Combining PD-1 inhibitors with other immunotherapy is also being explored. Anticipating results based on preclinical models is difficult; and even if additive or synergistic efficacy is possible, so is additional toxicity, said Dr Gubens.

The combination of a PD-1 inhibitor plus CTLA-4 inhibition—which is already approved for the treatment of melanoma—is another possibility in NSCLC. Early data examining a nivolumab plus ipilimumab (Yervoy) combination as first-line treatment in NSCLC showed an improvement in the response rate over nivolumab monotherapy at every level of PD-L1 expression. Data from adequately powered phase 3 clinical trials are awaited.

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