Brahmer Shares Next Steps for Immunotherapy in Metastatic NSCLC

Julie R. Brahmer, MD

Immunotherapy has been established as the standard of care for patients with metastatic non—small cell lung cancer (NSCLC), and the next steps for research are creating a more personalized approach for individual patients, said Julie R. Brahmer, MD.

Three studies—KEYNOTE-024, KEYNOTE-189, and KEYNOTE-407—were pivotal in cementing pembrolizumab’s (Keytruda) role in the metastatic setting for patients with squamous and nonsquamous NSCLC.

KEYNOTE-407 was the basis for the October 2018 FDA approval of pembrolizumab in combination with carboplatin and paclitaxel/nab-paclitaxel (Abraxane) in patients with squamous metastatic NSCLC. In the phase III trial , the median overall survival (OS) was 15.9 months with the addition of pembrolizumab compared with 11.3 months with chemotherapy alone (HR, 0.64; 95% CI, 0.49-0.85; P = .001).¹ Median progression-free survival (PFS) in the experimental arm was 6.4 months versus 4.8 months in the control arm. The survival benefit was observed regardless of PD-L1 status.

Atezolizumab (Tecentriq) has also shown promise in the metastatic setting. The phase III IMpower150 trial evaluated the use of atezolizumab in combination with bevacizumab (Avastin), carboplatin, and paclitaxel (ABCP) in patients with metastatic NSCLC who had not previously received chemotherapy. The addition of atezolizumab to bevacizumab plus chemotherapy resulted in a significant improvement in progression-free survival, even in patients with EGFR-mutant disease.²

Brahmer, an associate professor of Oncology and co-director of the Upper Aerodigestive Department at the Bloomberg Institute for Cancer Immunotherapy, Johns Hopkins Medicine, said future research should continue to explore the use of immunotherapy combinations in patients with metastatic NSCLC.

OncLive: What is the current role of immunotherapy in NSCLC?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Brahmer discussed updates on the use of immunotherapy in patients with metastatic NSCLC.Brahmer: The majority of patients with metastatic NSCLC are being offered immunotherapy based on several trials. One of the KEYNOTE trials compared the use of pembrolizumab with chemotherapy in patients with high PD-L1 expression. Tumor proportion score has shown a clear improvement in survival, so pembrolizumab is one option for patients who do not have EGFR or ALK mutations. For the rest of the patients, the standard treatment approach is to combine immunotherapy with chemotherapy; this is also an option for patients who have high PD-L1 expression.

There were 2 separate KEYNOTE trials that evaluated the use of pembrolizumab in combination with chemotherapy versus chemotherapy alone. For cohort G of the KEYNOTE-021 trial, investigators looked at nonsquamous histologies and tested pembrolizumab with pemetrexed and carboplatin. The KEYNOTE-407 trial evaluated the use of nab-paclitaxel or paclitaxel and carboplatin plus pembrolizumab versus chemotherapy alone. Both trials showed an advantage with the addition of pembrolizumab to chemotherapy.

What is the benefit of testing these regimens in the incurable or metastatic setting?

The IMpower trials evaluated the addition of atezolizumab to chemotherapy and bevacizumab. The goal is improvement in PFS and OS, and we are waiting to hear updated data from these trials. These studies included patients with EGFR- and ALK-positive disease, and these patients seemed to benefit from the 4-drug combination. We have to decide how practical this is.Adding immunotherapy to chemotherapy improves the chance of response, particularly in patients who are symptomatic. You would want to decrease the size of their tumors. For several of these studies, investigators have looked at patient-reported outcomes (PROs) as well, [and they have shown] improvement in how patients can handle these regimens. There really is not a huge increase in toxicity when adding immunotherapy versus other drugs, such as VEGF inhibitors. However, immunotherapy-related toxicities are something to keep in mind.

What are some clinical trials that you are particularly excited to read out in the field?

Where do you feel is the largest unmet need in metastatic NSCLC?

[By evaluating PROs], we are looking at survivorship, patients who are doing well on immunotherapy for months and even years. If these patients are living longer, we have to think about the issues they are facing. Is their quality of life maintained? This is from a toxicity standpoint and disease-related factors.We need more data on different combination therapies. Hopefully, we will have the second primary endpoint soon for the CheckMate-227 trial evaluating PD-L1 as a biomarker with ipilimumab (Yervoy) and nivolumab (Opdivo). We will see if that improves PFS compared with what we are seeing with tumor mutational burden. There are certainly other combinations being studied out there, but it is all preliminary.The biggest unmet need is trying to personalize immunotherapy for patients in the metastatic setting. Is the best [treatment approach] combination chemotherapy plus immunotherapy or immunotherapy by itself? We know patients will progress at some point, so we need to personalize care for them.

References

1. Ares-Pas L, Luft A, Vincente D, et al. Pembrolizumab plus chemotherapy for squamous non—small cell lung cancer. N Engl J Med. 2018;379(21):2040-2051. doi: 10.1056/NEJMoa1810865.
2. Socinski M, Jotte R, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301. doi: 10.1056/NEJMoa1716948.