Optimizing Frontline Immunotherapy in NSCLC

Roy S. Herbst, MD, PhD

Immunotherapy continues to revolutionize the field of non—small cell lung cancer (NSCLC), with researchers now focusing on the optimal use of immune agents in the frontline setting.

“It has really been incredible what has happened in the last 20 years, but particularly in the last 10,” said Roy S. Herbst, MD, PhD, a professor of Medicine and chief of Medical Oncology, Yale Cancer Center and Smilow Cancer Hospital at Yale New Haven. “We have moved from the era of targeted therapy [in select patients] and then, of course, to immunotherapy.”

Herbst spoke on initial treatment with immunotherapy in patients with lung cancer during a presentation at the 11th New York Lung Cancer Symposium, providing a look back on the immunotherapy approvals and pivotal data for nivolumab (Opdivo), pembrolizumab (Keytruda), and atezolizumab (Tecentriq), along with a glance at what the field can expect next.

Choosing the Best Frontline Option

In October 2016, the FDA approved pembrolizumab in the frontline setting for patients with NSCLC, based on findings from the phase III randomized KEYNOTE-024 study, which showed that single-agent pembrolizumab led to a 40% reduction in the risk of death compared with doublet chemotherapy for untreated patients with advanced disease with ≥50% PD-L1 expression on cells.¹ The median progression-free survival (PFS) was also improved by 4.3 months.

“It does not get much better than this,” said Herbst. “This is historic.”

Pembrolizumab is the sole checkpoint inhibitor approved for frontline NSCLC, with nivolumab and atezolizumab both available for use after patients progress on chemotherapy.

“The world changed exactly 1 month ago, and this is KEYNOTE-024,” Herbst said. “It is the most clinically developed trial at this point because it really has moved pembrolizumab to the frontline setting in untreated patients with lung cancer.”

When it comes to nivolumab in the first-line setting, however, the phase III multicenter, open-label CheckMate-026 study results had the opposite impact. In CheckMate-026, there was not a PFS benefit observed with nivolumab over chemotherapy.² Patients who received nivolumab had a median PFS of 4.2 months compared with 5.9 months for patients treated with a chemotherapy doublet chosen by the treating physician. Additionally, there was no significant difference observed between the 2 arms for overall survival (OS) and response rate.

“Then, there’s this trial (CheckMate026), and you have got to scratch your head,” Herbst reflected. “As enthusiastic as we were, it would have been nice to see a second drug [succeed in frontline]. Most of us think that nivolumab and pembrolizumab are really not that different.”

However, CheckMate-026 was designed differently, as it included patients with ≥1% PD-L1 expression on cells. In a subgroup of patients with ≥5% PD-L1 expression, the median OS was 14.4 months with nivolumab and 13.2 months with chemotherapy. The 1-year survival was 56.3% and 53.6% with nivolumab and chemotherapy, respectively.

“Could it be that there were other factors involved?” Herbst questioned. “That is still under review.”

PD-L1 as a Biomarker: Is it Worthwhile?

Herbst spoke on biomarker results from the phase III CheckMate-057 trial, which compared nivolumab with docetaxel in patients with advanced NSCLC.³ Here, it was found that nivolumab-treated patients who harbored PD-L1 expression levels of ≥1%, ≥5%, and ≥10% had longer OS, PFS, and median duration of response, as well as higher objective response rates (ORRs).

“I have been working on this for a few years, and I have evolved in my thinking,” Herbst said. “Based on those data, the FDA and all of us said, ‘we don’t really need a biomarker to give nivolumab in second-line; we will give it to almost everyone.’”

PD-L1 expression in the KEYNOTE-001 and KEYNOTE-010 trials, which explored pembrolizumab versus docetaxel in advanced NSCLC had similar results.^4,5 PFS and OS were shorter among patients with a PD-L1—expression score of 1% to 49% or a score of less than 1% than among those with a score of at least 50% expression on cells.

Expression of PD-L1 is heterogeneous and varies with the antibody used, Herbst explained, suggesting it to be an imperfect biomarker. Additionally, the role of PD-L1 as a prognostic factor is not yet well defined, he added.

Immunotherapy to Stay, Combos on Horizon

Immunotherapy is also being looked at in combination as a frontline choice option in NSCLC.

For example, in a cohort of the phase II KEYNOTE-021 trial, treatment-naïve patients with stage IIIB/IV nonsquamous NSCLC were randomized to pembrolizumab plus carboplatin/pemetrexed or carboplatin/pemetrexed followed by maintenance pembrolizumab for 2 years.⁶ Results showed that the median PFS with the combination was 13 months versus 8.9 months with chemotherapy alone (HR, 0.53; P = .0102). There was no difference in OS between the 2 arms.

“The downside is that chemotherapy is going to kill the T cells to help things out; the positive is that it is going to kill the bad T cells,” Herbst explained. “However, it is a reason to try. It does suggest that combinations will be important, but more mature data are needed.”

Dual checkpoint blockade regimens are also being investigated for efficacy. In the phase Ib CheckMate-012 trial, upfront treatment with the combination of nivolumab and ipilimumab (Yervoy) showed a 57% ORR in patients with PD-L1—positive advanced NSCLC.⁷ The findings, while early, do seem to have benefit in patients, Herbst added.

Other ongoing clinical trials are exploring various combinations. A cohort of the phase Ia/Ib JVDF trial (NCT02443324) is exploring pembrolizumab plus the antiangiogenic agent ramucirumab (Cyramza) in 27 patients with NSCLC in both first-line and later lines of therapy.⁸ Early results of the second-to-fourth line cohort show a 30% ORR with the combination and an 85% disease-control rate.

Herbst also mentioned the benefit the immunotherapy advances have specifically had in patients with NSCLC who have brain metastases.

“We are going to see patients living longer, so let’s avoid some of the radiation therapy and preserve cognitive function as best we can,” Herbst said.

Research in the future, Herbst noted, will involve determining the role of macrophages, T cells, and suppressor cells “to figure how to get these cells more cooperative and have a better response.”

“We have now been looking at not only tumor cells with PD-L1, but PD-L1 on the immune cells, macrophages, dendritic cells, and T cells,” he added. “PD-L1 is present throughout the tumor microenvironment.”

There are several questions and challenges remaining, Herbst explained, including scheduling of agents, managing autoimmune conditions, treatment beyond progression, comparison of agents, approaches in PD-L1—negative patients, and how to optimally combine these therapies.

“Really, it’s an exciting time,” Herbst concluded. “We have all of the science.”

References

1. Reck M, Rodgriguez-Abreu D, Robinson AG, et al. KEYNOTE-024: Pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) as first-line therapy for advanced NSCLC with a PD-L1 tumor proportion score (TPS) ≥50%. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA8.
2. Socinski M, Creelan B, Horn L, et al. CheckMate 026: A phase 3 trial of nivolumab vs investigator’s choice (IC) of platinum-based doublet chemotherapy (PT-DC) as first-line therapy for stage IV/recurrent programmed death ligand 1 (PD-L1)−positive NSCLC. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. LBA7_PR.
3. Borghaei H, Paz-Ares L, Horn, L. Nivolumab versus docetaxel in advanced nonsquamous non—small-cell lung cancer. N Eng J Med. 2015; 373:1627-1639.
4. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non—small-cell lung cancer. N Eng J Med. 2015; 372:2018-2028.
5. Herbst RS, Baas P, Kim D-W, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540-1550.
6. Langer C, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study.
7. Lancet Oncol. 2016;17(11):1497-1508.
8. Hellmann MD, Gettinger SN, Goldman JW, et al. CheckMate 012: Safety and efficacy of first-line (1L) nivolumab (nivo; N) and ipilimumab (ipi; I) in advanced (adv) NSCLC. J Clin Oncol. 2016;34 (suppl; abstr 3001).
9. Herbst RS, Martin-Liberal J, Calvo E, et al. Interim safety and clinical activity in patients with advanced NSCLC from a multi-cohort phase 1 study of ramucirumab (R) plus pembrolizumab (P). Annals of Oncology 2016;27(6):1-36.

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