Immunotherapy Agents Drive Frontline Treatment Strategies in Advanced NSCLC

Several immunotherapeutic options are available for non–small cell lung cancer (NSCLC), allowing decisions to be made based on histology, PD-L1 expression, and patient preference in regard to their treatment goals. Looking ahead, there may also be efficacy in moving immunotherapy drugs up into the resectable, early-stage setting, according to Julie R. Brahmer, MD, MSc.

“For patients with metastatic NSCLC, therapy options are wide and varied, but immunotherapy is now the mainstay of first-line treatment for cancers without a tyrosine kinase inhibitor-treatable driver mutation,” said Brahmer, co-director of the Upper Aerodigestive Department within the Bloomberg–Kimmel Institute for Cancer Immunotherapy and a professor of oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center.

Despite efficacy seen in the frontline setting, second-line treatment strategies are not clear for patients who have progressive disease. “[Patients with] immunotherapy-refractory disease [represent] a huge unmet need, with multiple clinical trials ongoing to [solve for this],” Brahmer said.

During the 5th Annual International Congress on Immunotherapies in Cancer®, Brahmer discussed the use of immunotherapeutics as both as single agents and in combination, as well as the recent and ongoing studies that may support their use in patients with early-stage disease.¹

Single Agent First-Line Immunotherapies in Advanced Disease

The first-line treatment paradigm for patients with NSCLC is built around PD-L1 expression in both the tumor and/or immune cells, with several agents approved for indications stratified by expression. In particular, pembrolizumab (Keytruda) and atezolizumab (Tecentriq) stand out as the single-agent therapies of choice based on efficacy in patients with PD-L1–positive disease.

“PD-L1 level is associated with increased response rate and improved survival in patients treated with a checkpoint blockade,” Brahmer said. “We know that the higher the PD-L1 [expression], the higher the chance of a response, as noted in the original KEYNOTE-001 study.”

Specifically, data from KEYNOTE-001 (NCT01295827) showed that patients who were treatment naïve with a tumor proportion score (TPS) of at least 50% had an overall response rate of 50.0% compared with 19.2% in patients with a TPS of 1% to 49%, and 16.7% in those with a TPS less than 1%.²

Additionally, updated data from the KEYNOTE024 trial (NCT02220894) showed that patients with previously untreated advanced NSCLC with a PD-L1 expression of at least 50% experienced longer overall survival (OS) with pembrolizumab compared with chemotherapy (30.0 vs 14.2 months; HR, 0.63; 95% CI, 0.47-0.86).³

In addition to pembrolizumab, single-agent atezolizumab (Tecentriq) received approval for the treatment of patients with PD-L1–high disease, defined as PD-L1 staining of at least 50% of tumor cells or PD-L1–stained tumor-infiltrating immune cells covering at least 10% of the tumor area. The approval was based on data from IMpower110 (NCT02409342), in which atezolizumab demonstrated a median OS of 20.2 months (95% CI, 16.5 to not evaluable) at a median follow-up of 15.7 months compared with 13.1 months (95% CI, 7.4-16.5) in patients treated with platinum-based chemotherapy (HR, 0.59; 95% CI, 0.40-0.89; P = .0106).⁴

Frontline Combination Immunotherapy Regimens

Patient response rates can be increased by combining immunotherapy agents with other treatments, such as chemotherapy. The space has seen a number of FDA-approved agents within the past few years, primarily in patients without EGFR or ALK alterations.

“A nice [development] in these chemotherapy/ immunotherapy combinations is PD-L1 agnostic agents, where a survival benefit is seen across all patient subgroups,” Brahmer said.

The KEYNOTE-189 trial (NCT02578680) exemplified the benefit provided by an immunotherapy/chemotherapy combination in patients with previously untreated, metastatic nonsquamous NSCLC.5 The trial evaluated pembrolizumab or placebo plus pemetrexed and platinum. In final analysis data, the median OS was 22.0 months (95% CI, 19.5-24.5) in the chemoimmunotherapy arm compared with 10.6 months (95% CI, 8.7-13.6) in the placebo arm (HR, 0.56; 95% CI, 0.46-0.69). The 24-month OS rates were 45.7% and 27.93%, respectively.

“If you look across the different PD-L1 subtypes, there is improvement in survival regardless of PD-L1 [expression],” Brahmer noted.

Further, in KEYNOTE-407 (NCT02775435) pembrolizumab plus chemotherapy improved overall response rates compared with placebo plus chemotherapy (57.9% vs 38.4%, respectively).⁶ Patients across all PD-L1 subgroups were found to have improved response rates with the addition of pembrolizumab, as well: 63.2% versus 40.4%, respectively, in PD-L1–negative patients (TPS < 1%), 49.5% versus 41.3% for TPS 1%-49%, and 60.3% versus 32.9% for TPS of at least 50%.

In addition to its role as a single agent, atezolizumab also demonstrated efficacy in combination with carboplatin and nab-paclitaxel in patients with nonsquamous disease in IMpower130 (NCT02367781). Findings showed that the immunotherapy/chemotherapy regimen significantly improved OS in the intention-to-treat wild-type population.7 Patients who received atezolizumab had a median OS of 18.6 months (95% CI, 16.0-21.2) compared with 13.9 months (95% CI, 12.0-18.7) for those who received chemotherapy alone (HR, 0.79; 95% CI, 0.64-0.98; P = .033).

Although a handful of biomarkers, such as PD-L1 expression, inform treatment with immunotherapy, their utility does not strictly guide treatment decisions with combination regimens.

“For chemotherapy in combination with a PD-1 antibody, the PD-L1 or tumor mutational burden biomarkers cancel out in this setting,” she explained. “Improvement in OS is seen across most subsets.”

Options Following Immunotherapy

Currently, there is an unmet need regarding treatments for patients who progress on a single agent or combination immunotherapy regimen. “This is where clinical trials, at least in a lot of our practice, fill that void,” Brahmner said. However, she added that response rates right now are approximately 10% to 20% for patients with refractory disease. “We have a lot of work to do in this space.”

The Future of Immunotherapeutics in Resectable Early-Stage Disease

Currently, there is an unmet need regarding treatments for patients who progress on a single-agent or combination immunotherapy regimen. “This is where clinical trials fill that void,” Brahmer said. However, she added that response rates right now are approximately 10% to 20% for patients with refractory disease: “We have a lot of work to do in this space.”

The Future of Immunotherapeutics in Resectable Early-Stage Disease

Neoadjuvant PD-1 and PD-L1 agents have been shown, notably, to be safe and feasible in patients with resectable NSCLC, demonstrating promising major pathologic response (mPR) rates within this patient population.

These results include data from the NADIM trial (NCT03081689), which assessed the efficacy of neoadjuvant chemotherapy and nivolumab (Opdivo) in patients with stage IIIA local NSCLC determined to be surgically resectable by a multidisciplinary clinical team.⁸

Enrolled patients received 3 cycles of nivolumab plus paclitaxel and carboplatin followed by adjuvant nivolumab for 1 year. Patients then underwent tumor assessment prior to surgery. The combination resulted in a high complete pathologic response rate. Specifically, 41 surgeries were performed and all tumors were deemed resectable. Thirty-four patients (83%) achieved mPR (95% CI, 71%-95%) and 24 (71%) had a complete pathologic response (95% CI, 54%-87%). Downstaging was seen in 90% (95% CI, 81%-100%) of cases. At 24-month follow up, progression-free survival was 77.1% (95% CI, 59.9%-87.7%).⁹

Additionally, CheckMate 816 (NCT02998528) is currently comparing the use of neoadjuvant nivolumab and ipilimumab (Yervoy) or nivolumab plus chemotherapy versus chemotherapy alone to determine the safety and efficacy of each regimen for patients with early-stage NSCLC.

“Immunotherapy does hold the promise to help increase the chance of cure in resectable early-stage disease, but we have to wait for the results of the clinical trials that are currently ongoing,” Brahmer concluded.

References

1. Brahmer, JR. Immunotherapy in non–small cell lung cancer. Presented at: 5th Annual International Congress on Immunotherapies in Cancer; December 12, 2020; Virtual. Accessed December 15, 2020.
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8. Provencio M, Nadal E, Insa A, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2020;21(11):P1413-1422. doi:10.1016/S1470-2045(20)30453-8
9. Provencio M, Nadal E, Garcia-Campelo R, et al. Neoadjuvant chemo-immunotherapy for the treatment of stage IIIA resectable non-small-cell lung cancer (NSCLC): a phase II multicenter exploratory study—final data of patients who underwent surgical assessment. J Clin Oncol. 2019;37(suppl 15):8509. doi:10.1200/JCO.2019.37.15_suppl.8509