PD-1 Inhibition Reigns Supreme in Advanced Squamous NSCLC

Ronan J. Kelly, MD, MBA

Compared with advanced nonsquamous non–small cell lung cancer (NSCLC), there is really only 1 standard of care for patients with newly diagnosed advanced squamous NSCLC: pembrolizumab (Keytruda) plus standard chemotherapy, explained Ronan J. Kelly, MD, MBA.

In a presentation during the 2020 Institutional Perspectives in Cancer webinar on Lung Cancer, Kelly, who is chief of oncology for the 10 Baylor Scott & White Health’s North Texas Cancer Centers and director of oncology on the campus of Baylor Charles A. Sammons Cancer Center at Baylor University Medical Center, explained how the results of the KEYNOTE-407 trial have positioned pembrolizumab plus chemotherapy as the frontline standard of care in this setting.

KEYNOTE-407

The phase 3 KEYNOTE-407 trial enrolled patients with untreated stage IV NSCLC with squamous histology; those with symptomatic brain metastases or pneumonitis requiring systemic steroids were excluded from enrollment. Patients were randomized 1:1 to 200 mg of pembrolizumab plus carboplatin at an area under the curve (AUC) of 6 and either 200 mg/m2 of paclitaxel every 3 weeks or 100 mg/m2 of nab-paclitaxel (Abraxane) every week for four 3-week cycles (n = 278), or placebo plus the same schedule of chemotherapy (n = 281). Pembrolizumab and placebo were continued for up to 31 cycles, and patients with progressive disease on placebo were allowed to cross over to pembrolizumab for up to 35 cycles of treatment.¹

Progression-free survival (PFS) per RECIST v1.1, blinded independent central review (BICR) and overall survival served as primary end points of the study. Objective response rate (ORR) and duration of response (DOR) served as secondary end points of the trial.

Patients were stratified by PD-L1 expression (tumor proportion score [TPS] <1% vs ≥1%), choice of taxane (paclitaxel vs nab-paclitaxel), and geographic region (east Asia vs rest of the world). In each arm, approximately 35% of patients had less than 1% PD-L1 expression, approximately 40% had 1% to 49% PD-L1 expression, and approximately 25% had 50% or greater PD-L1 expression. The majority of patients (approximately 81%) were not enrolled in east Asia.

The median OS was 15.9 months with pembrolizumab versus 11.3 months with placebo, meeting the primary end point of the study (HR, 0.64; 95% CI, 0.49-0.85; P < .001).

“The use of pembrolizumab broadly improved the hazard ratios for death across multiple different subgroups,” said Kelly. “We had seen previously that PD-L1 status in squamous cell lung cancer is perhaps not as important as it is in adenocarcinoma. However, in this study, there wasn’t a huge difference in terms of survival depending on PD-L1 status.”

The hazard ratios for death in the PD-L1–expression subgroups of less than 1%, 1% to 49%, and 50% or greater were 0.61 (95% CI, 0.38-0.98), 0.57 (95% CI, 0.36-0.90), and 0.64 (95% CI, 0.37-1.10), respectively.

“We really didn’t see a huge difference depending on the PD-L1 expression, which I think helps doctors in the community. Maybe we don’t have to wait for the PD-L1 status to come back. We can be confident that if we give this drug to a patient with squamous cell disease, they can derive benefit,” said Kelly.

Similar OS was seen regardless of whether patients received paclitaxel (HR, 0.67; 95% CI, 0.48-0.93) or nab-paclitaxel (HR, 0.59; 95% CI, 0.36-0.98), added Kelly.

The median PFS was 6.4 months with pembrolizumab versus 4.8 months with placebo, translating to a 44% reduction in the risk of progression or death (HR, 0.56; 95% CI, 0.45-0.70; P < .001).

All subgroups benefitted from the addition of pembrolizumab to chemotherapy, said Kelly, who added that the magnitude of benefit was not substantially different with regard to the use of paclitaxel (HR, 0.52; 95% CI, 0.40-0.68) versus nab-paclitaxel (HR, 0.65; 95% CI, 0.45-0.94).

Moreover, the ORR was higher with pembrolizumab, at 57.9% versus 38.4% with placebo.

On October 30, 2018, the FDA approved first-line pembrolizumab for use in combination with carboplatin and either paclitaxel or nab-paclitaxel for the treatment of patients with metastatic squamous NSCLC, according to results from KEYNOTE-407.

IMpower131

Similarly, the phase 3 IMpower131 trial enrolled patients with untreated stage IV NSCLC with squamous histology. Patients were randomized to 1 of 3 arms: 1200 mg of intravenous (IV) atezolizumab (Tecentriq) plus carboplatin at an AUC of 6 every 3 weeks and 100 mg/m² of IV nab-paclitaxel every week for 4 to 6 cycles (ACP; n = 338); the same schedule of atezolizumab and carboplatin plus 200 mg/m2 of IV paclitaxel every 3 weeks for 4 to 6 cycles (ACNP; n = 343); or the same schedule of carboplatin plus 100 mg/m² of IV nab-paclitaxel every week for 4 to 6 cycles (CNP; n = 340).²

Investigator-assessed PFS served as primary end point of the study. OS, quality of life, ORR, and DOR served as secondary end points of the trial.

Approximately half of patients had low PD-L1 expression, and approximately 35% had high PD-L1 expression. PD-L1 subgroups were defined as tumor cell (TC) TC2/3 or immune cell (IC) IC2/3 (approximately 30%) and TC1/2/3 or IC1/2/3 (approximately 50%). Additional PD-L1 subpopulations were defined as TC3 or IC3 (high expression; approximately 14%), TC1/2 or IC1/2 (low expression; approximately 35%), and TC0 and IC0 (negative; approximately 50%).

The median PFS was 6.3 months in the ACNP arm versus 5.6 months in the CNP arm (HR, 0.71; 95% CI, 0.60-0.85; P = .0001). However, the PFS benefit failed to translate to an improvement in OS, demonstrating a median OS of 14.2 versus 13.5 months, respectively (HR, 0.88; 95% CI, 0.73-1.05; P = .16).

“This was surprising. We did not expect to see a negative study in terms of OS,” said Kelly.

In general, higher TC or IC expression correlated with improved PFS and OS.

“There may be a difference between a PD-1 inhibitor and a PD-L1 inhibitor, and we need to study that in prospective trials moving forward to see if that [has any bearing] on why these 2 similar trials [displayed discordant results],” concluded Kelly.

References

1. Paz-Ares L, Luft. A, Vicente 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. Jotte R, Cappuzzo F, Vynnychenko I, et al. Atezolizumab in combination with carboplatin and nab-paclitaxel in advanced squamous NSCLC (IMpower131): results from a randomized phase III trial. J Thorac Oncol. 2020;15(8):1351-1360. doi:10.1016/j.jtho.2020.03.028