Survival Significantly Improved With Frontline Pembrolizumab Combination in NSCLC

Leena Gandhi, MD, PhD

Results from the phase III KEYNOTE-189 trial, presented at the 2018 AACR Annual Meeting, indicated that the combination of pembrolizumab (Keytruda) with standard chemotherapy in the frontline setting reduced the risk of death by more than 50% in patients with nonsquamous non-small cell lung cancer (NSCLC) withoutEGFRorALKmutations. These results were also published in the New England Journal of Medicine.^1,2

Patients in this trial were given frontline pembrolizumab or placebo in combination with pemetrexed (Alimta) and either cisplatin or carboplatin. The estimated 12-month overall survival (OS) rate at a median follow-up of 10.5 monbths was 69.2% (95% CI, 64.1-73.8) in the pembrolizumab arm compared with 49.4% (95% CI, 42.1-56.2) in the control group (HR, 0.49; 95% CI, 0.38-0.64;P<.001).

The pembrolizumab cohort did not reach median OS, compared to the 11.3 months (95% CI, 8.7-15.1) found in the chemotherapy-alone arm. The OS benefit was observed and was irrespective of PD-L1 status. KEYNOTE-189 also met the coprimary endpoint of progression-free survival (PFS), where there was a median PFS of 8.8 months (95% CI, 7.6-9.2) in the pembrolizumab group compared to 4.9 months (95% CI, 4.7-5.5) in the control arm (HR, 0.52; 95% CI, 0.43 to 0.64;P<.001).

&ldquo;Adding pembrolizumab to pemetrexed and platinum induction therapy and pemetrexed maintenance therapy significantly improved overall survival, progression-free survival, and overall response rate, in patients with previously untreated metastatic nonsquamous non—small cell lung cancer withoutEGFRorALKalternations,&rdquo;said Leena Gandhi, MD, PhD, the lead author of the study and associate professor in the Department of Medicine and director of Thoracic Medical Oncology Program at the Perlmutter Cancer Center at NYU Langone Health.

The regimen could demonstrate, &ldquo;a new standard of care for first-line treatment of this group, irrespective of PD-L1 expression,&rdquo; Gandhi added during the AACR press conference.

KEYNOTE-189 was a double-blind, phase III trial that had accrued 616 patients with advanced or metastatic nonsquamous NSCLC, regardless of PD-L1 expression. Patients were notEGFR-orALK-positive, and had not received systemic therapy for advanced disease. Patients were randomized 2:1 in favor of the pembrolizumab arm.

Patients in the experimental arm (n = 410) received pembrolizumab at a 200-mg fixed dose every 3 weeks plus 500 mg/m²of pemetrexed plus either 75 mg/m²of cisplatin or carboplatin (AUC 5) on day 1 every 3 weeks for 4 cycles. This was followed with 200 mg of pembrolizumab plus 500 mg/m²of pemetrexed every 3 weeks. The control group (n = 206) received an identical regimen, except pembrolizumab was replaced with a placebo.

Patients received treatment until disease progression, unacceptable toxicity, physician decision, or consent withdrawal. Patients in the control arm with disease progression were allowed to cross over to receive pembrolizumab.

Secondary endpoints in the study included overall response rate (ORR) and duration of response.

Between the 2 arms, patient characteristics were well balanced. Median age was 65.0 years in the pembrolizumab arm (range, 34.0-84.0), where 62.0% of the patients were male, and all but 1 of the patients had an ECOG performance status of 0 or 1. Approximately 88.3% of the cohort were current/former smokers, and 96.1% of patients had adenocarcinoma.

PD-L1 expression level in this cohort, measured by tumor proportion score (% of tumor cells with membranous PD-L1 staining), was <1% in 31% of patients; &ge;1% in 63.4%; 1% to 49% in 31.2% of patients; &ge;50% in 32.2%; and not evaluable in 5.6%.

The pembrolizumab OS benefit was observed across PD-L1 subgroups, which included the <1% expression group (12-month OS rate, 61.7% vs. 52.2%; HR, 0.59; 95% CI, 0.38-0.92); the 1% to 49% cohort (12-month OS rate, 71.5% vs. 50.9%; HR, 0.55; 95% CI, 0.34-0.90), and those with a score of 50% or greater (12-month OS rate, 73.0% vs. 48.1%; HR, 0.42; 95% CI, 0.26-0.68).

Regarding the need for PD-L1 testing and the efficacy across subgroups, Gandhi noted, &ldquo;I think that for most of us in the field, we would be quite hesitant to give up on PD-L1, or some biomarker to select patients because clearly still not all patients are benefiting. We do need to focus more on how to differentiate the patients who will get the most benefit. PD-L1 may be part of that story here, but maybe not the whole story.&rdquo;

The ORR per blinded, independent central radiologic review in the pembrolizumab arm versus the chemotherapy alone arm was 47.6% (95% CI, 42.6-52.5) and 18.9% (95% CI, 13.8-25.0) (P<.001), while there was a disease control rate of 84.6% versus 70.4%, and the median duration of response was 11.2 months versus 7.8 months in the pembrolizumab versus control arms, respectively.

The rate of discontinuation of all study drugs due to adverse events (AEs) was 13.8% in the pembrolizumab arm and 7.9% in the control arm. The discontinuation rate of pembrolizumab was 20.2% and placebo was 10.4%. Death related to AEs occurred in approximately 6.7% versus 5.9% of the pembrolizumab arm cimpared to control arms, respectively.

Diarrhea (30.9% vs 21.3%) and rash (20.2% vs 11.4%) were the only 2 AEs occurring in &ge;10% of patients that occurred more commonly in the pembrolizumab versus the chemotherapy-alone arm. Grade &ge;3 AEs occurring in at least 10% of patients in either arm were anemia (16.3% with pembrolizumab vs 15.3% in the control group) and neutropenia (15.8% vs 11.9%, respectively).

Acute kidney injury was found at a rate of 5.2% in the pembrolizumab arm versus 0.5% in the chemotherapy-alone arm. Also, 8 patients (2.0%) receiving the PD-1 inhibitor had grade &ge;3 acute kidney injury.

Immune-mediated AEs occurred in 22.7% of the pembrolizumab group versus 11.9% of the control group. This includes grade &ge;3 AEs in 8.9% versus 4.5% of patients, respectively. Pneumonitis led to 3 deaths in the pembrolizumab cohort.

Despite higher rates in the pembrolizumab arm, Gandhi added, &ldquo;The immune-mediated side effects&hellip;overall were not significantly more than they are with monotherapy, with similar numbers of grade 3 to 5 events and those leading to death as has been seen with monotherapy with pembrolizumab.&rdquo;

References:

1. Gandhi L, Rodgr&iacute;guez-Abreu D, Gadgeel S, et al. KEYNOTE-189: Randomized, double-blind, phase 3 study of pembrolizumab (pembro) or placebo plus pemetrexed (pem) and platinum as first-line therapy for metastatic NSCLC. Presented at 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT075.
2. Gandhi L, Rodgr&iacute;guez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non—small-cell lung cancer [published online April 16, 2018].N Engl J Med.