FDA Expands Alimta Approval for Use With Immunotherapy and Chemo in Lung Cancer

The FDA has expanded the indication for Alimta (pemetrexed) injection in combination with Keytruda (pembrolizumab) and platinum-based chemotherapy for the first-line treatment of patients with metastatic nonsquamous non—small cell lung cancer (NSCLC) without EGFR or ALK alterations.

The updated indication is based on data from the phase 3 KEYNOTE-189 trial, which was the basis for the FDA’s full approval of frontline Keytruda for use in combination with standard chemotherapy for patients with metastatic nonsquamous NSCLC.

"KEYNOTE-189 demonstrated an exceptional effect of the Alimta-pembrolizumab-platinum chemotherapy combination in the first-line setting, offering significantly improved survival in patients with metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations," said Anne White, president, Lilly Oncology. "This new indication reinforces Lilly's continued commitment to providing practice-changing treatment options that can make a meaningful difference for people living with lung cancer."

In the double-blind, phase 3 KEYNOTE-189 study, 616 patients with advanced or metastatic nonsquamous NSCLC, regardless of PD-L1 expression and were not EGFR- or ALK-positive, were randomized 2 to 1 to receive Keytruda plus Alimta and either cisplatin or carboplatin (410 patients), or chemotherapy alone (206 patients). Patients also had not received systemic therapy for their advanced disease.

Results showed that the addition of Keytruda to chemotherapy in the first-line setting reduced the risk of death by 51 percent in patients with NSCLC without EGFR or ALK mutations. The median overall survival (OS) was not reached in the Keytruda arm compared with 11.3 months in the chemotherapy-alone arm. At a median follow-up of 10.5 months, the estimated 12-month OS rate was 69.2 percent in the Keytruda arm versus 49.4 percent in the control arm.

Moreover, the study met the coprimary endpoint of progression-free survival (PFS), with a median PFS of 8.8 months in the Keytruda group versus 4.9 months in the control arm.

In the experimental arm, Keytruda was administered a 200-mg fixed dose every three weeks plus 500 mg/m² of Alimta plus either 75 mg/m² of cisplatin or carboplatin (AUC 5) on day 1 every three weeks for four cycles, followed by 200 mg of Keytruda plus 500 mg/m² of Alimta every three weeks. The regimen administered in the control arm was identical, except that Keytruda was replaced with placebo.

Patient characteristics were well balanced between the two arms. The median age was 65.0 years in the Keytruda arm (range, 34.0-84.0), 62.0 percent of the patients were male, and all but 1 of the patients had an ECOG performance status of 0 or 1. Current/former smokers comprised 88.3 percent of the cohort and 96.1 percent of patients had adenocarcinoma.

Additional results showed that the OS benefit with Keytruda was observed across PD-L1 subgroups, including the less than 1 percent expression group (12-month OS rate, 61.7 percent vs. 52.2 percent); the 1 percent to 49 percent cohort (12-month OS rate, 71.5 percent vs. 50.9 percent) and those with a score of 50 percent or higher (12-month OS rate, 73.0 percent vs. 48.1 percent).

The objective response rate per blinded, independent central radiologic review was 47.6 percent in the Keytruda arm and 18.9 percent with chemotherapy alone. The disease control rate was 84.6 percent versus 70.4 percent, and the median duration of response was 11.2 months versus 7.8 months in the Keytruda versus control arms, respectively.

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

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

The rate of acute kidney injury was 5.2 percent in the Keytruda arm versus 0.5 percent in the chemotherapy-alone arm. Eight patients (2.0 percent) receiving the PD-1 inhibitor had grade 3 or higher acute kidney injury.

Immune-mediated AEs occurred in 22.7 percent of the Keytruda group versus 11.9 percent of the control group, including grade 3 or higher AEs in 8.9 percent versus 4.5 percent, respectively. Pneumonitis led to 3 deaths in the Keytruda cohort.

The immunotherapy/chemotherapy regimen was initially granted an accelerated approval in June 2018 for the first-line treatment of patients with metastatic nonsquamous NSCLC, based findings from the cohort G of the phase 2 study KEYNOTE-021 trial, in which the 12-month PFS rate was 56 percent with Keytruda plus Alimta and carboplatin compared with 34 percent with chemotherapy alone.

This article originally appeared on OncLive as "FDA Expands Pemetrexed Approval for Frontline Pembrolizumab/Chemo Combo in NSCLC."