FDA Expands Alimta’s Label for Initial Treatment of Metastatic Lung Cancer

FDA Expands Alimta’s Label for Initial Treatment of Metastatic Lung Cancer

The U.S. Food and Drug Administration has expanded Alimta‘s (pemetrexed) label to include a combination with Keytruda (pembrolizumab) and platinum chemotherapy for the initial treatment of certain metastatic non-small cell lung cancer (NSCLC) patients.

The triple combination, which is for patients with non-squamous disease and who have no EGFR or ALK mutations in their tumors, received accelerated approval in June 2017, which was converted into full, regular approval by August 2018.

Keytruda, developed by Merck (known as MSD outside the U.S. and Canada), is an antibody that prevents the PD-1 receptor on immune cells from binding to its ligand PD-L1, produced by cancer cells. Cancers often use this binding to prevent immune surveillance. Keytruda is meant to activate T-cells and boost their ability to identify and fight tumor cells.

In the Phase 1/2 KEYNOTE-021 clinical trial (NCT02039674), a combination of Keytruda, Eli Lilly‘s Alimta, and carboplatin was significantly better at delaying disease progression or death than Alimta and platinum chemotherapy alone — from a median of 8.9 months to 13 months.

The triple combination also nearly doubled the number of responders, from 29% to 55%. Responses were independent of a patient’s PD-L1 status — a common predictor of responses to PD-1 inhibitors.

These findings led the FDA to grant accelerated approval to this combination, contingent on confirmation of clinical benefit in a larger clinical trial.

For this purpose, Merck, in collaboration with Lilly, designed a Phase 3 trial — called KEYNOTE-189 (NCT02578680) — to confirm that Keytruda plus Alimta and platinum chemotherapy improved the survival outcomes of metastatic non-squamous NSCLC patients. In particular, researchers measured the time to disease progression or death and the overall survival of these patients.

KEYNOTE-189 included 616 patients with any level of PD-L1 expression, without EGFR or ALK mutations, and who had not received any prior treatment for their metastatic disease.

They received treatment for a maximum of two years, or until they experienced signs of disease progression or toxicity. Patients in the placebo arm were allowed to move to Keytruda if their disease worsened.

The findings from KEYNOTE-189 confirmed those of KEYNOTE-021: Keytruda reduced the risk of disease progression or death by 48% and increased response rates from 19% to 48%.

In addition, the treatment extended patients’ lives, regardless of their PD-L1 levels. One year after starting the treatment, 69.2% of patients receiving Keytruda were still alive, compared with 49.4% in the control arm.

The most common adverse reactions were fatigue, nausea, constipation, diarrhea, reduced appetite, rash, vomiting, cough, shortness of breath, and fever. However, severe adverse events occurred at similar rates between the two groups: 67.2% compared with 65.8%.

“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 non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations,” Anne White, president of Lilly Oncology, said in a press release. “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.”

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