Merck, Eisai's Keytruda-Lenvima combo wins simultaneous OKs in U.S., Canada and Australia

Talk about making pharma history. Merck & Co.’s Keytruda has racked up yet another first-of-its-kind approval, this time in a combo with partner Eisai’s Lenvima.

Drug regulators from the U.S., Canada and Australia have concurrently granted green lights to the Keytruda-Lenvima pair for women with certain advanced endometrial carcinoma.

The simultaneous decisions are the first made under Project Orbis, a collaboration among the FDA, the Australian Therapeutic Goods Administration (TGA) and Health Canada that aims to cut cancer drugs’ review time across country borders. The pilot program allows for concurrent submissions by the sponsors and collaborative reviews by all three agencies.

The nod is for endometrial cancer that’s not microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) and for patients whose tumors have progressed following prior treatment. Sound familiar? That’s because Keytruda already has FDA approval as a monotherapy for MSI-H or dMMR cancers; its green light in that indication marked the first time the FDA approved a drug based on a biomarker rather than tumor location, otherwise known as a tissue-agnostic therapy.

Under Project Orbits, the FDA doles out decisions under the “accelerated approval” pathway, while Health Canada uses its counterpart program of conditional approval and TGA its provisional approval.

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In Keytruda-Lenvima’s case, the FDA based its decision on tumor shrinkage results from the single-arm Keynote-146 study. Among the 94 patients with cancers that were not MSI-H or dMMR, the combo triggered responses in 38.3% of participants, with 10 patients (10.6%) showing no signs of cancer following treatment. Of the responders, 25 experienced benefits for longer than six months.

The combo's response rate was 24 to 25 percentage points higher than those Keytruda and Lenvima alone have historically posted, SVB Leerink analyst Daina Graybosch wrote in a Wednesday note to clients. Her team has set improvement of 20 percentage points as the bar for proving a combination's use in single-arm studies where anti-PD-1/L1 has failed alone. “With this approval as a precedent, we see a clearer path for combination accelerated approval in high-unmet need indications with poor response to anti-PD(L)1 alone,” she said.

Endometrial cancer is the most common cancer of the female genital tract, according to the FDA. And of all the cases, at least 75% are not MSI-H or dMMR, Takashi Owa, Eisai’s oncology chief discovery officer, said in a statement.

Based on the data, Graybosch's team has estimated U.S. sales for the combo between $86 million and $240 million by 2022. The wide range is the result of very competitive historical results from other therapies. Avastin and chemo previously exhibited a 72% overall response rate and extended patients' lives by a median of 23.5 months, though Graybosch cautioned it as an “overly positive comparison” because it enrolled many untreated and platinum-sensitive recurrent patients. A more fair comparator would be the combo of Novartis' mTOR inhibitor Afinitor and Femara; the pair produced a 32% response rate and extended patients' lives by a median 14 months in a separate phase 2 study featuring a majority recurrent population. 

“Given these competitive off-label options, we believe an additional study of Keytruda + Lenvima with survival benefit will be necessary to reach full potential,” Graybosch's team said in the note. Phase 3 studies testing the combo in the second-line and first-line settings are expected to read out around 2022 and 2023. 

The FDA also reviewed the combo under the agency’s Real-Time Oncology Review pilot program, which allows its experts to evaluate data as soon as they read out and before the drugmakers completed the submission of the entire drug application. Keytruda has benefited from the program before when its use, in tandem with Eli Lilly’s Alimta and platinum chemo, was fully approved in previously untreated non-squamous non-small cell lung cancer (NSCLC) a year ago.

Merck nabbed half of Lenvima’s rights back in March 2018. The kinase inhibitor also bears nods in thyroid cancer, in combination with Novartis’ Afinitor in kidney cancer and in first-line liver cancer.

While the current go-ahead is the first for the pairing of Keytruda and Lenvima, the combo also boasts two FDA “breakthrough” designations in advanced or metastatic kidney cancer and newly diagnosed liver cancer; other studies in melanoma, bladder cancer, NSCLC and more are ongoing.

Lenvima is now credited as a key growth driver for both Merck and Eisai. Thanks to its liver cancer launches in different countries, especially in the U.S. and China, Lenvima sales more than doubled year over year in the three months ended in June, reaching 24.76 billion yen ($228.8 million), Eisai said in July.

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As for Keytruda, the unshakeable PD-1 king just keeps steamrolling with Street-beating sales numbers one quarter after another. A pooled analysis from three trials recently showed the Keytruda-chemo combo could cut the risk of death by 44% over chemo alone in PD-L1-negative patients with advanced NSCLC, a population where it faced doubts.