ESMO: Merck, in flurry of studies, shows Keytruda's power and limitations

At this year’s congress of the European Society for Medical Oncology (ESMO), Merck & Co. unleashed a flurry of studies showing Keytruda’s power across multiple tumor types. But there was one notable miss.

Across four separate studies, Merck’s PD-1 juggernaut—in combination with other cancer meds—charted complete and partial wins in cervical cancer, early breast cancer and stomach cancer. At the same time, Keytruda missed the mark in aggressive prostate cancer.

First, the good news: At around 18 months in the phase 3 study coded KEYNOTE-A18, Keytruda plus concurrent chemoradiotherapy slashed the risk of disease progression or death by 30% versus chemoradiotherapy alone in newly diagnosed patients with high-risk, locally advanced cervical cancer.

At the 24-month mark, progression-free survival ticked up to 67.8% for patients on the Keytruda combo, versus 57.3% for those who received concurrent chemoradiotherapy alone.

The data looked good when it came to Keytruda's ability to help patients live longer overall, too, though the results weren't mature and didn’t hit statistical significance at the time of Merck’s interim analysis, the company said in a press release.

KEYNOTE-A18 is still running, with Merck continuing to monitor for more overall survival results.

There hasn’t been an update to treatment standards for patients with locally advanced cervical cancer since 1999, Marjorie Green, senior vice president and head of late-stage oncology development at Merck, said in an interview.

Based on what the company has seen from the overall survival data so far, intervening in the disease early by adding Keytruda to chemoradiotherapy “really can help prevent patients from having to deal with that recurrence and death from cancer,” she said.

With the positive results in hand, Merck has snagged a priority review for its Keytruda-radiochemotherapy combination in newly diagnosed, high-risk locally advanced cervical cancer. The FDA is set to decide on approval by Jan. 20, 2024.

Keytruda already boasts cervical cancer approvals in later-stage disease. The PD-1 inhibitor is cleared to treat persistent, recurrent or metastatic cervical cancer in patients with PD-L1-expressing tumors either with or without Avastin. The drug is also approved alone for the treatment of recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

Meanwhile, Merck also unveiled more detailed results from the late-stage trial KEYNOTE-756, which is evaluating Keytruda plus chemotherapy as a neoadjuvant treatment, followed by Keytruda plus endocrine therapy as an adjuvant regimen for patients with high-risk, early-stage estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer.

Those who received the Keytruda-chemotherapy regimen ahead of surgery charted a 24.3% pathological complete response (pCR) rate versus 15.6% for patients who received chemotherapy alone. PCR is defined as a lack of all signs of cancer in tissue samples analyzed after completion of neoadjuvant therapy and surgery.

KEYNOTE-756 is ongoing with the aim to evaluate event-free survival, the study’s other dual primary endpoint.

As for the last spot of good news, Keytruda plus Herceptin and chemotherapy cut the risk of disease progression or death at 28.4 months by 28% in newly diagnosed HER2-positive stomach cancer versus Herceptin and chemotherapy alone.

Keytruda scored its original gastric cancer approval in 2021 under the FDA's accelerated approval program based on tumor shrinkage data. Its continued approval hinges on positive confirmatory data. Now, the company is working with the FDA to update the current indication to include disease progression data in patients whose tumors express PD-L1, the company said in June.

In Merck’s phase 3 trial, dubbed KEYNOTE-811, the Keytruda-Herceptin-chemotherapy triad reduced the risk of disease progression or death by 30% versus Herceptin and chemotherapy alone in patients with PD-L1-expressing tumors. The Keytruda trio showed no benefit in PD-L1 negative patients.

During an interim analysis at a median follow-up period of 38.5 months, the Keytruda regimen charted a “positive trend” in overall survival, though the data did not reach statistical significance at the time of the review. Merck will continue to monitor overall survival in KEYNOTE-811, the company said.

It wasn’t all good news for Keytruda at ESMO, however, with Merck revealing more details on the PD-1 inhibitor’s miss in metastatic castration-resistant prostate cancer (mCRPC).

Earlier this year, Merck said that Keytruda, used on top of Astellas and Pfizer’s Xtandi and androgen deprivation therapy, didn’t add any survival benefit for mCRPC patients who hadn’t received prior chemo. The drug didn’t help stave off cancer progression, either.

Based on the observation, Merck decided to discontinue the study, coded KEYNOTE-641, at the recommendation of an independent data monitoring committee, the company said in February.

Keytruda has had a solid run in recent weeks. Elsewhere at ESMO, the PD-1 superstar showed that in tandem with Seagen and Astellas’ antibody-drug conjugate Padcev, it could reduce the risk of death by 53% over chemo alone in bladder cancer patients eligible for cisplatin or carboplatin-containing chemotherapy.

The median overall survival result for combo regimen patients was 31.5 months, compared to 16.1 months for those on chemotherapy.

Meanwhile, Keytruda recently snagged a much-coveted approval to be used both as part of a neoadjuvant regimen before surgery and as an adjuvant therapy after surgery in patients with resectable non-small cell lung cancer.

Still, there are rough waters ahead: Aside from 2028—the year Keytruda loses its exclusivity—Merck must now fear for 2026, when the Inflation Reduction Act will allow Medicare to negotiate prices for the drugs on which it spends the most.