In new PD-1 showdown, GSK's Jemperli loses initial edge on Merck's Keytruda

After GSK late last year celebrated a head-to-head win for its cancer drug Jemperli against Merck & Co.’s Keytruda, the companies are offering another opportunity to compare their PD-1 inhibitors side by side. Only this time, the GSK latecomer appears to have lost its competitive edge, according to a cross-trial review of the latest results.

At the Society of Gynecologic Oncology annual meeting on Monday, both GSK and Merck provided a closer look at their PD-1 drugs’ phase 3 data in first-line endometrial cancer.

Both drugs showed that their addition to chemotherapy can significantly improve patient outcomes over chemo alone. But the results once again suggested that for GSK, challenging the world’s best-selling immunotherapy won’t be an easy task.

When used on top of chemo, GSK’s Jemperli pared down the risk of tumor progression or death by a whopping 72% in patients with primary advanced or first recurrent endometrial cancer with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors. The data came from a two-year follow-up of the phase 3 RUBY trial.

By comparison, Merck’s Keytruda, used in tandem with the same chemo regimen, posted a 70% relative risk reduction in a similar dMMR patient population. The Keytruda data were derived from a one-year follow-up of the phase 3 NRG-GY018 trial.

The two drugs' impressive benefits in dMMR were largely expected: PD-1 inhibitors are known to work well in tumors bearing this biomarker, and both Keytruda and Jemperli boast FDA approvals in previously treated dMMR cancers regardless of the tumor location.

The competition, then, naturally came down to the results in the MMR proficient (pMMR) subgroup. This patient subgroup makes up about two-thirds of all endometrial cancer cases, according to Merck Research Laboratories’ chief medical officer Eliav Barr, M.D. 

In that population, GSK’s Jemperli looked weaker than its rival.

Jemperli underwhelmed in key subgroup

In pMMR patients, the Jemperli regimen’s relative risk of disease progression or death was 24% lower than chemo alone after roughly two years of follow-up. In contrast, Keytruda was linked to a 46% risk reduction but over a much smaller timeframe. The results were also simultaneously published in The New England Journal of Medicine (here and here).

The Keytruda trial investigators cautioned in their NEJM article that the pMMR patients were only followed for a median of 7.9 months, representing one key study limitation. And in both dMMR and pMMR patients outside the U.S., the Keytruda arm performed even worse than the chemo group.

The trials had some other differences that complicate making a direct comparison. During an interview with Fierce Pharma, GSK’s oncology development head Hesham Abdullah noted that the Jemperli trial enrolled patients with carcinosarcoma, a subtype linked with poor prognostic characteristics.

“The results from the RUBY clinical trial, especially given the difficult-to-treat histologies included in the trial, demonstrate support for” using Jemperli in first-line endometrial cancer, the RUBY trial principal investigator, Mansoor Raza Mirza from the Copenhagen University Hospital, said in a statement provided by GSK.

GSK also had more data to share on patient survival. In the entire RUBY trial, the Jemperli-chemo combo cut the risk of death by 36% over chemo alone. The data at this point was immature and just narrowly missed statistical significance, Abdullah said. Once again, the overall survival benefit was milder in the pMMR group, with a risk reduction of 27%.

A tough battle playing catch-up

Jemperli’s relatively low 24% progression-free survival (PFS) showing in pMMR patients could raise questions about its clinical meaningfulness. But Abdullah argued that the PFS data, together with a “strong trend” for overall survival improvement, are clinically relevant.

GSK has pegged first-line endometrial cancer as a potential inflection point for Jemperli, which only generated £21 million last year. The British pharma plans to file for an approval by June.

But the data comparison now put the GSK drug in a disadvantage in the market.

During an email interview with Fierce Pharma before the data release, SVB Securities analyst Daina Graybosch, Ph.D., said that if Jemperli’s RUBY results come in numerically lower than Keytruda's, GSK would struggle to get revenue and market share.

“Merck has a massive loyalty and experience advantage in endometrial [cancer],” Graybosch said. Merck has built a fortress of clinical data around its top drug Keytruda, which generated $20.9 billion in 2022 sales.

In endometrial cancer specifically, Keytruda has an additional approval for use alongside Eisai-partnered Lenvima in previously treated pMMR disease.

Even if Jemperli had shown better data, Graybosch argued that it would take more than one indirect comparison for GSK to really make a meaningful impact on clinical practice. Only if Jemperli builds a “real trend of overperformance” through multiple trials would people start to ask whether it's a better PD-1 drug, she said. 

GSK did recently tout a Jemperli head-to-head win against Keytruda in front-line nonsquamous non-small cell lung cancer, showing a numerical advantage in tumor response and PFS in a phase 2 trial. But Graybosch said she wouldn’t read too much into that trial given it was small, and that Jemperli’s outperformance wasn’t enough to impress her from a statistical point of view.

Instead, that phase 2 trial gave GSK “strong support” that Jemperli isn’t worse than Keytruda, Graybosch said. That will give researchers more confidence in future Jemperli combination trials, especially if Jemperli monotherapy underperforms historical data.

As for Keytruda, the NRG-GY018 trial investigators didn’t yet have any overall survival data to share. But Merck’s Barr argued that the PFS benefits across dMMR and pMMR populations are substantial, and that getting the most effective therapy upfront to save patient additional rounds of therapy is important because cancers can become more and more resistant to treatment over time.

He also cautioned that the final overall survival data might not be that significant because patients in the control arm were also allowed to receive subsequent Keytruda treatment.

Merck is also talking to the FDA about filing Keytruda in front-line endometrial cancer. Besides Keytruda-plus-chemo, Merck is working with Eisai to test Keytruda and Lenvima in the same setting in the Leap-001 trial. That study bears an expected primary completion date in November, according to