ESMO: Regeneron, Sanofi take another stab at lung cancer with Libtayo-chemo win. Should Merck worry?

In the increasingly crowded market for immunotherapy in newly diagnosed non-small cell lung cancer, Regeneron and Sanofi hope to expand Libtayo into a broader population with a chemo combo regimen. And now, they've turned up competitive data that could pressure entrenched players Merck & Co. and Bristol Myers Squibb.

Libtayo, used on top of platinum doublet chemotherapy, reduced the risk of death by 29% over chemo alone in patients with previously untreated, advanced non-small cell lung cancer, according to data released at the European Society for Medical Oncology 2021 virtual congress.

The 29% improvement in patient survival may not seem so impressive, especially after Keytruda put up a massive 51% risk reduction. But a closer look at the results as offered by Regeneron and Sanofi could give rivals Merck and Bristol Myers pause.

The phase 3 Empower-Lung 3 trial included both squamous (43%) and nonsquamous (57%) NSCLC patients, all without actionable mutations. The Libtayo-chemo combo extended patient survival to a median 21.9 months, versus 13 months for the solo chemo group.

Difficult comparison looks good for Libtayo

By contrast, in Keytruda’s historic Keynote-189 trial, where the Merck PD-1 posted the 51% death risk reduction at an interim analysis, Keytruda and chemo prolonged survival for nonsquamous patients to about 22 months, whereas the control group recorded 10.6 months at final analysis. Then, in the Keynote-407 trial, squamous patients who took Keytruda and chemo lived a median 15.9 months, compared with 11.3 months for solo chemo, leading to a death risk reduction of 36% at interim.

RELATED: Sanofi, Regeneron stop Libtayo-chemo lung cancer trial early on strong survival data

Notice the difference? Libtayo’s overall survival showing across disease subtypes looked very similar to Keytruda’s at its best in the nonsquamous group, and the chemo arm appeared to have performed better in Empower-Lung 3 than in the Keytruda trials.

Regeneron entered the study expecting to see about 12 months of median overall survival for the chemo group, Israel Lowy, senior VP of translational and clinical sciences of oncology at Regeneron, told Fierce Pharma in an interview.

Still, one can't conclude that Libtayo is necessarily better than Keytruda, because there's an important difference between the studies: Empower-Lung 3 enrolled both advanced (stage 3) and metastatic (stage 4) patients, while the Keytruda trials only included stage 4 disease. In the Libtayo trial, 15% of patients had inoperable locally advanced disease not eligible for definitive chemoradiation.

But Lowy argued that including those earlier-stage patients didn’t push up Libtayo’s survival performance. According to him, advanced patients who aren’t eligible for surgery or chemoradiation have large tumor masses, so they don’t necessarily do better than patients with small metastases. He did notice, however, that relative to the nonsquamous population, the squamous group appeared to have done better for Libtayo compared with results seen in other trials.

RELATED: Sanofi, Regeneron's Libtayo snags lung cancer nod, taking a stab at Keytruda's megablockbuster lead

A more straightforward comparison could be made with Opdivo, whose use alongside Bristol’s CTLA-4 inhibitor Yervoy and chemo snagged their front-line NSCLC approval last May.

In the CheckMate 9LA trial, the Opdivo-Yervoy-chemo cocktail cut patients’ risk of death by 31% over chemo. Patients with recurrent or stage 4 disease who took the Bristol regimen lived a median 14.1 months, versus 10.7 months for chemo at an interim analysis. The trial also recruited both squamous (31%) and nonsquamous (69%) subtypes.

One weak point for Libtayo-chemo lies in the PD-L1-negative group. In a subgroup analysis, patients with PD-L1 expression below 1%, who make up about one-third of the total trial population, performed similarly between the Libtayo regimen and solo chemo in terms of overall survival. Although the trial isn’t powered to statistically perform that analysis, the number could spell trouble for Libtayo potentially for PD-L1 nonexpressers. (Graphic for subgroup analysis can be found at the bottom of the article)

The Libtayo trial used a different companion diagnostic (SP263) than in the Keynote trials, Petra Rietschel, M.D., Ph.D., Regeneron’s executive director of immuno-oncology clinical development, wrote in a post on ESMO’s online platform during Libtayo’s presentation. “The difference in results might be due to SP263 being more sensitive and identifying a truly negative subset,” she wrote.

Cross-trial comparisons can be difficult, given different trial designs. But the new data at least showed Libtayo can be competitive in front-line NSCLC. With the 22-month overall survival data, Regeneron’s “sales reps will have plenty of firepower when detailing Libtayo as a viable anti-PD-1 option in 1L NSCLC,” Piper Sandler analyst Christopher Raymond wrote in an August note to investors.

It takes more than data

But as Evercore ISI analyst Josh Schimmer noted in an August report, “it will take more than clinical data alone to gain a foothold in 1L NSCLC.” He didn’t yet see a niche market for Libtayo but said he would keep an eye on the companies’ commercialization plans, including potential discounting.

Thanks to an FDA nod in February, Libtayo monotherapy is already allowed for front-line treatment of patients with locally advanced or metastatic NSCLC whose tumors have high levels of PD-L1 expression—50% or more. That population, according to Lowy, makes up about 30% of the NSCLC pool.

RELATED: WCLC: With Keytruda-Yervoy data, Merck casts doubt on Opdivo's place in lung cancer

“We’re under no illusion that we’re suddenly going to take over the market,” Lowy said. “But we do believe that when one looks across different agents and you ask yourself the question of which one of these have delivered consistent results again and again with either monotherapy or chemo combination, we’re one of only two agents that have done that.”

Keytruda is the other PD-1/L1 that also succeeded as a monotherapy in PD-L1-high NSCLC.

Libtayo’s launch in lung cancer is progressing well, according to Regeneron. “Lung cancer thought leaders recognized Libtayo’s clinical differentiation, highlighting the rapid response rates and efficacy in patients with clinically stable brain metastases or high PD-L1 expression,” Regeneron’s commercial chief Marion McCourt said during a conference call in early August.

The Empower-Lung 3 trial also has a second part that pairs Libtayo with Yervoy and chemo in patients with PD-L1 expression at lower than 50%. Lowy said the company started the trial amid a general excitement over CTLA-4 inhibitors' potential boosting effect on PD-1 blockade.

But as data mature, “if you have a good anti-PD1 plus standard chemotherapy, it’s hard to convince yourself that combinations including CTLA-4 to date really do better than that, and it sometimes comes with the cost of additional toxicities associated with CTLA-4,” he said. So the company has stopped that cohort early, pending readout, and doesn’t plan to seek regulatory approvals with it, he added.

RELATED: Lower Libtayo's price before Chinese PD-1s do, says analyst in open letter to Regeneron CEO

More competitors are on the horizon. AstraZeneca recently reported that its combination of Imfinzi, its investigational CTLA-4 agent tremelimumab and chemotherapy cut the risk of death by 23% over chemo alone in previously untreated stage 4 NSCLC.

Eli Lilly and its Chinese partner Innovent Biologics have an application under FDA review for China-approved PD-1 inhibitor Tyvyt in a combo with Lilly’s own Alimta and platinum chemo for newly diagnosed nonsquamous NSCLC.

Looming competition from potentially cheaper China-made drugs could shift the discussion around checkpoint inhibitors to choosing between “data-led” products like Keytruda and “fairly priced” newcomers, Bernstein analyst Rony Gal recently observed. In a letter to Regeneron CEO Len Schleifer, he called on the U.S. pharma to play the price card first to gain a firmer foothold for Libtayo.

Editor's Note: The story has been updated with additional information about Libtayo's performance in PD-L1 nonexpressers.

Empower-Lung 3 subgroup OS analysis (Miranda Gogishvili/ESMO 2021)