ASCO: Merck bills Keytruda, used around surgery, as new standard in 'messy' early lung cancer realm

As doctors weigh various immunotherapy strategies for the treatment of early-stage non-small cell lung cancer (NSCLC), Merck & Co. has now unveiled new data that it hopes can establish Keytruda, used both before and after surgery, as a new standard of care.

Using Keytruda around surgery reduced the risk of disease recurrence, progression or death by 42% in patients with resectable stage 2 to 3b NSCLC, according to data to be presented at the American Society of Clinical Oncology's (ASCO) annual meeting.

Keytruda mounted that event-free survival (EFS) benefit during an interim analysis of the KEYNOTE-671 trial. In the study, the PD-1 inhibitor is being used on top of neoadjuvant chemo before surgery and then as a single-agent adjuvant therapy after surgery. It’s being pitted against neoadjuvant chemo alone followed by resection and placebo. The continuous use of a treatment before and after surgery is known as a perioperative regimen.

“We anticipate that this will be a really major addition to treatment standards for patients with early-stage lung cancer,” Eliav Barr, M.D., chief medical officer at Merck Research Laboratories, said in an interview with Fierce Pharma ahead of the data release.

Based on the phase 3 data, Merck is seeking FDA approval for Keytruda as a perioperative treatment in early lung cancer. It's slated to receive a decision from the agency by October 16.

KEYNOTE-671 adds to a stable of positive immunotherapy readouts in early NSCLC, potentially complicating doctors’ treatment choices. Speaking with analysts with SVB Securities, two cancer experts described the landscape as “messy” because of the various approaches.

Roche’s Tecentriq was the first PD-1/L1 inhibitor to enter early-stage NSCLC as an adjuvant treatment, only to be beaten by Keytruda with a broader nod in January. Bristol Myers Squibb’s Opdivo is currently the only PD-1/L1 therapy allowed in the neoadjuvant setting thanks to its showing in the CheckMate-816 trial. AstraZeneca recently posted a positive—but very early—readout for Imfinzi in the perioperative setting from the AEGEAN trial.

KEYNOTE-671’s 42% reduction in EFS appeared to be a best-in-class showing so far. In CheckMate-816, neoadjuvant Opdivo delivered a 37% reduction in patients with stages 1b to 3a NSCLC, a population that’s slightly earlier-stage than those studied in KEYNOTE-671. In AEGEAN, the still immature dataset pointed to a 32% benefit in stage 2 to 3b disease.

Still, Keytruda doesn’t exactly have a decisive win over the other agents after considering the intrinsic flaws in cross-trial comparisons.

Perioperative Keytruda’s 42% showing isn’t materially different from neoadjuvant Opdivo’s 37%. Even though Keytruda came above the 40% threshold that several experts have said would constitute a meaningful benefit, it came below the 45% bar that the two lung cancer experts interviewed by SVB wanted to see. Specifically, those experts said the 45% bar would convince them that patients are really benefiting from adjuvant treatment on top of neoadjuvant therapy, according to the analysts' Wednesday note.

This is important to Keytruda’s—and the PD-1 class’s—sales potential because the adjuvant portion of treatment runs longer.


Interpretation of ASCO results


The new KEYNOTE-671 data showed that patients who received Keytruda went a median 34.1 months without a negative event versus 17 months for control. While Keytruda produced the best median EFS among its competition, its control arm appeared to have underperformed expectations. The median EFS for control was 20.8 months in the Opdivo trial and 25.9 months in the Imfinzi study.

KEYNOTE-671 evaluated “pretty much a standard population of patients around the world,” Barr said, suggesting that it matched real-world experience for such a perioperative clinical program.

The proportion of different cancer stages and geographic location of patients may also affect the data, Heather Wakelee, M.D., from Stanford University and principal investigator of KEYNOTE-671, said in a separate interview with Fierce Pharma.

SVB’s immuno-oncology analyst Daina Graybosch, Ph.D., said in another interview before ASCO that she wouldn’t worry too much about differences in median disease progression among some I-O trials. Calling the median number potentially “misleading,” Graybosch said some drugs may get lucky with where exactly the median falls.

Instead, Graybosch said she would focus on risk reduction and the EFS rate at a specific time after treatment.

Keytruda’s two-year EFS rate, at 62.4%, looked slightly smaller than the 63.3% and 63.8% demonstrated by Opdivo and Imfinzi, respectively. But in KEYNOTE-671, Keytruda offered an absolute improvement of 21.8 percentage points over control, whereas the numbers were 18.5 and 10.9 for Opdivo and Imfinzi, respectively.

Compared with AEGEAN, KEYNOTE-671 also has more mature data as 73% of patients had received their adjuvant therapy by the interim analysis, according to Barr. The rest of the patients had problems that prevented them from getting the adjuvant regimen, he noted.

As for various patient subgroups, Keytruda, as expected, showed stronger benefits in patients with higher PD-L1 expression levels. The reductions in EFS events were 23%, 49% and 58% in the PD-L1-negative, PD-L1 1% to 49%, and PD-L1 of at least 50% subgroups, Wakelee told Fierce Pharma.

A small group of patients who had never smoked appeared to have had little benefit from Keytruda, Wakelee noted. But she pointed out the number was too small to reach any conclusions, and that there was no harm from Keytruda treatment.

The KEYNOTE-671 trial won’t definitively answer the question as to whether continued treatment after surgery is necessary on top of a short treatment before surgery, Graybosch said. That would require a large separate trial that randomizes patients at different treatment points to tease out each component’s contribution.

But both Barr and Wakelee pointed to an analysis that they argue could demonstrate the benefit from the additional adjuvant treatment. The data looked at patients who didn’t achieve what’s known as a major pathological response—defined as very little residual tumor during surgery—after neoadjuvant treatment. The majority of patients in KEYNOTE-671 didn’t reach that status.

Because a major pathological response is an indicator of better treatment outcomes, it’s expected that patients who achieved that result while on Keytruda will drive the EFS benefit, Wakelee explained.

“Therefore, if you’re seeing benefit in those who did not have any kind of major pathological response, it’s tempting to think that some of that benefit, if not all of it, comes from the adjuvant treatment portion," she said.

Among those patients, Keytruda was associated with a 27% reduction in recurrence, progression or death.

In a similar analysis but among patients who didn’t achieve the more stringent complete pathological response—meaning no residual disease in resected tissue—Keytruda showed a 31% edge in EFS, according to Barr.

What’s more, Keytruda also showed a positive trend toward extending lives in the overall trial population, cutting the risk of death by 27%.

Barr said it’s “very likely” that the overall survival data will reach statistical significance at the next planned interim analysis this summer. And Wakelee said “it would be awfully hard” for it not to hit the statistical bar given the data so far.

However, once again complicating the data comparison, Opdivo has recorded a wider 38% reduction in death risk at a longer follow-up of CheckMate-816, according to data presented at the European Lung Cancer Congress 2023 in March. That number is also approaching statistical significance.

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