Atezolizumab in NSCLC: Push the Positive, Bury the Negative?

Megan Brooks

July 26, 2023

Recently published conclusions from the first interim analysis of overall survival in the IMpower010 trial of adjuvant atezolizumab for non–small cell lung cancer (NSCLC) have met with some pushback on Twitter.

Here's why.

At a median follow-up of 45.3 months, 127 of 507 patients (25%) in the atezolizumab group and 124 of 498 (24.9%) in the best supportive care group had died.

Among all 882 patients with stage II–IIIA disease, the investigators found no significant improvement in overall survival with atezolizumab compared with best supportive care (hazard ratio [HR], 0.95; 95% CI, 0.74 – 1.24).

The researchers, however, concluded that the trial showed a "positive" trend favoring atezolizumab in PD-L1 subgroup analyses.

In a subgroup of 476 patients with tumor PD-L1 expression ≥1%, patients who received atezolizumab exhibited a nonsignificant 29% improvement in overall survival (HR, 0.71; 95% CI, 0.49 – 1.03). The best results were in the subgroup of 229 patients with tumor PD-L1 expression ≥50% ― these patients exhibited a 57% improvement in overall survival with atezolizumab (HR, 0.43; 95% CI, 0.24 – 0.78). Those with PD-L1 expression 1% to 49%, however, demonstrated no improvement in overall survival (HR, 0.95).

In a Twitter post, H. Jack West, MD, City of Hope Comprehensive Cancer Center, Duarte, California, urged caution in interpreting the study data: "Let's be clear: OS results are neg for OS benefit in PD-L1+ NSCLC. If we're going to rely on smaller subgroups to highlight HR of 0.43 for those w/high PD-L1, we should also note HR for OS was 0.95 (i.e., NO trend for OS benefit) for those w/PD-L1 1-49%."

The tweet continued: "With favorable results driven entirely by a 30% subgroup, it's understandable that Roche would want to also promote benefit in broader population. But we shouldn't perpetuate misinformation that there's a benefit for broad group of PD-L1+, even if the effort is to market it this way."

In an interview with Medscape Medical News, West elaborated on his tweet, explaining that the way the overall survival data are presented in the paper is "disingenuous and misleading."

The paper clearly highlights that the drug was significantly beneficial for the narrower population who had high PD-L1 expression. But the hazard ratio of 0.95 for the entire population is like "where's Waldo in this paper. It's almost impossible to find, but it should have been prominently included in the figure of results by subgroup," West said.

"This is something that should have been objected to by the oncologists on the paper and by the reviews and the editors," West said.

Two other oncologists agreed.

Joel Grossman, MD, tweeted: "Bingo. I'm not sure we need cancer ground shots or lengthy treatises on common sense, but I am damn sure we need honest interpretation of clinical trial data as Jack shows here. We can't tolerate over broad borderline deception that leads to poor and wasteful decision making."

Jeff Ryckman, MD, tweeted: "Problem is, this is a routine FDA #CarteBlanche approval regardless of no benefit in PD-L1 1-49%. This will be Rx'd to everyone."

Regulatory "Gamesmanship"

The results of the IMpower010 analysis were published online last week in Annals of Oncology. The interim overall survival data were first reported last year at the World Conference on Lung Cancer.

IMpower010 was a global, randomized, open-label trial of 1280 patients with completely resected stage IB (tumors ≥4 cm) through stage IIIA NSCLC for whom tissue samples were available for PD-L1 analysis.

All patients received four cycles of chemotherapy with cisplatin plus either pemetrexed, gemcitabine, docetaxel, or vinorelbine and were randomly assigned in a 1:1 ratio to receive either 16 cycles of atezolizumab or best supportive care.

Interim disease-free survival (DFS) results from IMpower010, presented at ASCO 2021, showed that patients with PD-L1 expression ≥1% experienced a 34% improvement in DFS, equating to a 21% improvement across all randomly assigned patients with stage II–IIIA disease.

On the basis of DFS findings, in 2021, the US Food and Drug Administration granted atezolizumab a new indication — the adjuvant treatment following resection and platinum-based chemotherapy for patients with stage II–IIIA NSCLC whose tumors have PD-L1 expression ≥1%.

Looking at the big picture, West noted that regulatory approval for a drug allows for a certain amount of "gamesmanship."

"It behooves a company to work with FDA to get approval for a broader population than it should be, relative to where the true clinical benefit lies," he explained.

To this end, West noted that progression-free survival is increasingly being used as a primary endpoint in trials, but long-term data indicate that this surrogate endpoint is often not tethered to an overall survival benefit. However, drugs are often being approved now on the basis of a progression-free survival benefit.

"Unfortunately, that's the system we live in today, with a bias toward, 'If it could plausibly be interpreted as beneficial, we'll wave it through for the broadest population possible,' " West said.

The IMpower010 study and Annals of Oncology manuscript were funded by F. Hoffmann La Roche . Several authors have disclosed relationships with the company. West has a regular column on and reported personal fees from AstraZeneca, Genentech/Roche, Merck, and Regeneron.

Ann Oncol. Published online July 17, 2023. Full text

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