PD-LI Is Key to Survival Benefit With Atezolizumab in NSCLC

Liam Davenport

August 09, 2022

VIENNA — Immunotherapy with atezolizumab (Tecentriq) offers an overall survival benefit in comparison with best supportive care (BSC) for patients with resected non–small cell lung cancer (NSCLC) following platinum-based chemotherapy, but only for a subgroup of patients with tumors that express programmed cell death ligand 1 (PD-L1).

The new data come from an interim overall survival analysis from the IMpower010 trial. The results were presented on August 8 at the World Conference on Lung Cancer (WCLC) 2022, held in Vienna, Austria, and also online.

The lung cancer community has been eagerly awaiting the data on overall survival from this trial to see whether they echo earlier results that showed a significant improvement in disease-free survival (DFS). Those results led to the approval of atezolizumab in this patient population.

The earlier data on DFS, which was the primary endpoint for this trial, were presented at ASCO's 2021 annual meeting and were later published in The Lancet. The results showed that atezolizumab yielded a significant improvement in DFS over BSC after adjuvant chemotherapy. As reported at the time by Medscape Medical News, the benefit with atezolizumab was greatest for patients with tumors that expressed PD-L1; DFS was improved by 34% in patients with resected stage II–IIIA NSCLC.

The new data focus on overall survival, which was a secondary endpoint. They come from a first prespecified interim analysis that was conducted after a median follow-up of just over 45 months

Dr Enriqueta Felip Font

The results were presented at the WCLC meeting by Enriqueta Felip Font, MD, PhD, head of the Lung Cancer Unit at Vall d`Hebron University Hospital in Barcelona, Spain.

They show that overall, for all patients with stage II–IIIA disease, there was no significant improvement in overall survival with atezolizumab in comparison with BSC.

However, there was a trend toward an improvement of 29% in a subgroup of patients with tumor PD-L1 expression ≥1%.

The researchers found that the best results were among patients with tumor PD-L1 expression ≥50% ― for these patients, there was a 57% improvement in overall survival with atezolizumab, a difference over BSC that Felip described as "clinically meaningful."

She concluded that these new data "support the previously reported positive benefit-risk profile of adjuvant atezolizumab...and contribute to evidence supporting standard-of-care use."

Atezolizumab Already Approved

Discussing the results, Benjamin Besse, MD, PhD, director of clinical research at the Gustave Roussy Institute, Paris, France, pointed out that atezolizumab is already approved for use in these patients but noted that regulatory agencies around the world had taken slightly different approaches to the product labeling, which was based on the DFS results.

In 2021, the US Food and Drug Administration approved atezolizumab as an adjuvant treatment following resection and platinum-based chemotherapy for patients with stage II–IIIA NSCLC whose tumors have PD-L1 expression ≥1%.

A similar path was taken in China and Japan. However, the European Medicines Agency reserved atezolizumab for NSCLC patients whose tumors have expression of PD-L1 ≥50%.

Besse said that although there is "enough evidence to use adjuvant immunotherapy in stage II and stage IIIA resected NSCLC," the divergent path taken over PD-L1 expression in terms of licensing and the conflicting signals from other studies point to the possibility of getting "lost in subgroups" when analyzing the data.

Turning to the new data on overall survival with atezolizumab, he said that longer follow-up is required. The survival curves between atezolizumab and BSC in the IMpower 010 trial are separating, but they need to be watched to determine whether this trend continues. He emphasized that this is not always the case. He cited the results from the International Adjuvant Lung Cancer Trial (IALT), which used adjuvant cisplatin-based chemotherapy and showed that the overall survival benefits of a treatment early on in follow-up could can be later reserved, potentially because of late adverse effects.

Besse also highlighted that MRI has shown that tumors can have hot spots of PD-L1 expression, which raises the question of where PD-L1 is best tested to determine the level of tumor expression.

Indeed, previous studies that investigated circulating tumor cells have suggested that there is "strong discordance" between the PD-L1 expression as measured in tumor tissue and PD-L1 expression as determined using liquid biopsy.

He commented that the tumor cells that are circulating in the blood are probably "the most aggressive component of the disease," and circulating tumor DNA analysis indicates that "when you have minimal residual disease detectable after surgery, the prognosis is very, very poor."

He believes that minimal residual disease is therefore a "key tool," and he hopes that academia will be able to use it to conduct "deescalation trials with this very expensive drug."

Commenting on Twitter, Shankar Siva, MD, PhD, a radiation oncologist at the Peter MacCallum Cancer Center in Melbourne, Victoria, Australia, took up the question of the overall survival curves. He asked whether they are indeed "starting to separate" and highlighted the fact that the data are "still maturing."

https://twitter.com/_shankarsiva/status/1556543891339464704?s=21&t=IAMCEcYFB4nuPp31xbth6w

Siva also highlighted the previous IALT results and said that they offer a "cautionary historical tale of survival curves rejoining after adjuvant chemotherapy...watch this space!"

https://twitter.com/_shankarsiva/status/1556547085515767809?s=21&t=IAMCEcYFB4nuPp31xbth6w

 

Details of the Trial Participants

In her prersentation, Felip reminded the audience that IMpower010 enrolled patients with completely resected stage IB–IIIA NSCLC whose ECOG performance status was 0–1. In addition, they had undergone lobectomy, and tumor tissue was available for PD-L1 analysis.

A total of 1280 patients received one to four 21-day cycles of cisplatin-based doublet chemotherapy. Then 1005 patients were randomly assigned in a 1:1 ratio to receive atezolizumab once every 3 weeks for 16 weeks or 1 year or to receive BSC.

The primary endpoint was DFS, hierarchically tested in three prespecified populations. Overall survival in the intention-to-treat population was a secondary endpoint along with safety outcomes.

Felip reiterated that the original analysis, after a median follow-up of 32 months, showed that the hazard ratio for DFS in stage IB–IIIA get atezolizumab vs BSC was 0.81 (P = .0395).

The hazard ratio for DFS in all randomized stage II–IIIA patients was 0.79 (P = .0205), while that in stage II–IIIA patients with tumor PD-L1 expression ≥1% was 0.66 (P = .0039).

The current interim analysis for overall survival was conducted after the clinical cutoff date of April 18, 2022, at a median follow-up of 45.3 months.

In the intention-to-treat population of all randomized stage IB–IIIA patients, there was no significant difference in overall survival between those treated with atezolizumab and those who received BSC, at a hazard ratio of 0.995 (95% CI, 0.78 – 1.28; P = .995).

A similar pattern was seen in all randomized patients with stage II–IIIA NSCLC, at a hazard ratio of 0.95 (95% CI, 0.74 – 1.24).

However, there was a signal for improved overall survival with atezolizumab in stage II–IIIA patients with tumor PD-L1 expression ≥1%, at a hazard ratio of 0.71 (95% CI, 0.49 – 1.03).

Analysis by biomarker status showed that in stage II–IIIA patients with tumor PD-L1 expression 1%–49%, the hazard ratio for overall survival was 0.95, while that in patients with expression ≥50%, it was 0.43 (95% CI, 0.24 – 0.78).

Excluding patients with tumors positive for EGFR and ALK mutations slightly strengthened the association, at a hazard ratio for overall survival of 0.42 (95% CI, 0.23 – 0.78).

There were also signals that there was trend for improved overall survival with atezolizumab over BSC in patients whose ECOG performance status was 0, whose tumors had nonsquamous histology, and who had undergone lobectomy.

Felip also highlighted that in all the analyses, the median overall survival was not reached for patients in both the atezolizumab and the BSC arms. The study will therefore continue to the final DFS analysis, and there will be further follow-up for overall survival.

She added that after an additional 13 months of follow-up from the previous analysis, the safety profile for atezolizumab "remains broadly unchanged, with no new or unexpected safety signals."

Grade 3–4 adverse events were reported in 22.0% of patients given atezolizumab, vs 11.5% of patiengs who received BSC. Treatment-related grade 5 events were recorded in 0.8% and 0% of patients, respectively.

Serious adverse events occurred 17.8% of patients who received atezolizumab and in 8.5% of BSC patients. Adverse events that led to any treatment withdrawal occurred in 18.2% of patients on the intervention group, vs none of those in the control arm.

The study was funded by F Hoffmann-La Roche and Genentech. Felip has relationships with Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol–Myers Squibb, Eli Lilly, F. Hoffman-La Roche, GlaxoSmithKline, Janssen, Medical Trends, Merck Sharp & Dohme, Merck Serono, Peptomyc, Pfizer, Puma, Regeneron, Sanofi, Syneos Health, Takeda, Medscape, Peervoice, Springer, Touch Medical, and GRIFOLS. Besse has institutional relationships with 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Chugai Pharmaceutical Co, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, EISAI, Genzyme Corporation, GlaxoSmithKline, Inviata, IPSEN, Janssen, Onxeo, OSE Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals, and Turning Point Therapeutics.

World Conference on Lung Cancer (WCLC) 2022: Abstract PL03.09. Presented August 8, 2022.

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