Efficacy pronounced for patients with PD-L1 expression on 50% or more tumor cells

Use of the programmed death-ligand-1 (PD-L1) inhibitor atezolizumab (Tecentriq) after adjuvant chemotherapy extended disease-free survival compared with best supportive care in patients with resected stage II-IIIA non-small cell lung cancer (NSCLC) whose tumors expressed PD-L1 on 1% or more of tumor cells, the multi-center, phase III IMpower010 trial found.

The additional benefit from adjuvant immune checkpoint inhibitor therapy was particularly pronounced in patients with PD-L1 expression on 50% or more of tumor cells.

At a median follow-up of 32.2 months (interquartile range (IQR), 27.4-38.3 months), adjuvant atezolizumab reduced the risk of recurrence, new primary NSCLC, or death by 34% compared with best supportive care in the stage II-IIIA patient population whose tumors expressed PD-L1 on 1% or more of tumors cells, at a Hazard Ratio (HR) of 0.66 (95% CI, 0.50-0.88; P=0.003), Enriqueta Felip, MD, Vall d’Hebron University Hospital, Barcelona, Spain, and colleagues reported in the Lancet.

The same adjuvant regimen also improved disease-free survival by 21% in all patients with stage II-IIIA disease regardless of PD-L1 expression at a HR of 0.79 (95% CI, 0.64-0.96; P=0.020), Felip and colleagues noted.

However, the improvement in survival appeared to be largely driven by patients with PD-L1 expression on 50% or more of tumor cells among whom disease-free survival was extended by 57% compared with best supportive care at a HR of 0.43 (95% CI, 0.27-0.68).

In contrast, the benefit from adjuvant atezolizumab was much less pronounced among the stage II-IIIA population with PD-L1 expression on 1 to 49% of tumor cells where the primary endpoint was extended by only 13% at a HR of 0.87 (95% CI, 0.60-1.26), the study authors noted. And in patients in the stage II-IIIA population whose tumors expressed PD-L1 on less than 1% of tumor cells, adjuvant PD-L1 blockade had little effect on the primary endpoint compared with best supportive care at a HR of 0.97 (95% CI, 0.72-1.31).

“To our knowledge, IMpower010 is the first randomized phase 3 study to show significant improvement in disease-free survival with adjuvant immunotherapy following adjuvant chemotherapy in patients with early-stage resected NSCLC,” Felip and colleagues wrote.

“”[T]he positive primary endpoint results, along with a safety profile consistent with previous reports and no new safety signals, suggest that atezolizumab after adjuvant chemotherapy might offer a promising treatment option that extends disease-free survival in patients with stage II-IIIA resected early-stage NSCLC, specifically in patients whose tumors express PD-L1 on 1% or more of their tumor cells and especially in patients whose tumors express PD-L1 on 50% or more of tumor cells,” they suggested.

Following resection, a total of 1005 patients received one of 4 adjuvant cisplatin-based chemotherapy regimens for up to four 21-day cycles. After randomization, patients received either 1200 mg of the PD-L1 inhibitor intravenously on day 1 of each 21-day cycle for up to 16 cycles over the course of 1 year or best supportive care. Best supportive care included observation and regular scans for disease recurrence, the investigators noted.

The median number of cycles of atezolizumab given was 16 (IQR, 7-16 cycles) and almost two-thirds of patients randomized to atezolizumab received all 16 cycles of PD-L1 inhibitor therapy.

“In all patients in the stage II-IIIA population, the 3-year disease-free survival rates were 56% in the atezolizumab group and 49% in the best supportive care group,” the researchers reported.

In the intent-to-treat population, defined as those with stage IB-IIIA disease, disease-free survival rates were 58% in the PD-L1 inhibitor arm compared with 53% for the best supportive care arm. Because this was a preplanned interim analysis, 5-year disease-free survival rates were not estimable in either treatment group, nor was overall survival.

Grade 3 to 4 adverse events (AEs) occurred in 22% of patients receiving atezolizumab compared with 12% of patients receiving best supportive care. Some 18% of patients in the PD-L1 inhibitor group developed serious AEs compared with 8% of those treated with best supportive care, although grade 3 to 4 treatment-related AEs occur in only 11% of the PD-L1 inhibitor-treatment group.

The most common atezolizumab-related AEs were hypothyroidism, pruritis, and rash. The most common immune-mediated AEs were hepatic laboratory abnormalities, rash, and hypothyroidism.

The authors pointed out that, up until the ADAURA trial where it was shown that 3 years of adjuvant osimertinib (Tagrisso) in patients with EGFR-driven NSCLC improved disease-free survival, no improvements in disease-free survival had been achieved for over 15 years.

“The results from our study (ImPower010) now provide another positive outcome with adjuvant treatment in patients with resected stage II-IIIA NSCLC,” Felip and colleagues wrote, although as they also emphasized, all patients in the study received chemotherapy as part of the protocol which remains an important part of adjuvant treatment.

Commenting on the findings, Justin Gainor, MD, Massachusetts General Hospital, Boston, Massachusetts, noted that “IMpower010 represents an important landmark in thoracic oncology, marking the first randomized study of adjuvant PD-L1 blockade in NSCLC.”

Moving forward, however, Gainor also suggested that the most important question facing oncologists is: Which patients are the most likely to benefit from adjuvant PD-L1 inhibitor therapy?

“IMpower010 suggests that PD-L1 expression might enrich for clinical benefit among stage II-III patients receiving adjuvant atezolizumab,” he wrote.

At the same time, the study raises questions about the optimal level of PD-L1 expression cutoff, given that the disease-free survival benefit was considerably more pronounced in patients with PD-L1 expression on 50% or more of tumor cells compared to those with PD-L1 expression on only 1% or more of tumor cells, with even less benefit seen among patients with PD-L1 expression on 1-49% of tumor cells.

“[T]hese results align with standard PD-L1 cutoffs in the metastatic setting (≥50%, 1-49% and <1%) and are consistent with findings from KEYNOTE 042,” Gainor noted.

In KEYNOTE 042, the PD-1 inhibitor, pembrolizumab (Keytruda), significantly improved survival in patients with metastatic NSCLC with PD-L1 expression on 1% or more of tumors cells, but again, the survival benefit was predominantly driven by patients with PD-L1 expression on 50% of more of tumor cells, Gainor pointed out.

Nevertheless, IMpower010 represents an important step forward, Gainor noted.

“In my view, adjuvant atezolizumab should be a new standard of care for patients with surgically resected, PD-L1-psotive stage II-IIIA NSCLC after completion of adjuvant chemotherapy, with particular emphasis on those patients with PD-L1 expression on 50% or more tumor cells,” he wrote, and concluded, “More broadly, the success of adjuvant PD-L1 blockade in patients with NSCLC, along with recent data in melanoma, sets the stage for continued expansion of immune checkpoint inhibitors into the adjuvant setting across disease areas over the ensuing decade.”

  1. PD-L1 blockade with the immune checkpoint inhibitor atezolizumab extended disease-free survival compared with best supportive care in resected, stage II-IIIA NSCLC patients.
  2. NSCLC patients with lower PD-L1 levels of tumor expression benefitted to a much lesser extent from adjuvant atezolizumab while those with virtually no PD-L1 tumor expression did not benefit from adjuvant PD-L1 blockade at all.

Pam Harrison, Contributing Writer, BreakingMED™

The study was funded by Hoffman-La Roche and Genentech.

Disclosures: Felip has received advisory or consulting fees from 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, and Takeda as well as honoraria from Amgen, AstraZeneca, Bristol–Myers Squibb, Eli Lilly, F Hoffman-La Roche, Janssen, Medscape, Medical Trends, MSD, Merck Serono, Peervoice, Pfizer, Springer, and Touch Medical. She has also received personal fees from GRIFOLS.

Gainor has served as a compensated consultant for Genentech/Roche and has also served as a compensated consultant or received honoraria from Bristol–Myers Squibb, Takeda, Loxo/Lilly, Blueprint, Oncorus, Regeneron, Gilead, Moderna, AstraZeneca, EMD Serono, Pfizer, Novartis, Merck, GlydeBio, and Karyopharm. He has also received research support from Novartis and institutional research support from Bristol–Myers Squibb, Tesaro, Moderna, Blueprint, Jounce, Array Biopharma, Merck, Adaptimmune, Novartis, and Alexo.

 

Cat ID: 24

Topic ID: 78,24,730,24,192,65,925