Diving Into Adjuvant Approaches in Early-Stage Resectable NSCLC: PD-L1 Expression and Genomic Considerations

In stage IB to IIIA non–small cell lung cancer (NSCLC) investigators await long-term overall survival (OS) data as clear disease-free survival (DFS) benefits have been observed in patients treated with pembrolizumab (Keytruda) and in patients, especially those with PD-L1 expression of 50% or greater, treated with atezolizumab (Tecentriq), according to Corey J. Langer, MD, FACP. In a presentation at the 21st Annual Winter Lung Cancer Conference^®, Langer detailed data from the phase 3 IMpower010 (NCT02486718) and KEYNOTE-091 (NCT02504372) studies, which examined these agents in NSCLC, and also highlighted the benefits of osimertinib (Tagrisso) and alectinib (Alecensa) in EGFR- and ALK-positive NSCLC, respectively, including in patients with central nervous system (CNS) progression.¹

“Unfortunately, outcomes remain quite poor even in the curative setting [for NSCLC],” Langer, director of Thoracic Oncology at the Abramson Cancer Center and a professor of medicine at the Perelman School of Medicine, both at the University of Pennsylvania in Philadelphia, said during the presentation. “The LACE [Collaborative Group’s] meta-analysis documented an approximate 5.5% absolute improvement in 5-year survival with conventional adjuvant cisplatin-based chemotherapy. This included studies that were positive as well as those that were clearly negative. The benefits were confined largely to patients with node-positive disease, N1 and N2, and [or] to those with tumors larger than 4 cm.”

In both the IMpower010 study, which investigated immunotherapy following surgery and mandatory chemotherapy, and the KEYNOTE-091 study, which examined immunotherapy following optional chemotherapy and surgery, the primary end point was disease-free survival (DFS). The studies enrolled patients with completely resected stage IB to IIIA NSCLC per AJCC version 7 criteria with tumor tissue available for PD-L1 analysis.^2,3

DFS Improvements Seen in IMpower010: PD-L1 Status Examined

In IMpower010, the median DFS in the intention-to-treat (ITT) population was not reached (NR; 95% CI, 36.1-not evaluable [NE]) in the atezolizumab arm (n = 507) vs 37.2 months (95% CI, 31.6-NE) in the best supportive care (BSC) arm (n = 498; HR, 0.81; 95% CI, 0.67-0.99; P = .040).²

“Looking at that higher-risk population with stage II and IIIA [disease] who are PD-L1 positive [n = 476], the HR is a bit more favorable at 0.66 [95% CI, 0.50-0.88]. We see a 12% absolute improvement in DFS at 3 years and that separation continues over time. The statistical significance is not met for all comers or for the all randomly assigned stage II and IIIA patients independent of PD-L1 status,” Langer said.

When examining DFS and PD-L1 status excluding patients with EGFR- or ALK-positive NSCLC for patients treated with atezolizumab vs BSC, the patients who derived the most benefit were those with a PD-L1 expression of 50% or greater (n = 209; HR, 0.43; 95% CI, 0.26-0.71). Patients with PD-L1 expression of 1% or greater (n = 410; HR, 0.62; 95% CI, 0.45-0.86), 1% to 49% (n = 201; HR, 0.82; 95% CI, 0.54-1.25), and less than 1% (n = 312; HR, 0.92; 95% CI, 0.59-0.93), all derived a benefit with atezolizumab vs BSC.⁴

“The group that does the best and we’ve seen this trend certainly with neoadjuvant [therapy], are those with higher levels of expression,” Langer explained. “In that group [of patients with PD-L1 expression] 50% or higher, at 3 years you see a 25% absolute improvement in DFS, and this may or may not trend long term into a survival benefit.”

OS data are not yet mature from IMpower010; however, a clinically meaningful OS trend was observed for patients with PD-L1 expression of 50% or greater, excluding those with EGFR- or ALK-positive disease. Five-year OS rates were 84.8% in the atezolizumab arm vs 67.5% in the BSC arm; the median OS was NR in either arm (HR, 0.42; 95% CI, 0.23-0.78).⁵

Subgroup analyses regarding OS revealed patients with EGFR- or ALK-positive disease and PD-L1 expression of 50% or greater experienced the most benefit with atezolizumab vs BSC and no benefit was observed of those with expression less than 1%.

Langer noted that in IMpower-010, ctDNA appeared prognostic, but “was neither predictive nor sufficiently sensitive for de-escalation decisions.” The median DFS was improved with atezolizumab vs BSC in those who were ctDNA-positive and -negative.¹

KEYNOTE-091 Reveals Different Data Than Expected With PD-L1 Expression

In KEYNOTE-091 the dual primary end point of DFS benefit was met in the overall population of patients who received pembrolizumab vs placebo and OS data are not yet mature.³

In terms of DFS data, Langer explained that “the group we’d expect to benefit the most paradoxically doesn’t seem to. The HR for [patients with] 50% or higher [PD-L1 expression], is 0.82 with a P value of 0.14. We’ve not quite figured this out. The group that seems to have the greatest benefit is the 1% to 49% group with an approximate 13-month improvement in median DFS [and a] HR of 0.67. It’s been speculated, although I don’t think we can necessarily point to this as the major reason, that the reason the 50% or higher group did not realize a clear benefit is the placebo group seemed to over perform amongst those who had 50% or higher expression.”¹

Langer also noted there was not an imbalance in baseline characteristics or toxicity in the group of patients who had a PD-L1 expression of 50% or greater given pembrolizumab (n = 168) vs placebo (n = 165) and median DFS was NR in either arm. The 3-year DFS rates were 65.9% compared with 57.6%, respectively.³

Langer also presented the OS HRs from several trials in the neoadjuvant setting, including the phase 3 KEYNOTE-671 (NCT03425643), Neotorch (NCT04158440), and CheckMate 816 (NCT02998528) trials. He explained, “the HR is 0.62 to 0.72 for the neoadjuvant or periadjuvant approaches. The HR is coming close to 1 for the adjuvant approaches. Ideally, we need a clinical trial comparing these approaches.” In the IMpower010 trial, at a median follow-up of approximately 45 months in the ITT stage IB-IIIA NSCLC population, the HR for OS was 0.995 (95% CI, 0.78-1.28; P = .9661).⁶ In KEYNOTE-091, at a median follow-up of 35.6 months, the HR for OS was 0.87 (95% CI, 0.67-1.15; P = .17).³

Osimertinib Becomes SOC For EGFR-Mutated Disease

“We have 2 long term trials that have been reported that are clearly positive, but this is after a lot of negative trials,” Langer said of the studies examining oncogene driver mutations. “The ADUARA trial changed all that. [It] was first reported 3 years ago [and] led to an FDA approval based initially on DFS data.”

In December 2020, data from ADUARA trial supported the approval of osimertinib for the adjuvant treatment of patients with NSCLC harboring exon 19 deletions or exon 21 L858R mutations.⁷ Findings from the final DFS analysis revealed that the median DFS was 65.8 months (95% CI, 54.4-NE) in the osimertinib arm (n = 339) vs 21.9 months (95% CI, 16.6-27.5) in the placebo arm (n = 343; HR, 0.23; 95% CI, 0.18-0.30).⁸ Benefit was also observed regardless of whether adjuvant chemotherapy was administered.

“There were skeptics like me who wondered after 3 years might the curves start to come together,” Langer asked. “It’s these data that convinced me to start using osimertinib in this setting. It wasn’t just an overall DFS benefit, but a CNS benefit as well. The HR for DFS specifically in the brain, mirroring the extracranial benefit, was 0.24 with nice separation occurring at approximately 6 to 12 months.”

ADAURA is the first phase 3 study examining a targeted agent in the adjuvant setting for NSCLC that demonstrated an OS benefit.⁸

“My major criticism [is that] 39% of those with progression on the control arm crossed over to osimertinib. What happened to the other 62%? They were not getting state of the art treatment and it absolutely underscores the necessity of obtaining molecular testing in early-stage NSCLC which before this we were not doing routinely,” Langer said.

Testing for ALK Alterations in NSCLC

“Up until very recently, the SOC in resected ALK-positive [disease] was adjuvant platinum-based chemotherapy alone,” Langer noted. “This is an advanced disease—approximately 4% to 8% of all our patients. [Patients] tend to be younger at a median age of 55, [are] nonsmokers, and [are at] particularly high-risk for CNS metastases [as] up to 60% of patients within the first 2 to 3 years will have brain involvement. Alectinib [is] quite active in advanced disease.”

Langer cited 3 phase 3 trials which demonstrated treatment with alectinib (Alecensa) resulted in statistically significant and clinically meaningful improvements in DFS vs platinum-based chemotherapy. He explained the phase 3, open-label superiority study ALINA (NCT03456076) examined DFS in a younger cohort of patients with stage IB to IIIA NSCLC who were a median age of 54 years old in the alectinib arm (n = 130) and 57 years in the chemotherapy arm (n = 127). The median DFS was NR vs 41.3 months (95% CI, 28.5-NE), respectively (HR, 0.24; 95% CI, 0.13-0.43; P < .0001). Additionally, the CNS DFS HR was 0.22 (95% CI, 0.08-0.58) and all key subgroups examined experienced benefit with alectinib vs chemotherapy.⁹

Langer noted that platinum-based chemotherapy was not given in the investigative arm in the ALINA trial unlike the ADUARA trial. ALINA is the first phase 3 trial to demonstrate positive results with an ALK inhibitor in stage IB to IIIA NSCLC. OS data from the trial are still immature.

“I would argue [that alectinib is the] SOC at this point in ALK-positive stage IB through IIIA [disease]. I don’t think there will be too much debate about that. The big question is whether we should include chemotherapy or not [as] we still see a 5% advantage [with it]. We probably need a trial comparing alectinib alone to chemotherapy plus alectinib. Is it necessary? Many would argue that the toxicity is not worth it. [We also should ask] what’s the ultimate optimal duration? Is it 2 years, 3 years, or indefinite?”

The phase 2 NAUTIKA-1 (NCT04302025) and phase 3 HORIZON-1 (NCT05170204) trials are ongoing examining alectinib in stage I to III NSCLC.¹

Editor’s Note: Dr Langer cited receiving institutional grant/research support from Pfizer, Lilly, Advantagene, Inovio, Celgene, Ariad (Takeda), Merck, Amgen Genentech/Roche, AstraZeneca, Trizell, Guardant, Fujifilm, and Navire. He is on data safety monitoring committees for Lilly, Incyte, SWOG, Oncocyte, VALOR, and SUMMIT Oncology, and is a Scientific Advisor forBristol Myers Squibb, Lilly, Pfizer, Boehringer-Ingelheim, AstraZeneca, Novartis, Abbott, Genentech/Roche, Bayer/Onyx, Celgene, Clarient, Clovis, Guardant, Merck, and Gilead.

References

1. Langer CJ. Adjuvant therapy in resectable NSCLC: state-of-the-art –2024. Presented at: 21st Annual Winter Lung Cancer Conference; February 2-4, 2024; Hollywood, FL.
2. Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2021;398(10308):1344-1357. doi:10.1016/S0140-6736(21)02098-5
3. Paz-Ares L, O’Brien MER, Mauer M, et al. Pembrolizumab (pembro) versus placebo for early-stage non-small cell lung cancer (NSCLC) following complete resection and adjuvant chemotherapy (chemo) when indicated: randomized, triple-blind, phase III EORTC-1416-LCG/ETOP 8-15 – PEARLS/KEYNOTE-091 study. Ann Oncol. 2022;33(4):451-453. doi:10.1016/j.annonc.2022.02.224
4. Felip E, Vallieres E, Zhou C, et al. IMpower010: sites of relapse and subsequent therapy from a phase III study of atezolizumab vs best supportive care after adjuvant chemotherapy in stage IB-IIIA NSCLC.Ann Oncol. 2021;32(suppl 5):1283-1346. doi:10.1016/annonc/annonc741
5. Wakelee H, Altorki N, Felip E, et al. IMpower010: overall survival interim analysis of a phase III study of atezolizumab vs best supportive care in resected NSCLC. J Thorac Oncol. 2022;17(9):S2. doi:10.1016/j.jtho.2022.07.013
6. Felip E, Altorki N, Zhou C, et al. Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial. Ann Oncol. 2023;34(10):907-919. doi:10.1016/j.annonc.2023.07.001
7. FDA approves osimertinib as adjuvant therapy for non-small cell lung cancer with EGFR mutations. FDA. December 18, 2020. Accessed February 6, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-adjuvant-therapy-non-small-cell-lung-cancer-egfr-mutations
8. Herbst RS, Wu YL, John T, et al. Adjuvant osimertinib for resected EGFR-mutated stage IB-IIIA non-small-cell lung cancer: updated results from the phase III randomized ADAURA trial. J Clin Oncol. 2023;41(10):1830-1840. doi:10.1200/JCO.22.02186
9. Solomon BJ, Ahn JS, Dziadziuszko R, et al. ALINA: efficacy and safety of adjuvant alectinib versus chemotherapy in patients with early-stage ALK+ non-small cell lung cancer (NSCLC). Ann Oncol. 2023;34(suppl 2):1254-1335. doi:10.1016/j.annonc.2023.10.051