Perioperative Trials Add to Growing Immunotherapy Landscape in Early-Stage NSCLC

Heather Wakelee, MD

Findings from the phase 3 CheckMate 816 (NCT02998528), KEYNOTE-091 (NCT02504372), and ADAURA (NCT02511106) trials have shown the value of considering neoadjuvant chemoimmunotherapy, immune monotherapy, and adjuvant targeted therapy, respectively, for patients with resectable non–small cell lung cancer (NSCLC), but the role of perioperative therapy remains to be seen as data continue to unfold from the phase 3 AEGEAN (NCT03800134), KEYNOTE-671 (NCT03425643), and NeoTORCH (NCT04158440) trials.

“Now we’ve got the perioperative trials—we’ve had 3 this fall, and if you look across these trials, it’s sort of positive, positive, positive. Everything has been positive,” Heather Wakelee, MD, said. “I did clinical trial work for a long time, where everything was negative, and so it’s weird to be in this new world, but very exciting for our patients. The problem is they’re very similar trial designs, so how do we then distinguish between them?”

In an OncLive^® Scientific Interchange and Workshop, Wakelee, who is a professor of medicine and chief of the Division of Oncology at Stanford University School of Medicine; interim medical director and deputy director at Stanford Cancer Institute in California; and president of the International Association for the Study of Lung Cancer, moderated a discussion on the evolving treatment paradigm in early-stage NSCLC.¹

Starting with neoadjuvant therapy, the faculty first considered data from CheckMate 816 in which neoadjuvant nivolumab (Opdivo) plus chemotherapy improved pathologic complete response (pCR), event-free survival (EFS), and demonstrated a favorable trend in overall survival (OS) vs chemotherapy alone in patients with stage IB to IIIA NSCLC. “CheckMate 816 had some patients [with stage I disease] in it, and the other trials, for the most part, do not. They were restricted to stage II and III, so that’s something to keep in mind,” Wakelee noted.

At 3 years, the pCR rate was 24.0% with the chemoimmunotherapy combination (n = 179) vs 2.2% with chemotherapy alone (n = 179; odds ratio, 13.94; 99% CI, 3.49-55.75; P <.0001). The median EFS was not reached (NR) with the combination vs 21.1 months with chemotherapy alone (HR, 0.68; 95% CI, 0.49-0.93). With a median follow-up of 41.4 months at the time of the analysis, the median OS was NR in either arm (HR, 0.62; 99.34% CI, 0.36-1.05; P = .0124).²

In the perioperative setting, durvalumab (Imfinzi) demonstrated significant benefit compared with placebo in the AEGEAN trial. The median EFS was NR (95% CI, 3.19-NR) with durvalumab (n = 366) and was 25.9 months (95% CI, 18.9-NR) with placebo (n = 374; HR, 0.68; 95% CI, 0.53-0.88; P =.003902). With a median follow-up of 11.7 months (range, 0-46.1) in censored patients, and only 31.9% maturity, the estimated 12- and 24-month EFS rates were 73.4% and 63.3% with durvalumab vs 64.5% and 52.4% with placebo. The pCR rate was 17.2% with durvalumab vs 4.3% with placebo, translating to a 13.0% absolute difference in response (95% CI, 8.7%-17.6%; P =.000036).³

The faculty also highlighted data from the KEYNOTE-671 trial, which showed both pCR (delta, 14.2%; 95% CI, 10.1%-18.7%) and EFS (HR, 0.58; 95% CI, 0.46-0.72; P <.00001) improvement with perioperative pembrolizumab vs placebo.⁴ Although the OS data were immature, they favored perioperative pembrolizumab (HR, 0.73; 95% CI, 0.54-0.99; P = .02124).

“The main advantage of the KEYNOTE-617 perioperative regimen would be once it’s FDA approved, it gives you some security that even if the patient has residual disease, you have that 1 year of adjuvant pembrolizumab that you can give them,” one of the panelists said.

Although results from only the stage III population have read out, panelists also pointed out results from the NeoTORCH trial, in which the addition of toripalimab to chemotherapy (n = 202) led to pCR in 24.8% of patients vs 1% of those on chemotherapy alone (n = 202; difference, 23.7%; 95% CI, 17.6%-29.8%; P <.0001). Moreover, the median EFS was NR (95% CI, 24.4-not evaluable) with the combination vs 15.1 months (95% CI, 10.6-21.9) with chemotherapy alone (HR, 0.40; 95% CI, 0.277-0.565; P <.0001).⁵ The faculty noted that the trial was conducted entirely in China and excluded patients with EGFR mutations. “If you’re excluding patients with EGFR, you pretty much excluded almost all your women and everybody with adenocarcinoma. So, this is a male squamous trial for the most part, but very positive,” Wakelee said.

In discussing each trial, Wakelee also pointed out that it’s important to distinguish between EFS and disease-free survival (DFS), the latter of which several adjuvant trials have based their primary end points on. “EFS is DFS plus any event that prevented the patient from going to surgery, so it’s not exactly the same thing,” Wakelee noted.

Moreover, the faculty considered the fact that approximately 20% of patients who undergo neoadjuvant therapy will not go to surgery, whereas a slightly higher percentage of patients who undergo surgery will not receive adjuvant therapy. “You start having to think about, well what matters most? Does the surgery matter most? Does the systemic therapy matter most? Because you’re going to lose out on some percentage of patients with either approach,” Wakelee stated.

With regard to targeted therapy in the adjuvant setting, results from the ADAURA trial showed that the 5-year OS rate with osimertinib (Tagrisso; n = 339)––the only targeted therapy with an indication in the adjuvant setting––was 88% (95% CI, 83%-91%) vs 78% (95% CI, 73%-82%) with placebo (n = 343; HR, 0.49; 95.03% CI, 0.34-0.70; P < .001). Similar magnitude of benefit was seen in patients who did not receive adjuvant chemotherapy (n = 272), with 5-year OS rates of 88% (95% CI, 81%-93%) and 79% (95% CI, 71%-85%) with osimertinib and placebo, respectively (HR, 0.47; 95% CI, 0.25-0.83). However, the faculty emphasized that this does not mean chemotherapy should be omitted in the adjuvant setting. In the stage IB population, 94% (95% CI, 86%-97%) of patients who received osimertinib were alive at 5 years compared with 88% (95% CI, 80%-93%) of those who received placebo.

“I do think this is positive, and for me, when I saw the data and it was positive in the [patients with stage] IB, II and IIIA [disease], that got my attention more. I haven’t been a strong [proponent] of [saying] we should be giving this to everybody with stage IB [disease], because of that question of overtreatment, but OS is hard to argue with,” Wakelee said.

At the final data cutoff, 22% of patients in the osimertinib arm and 54% of those in the placebo arm had received subsequent therapy. EGFR TKIs were the most common next therapy in the osimertinib and placebo arms, at 76% and 88%, respectively.⁶

Finally, the faculty touched on 2 adjuvant immunotherapy trials: IMpower010 and KEYNOTE-091. Although neither trial has demonstrated significant improvement in OS, both trials have demonstrated improvement in DFS (IMpower010: HR, 0.74; 95% CI, 0.59-0.93); KEYNOTE-091: HR, 0.76; 95% CI, 0.63-0.91; P =.0014).^7,8 “In the stage I patients in the adjuvant immune therapy trials, there really wasn’t benefit seen. We didn’t have them in most of the perioperative trials. We do have them in Checkmate-816, but it was a very small percentage, so it’s hard to know exactly what to do,” Wakelee said.

The panel concluded by acknowledging that until a trial comparing neoadjuvant therapy plus adjuvant therapy with adjuvant therapy alone is done, the field won’t be able to answer which approach is better. “That’s something that probably isn’t going to be done by pharma, but the cooperative groups are talking about it as a really important clinical question, because that’s going to really define for us [the optimal approach],” Wakelee stated.

Pamela Miel, MD, of The Oncology Institute of Hope & Innovation, concluded by stating, “I would like to have more information on minimal residual disease testing. How can we utilize that in monitoring patients not just right after pCR, but down the road, after treatment and then really communicate well with other providers, the pulmonologists, the radiation oncologist, the surgeon especially, and know ahead of time [a patient’s] ALK, EGFR and PD-L1 [status], because those matter now.”

References

1. The evolving treatment paradigm for stage I-IIIB NSCLC. Presented at: OncLive Scientific Interchange and Workshop. January 20, 2023; Virtual.
2. Forde PM, Spicer J, Girard N. Neoadjuvant nivolumab (N) + platinum-doublet chemotherapy (C) for resectable NSCLC: 3-y update from CheckMate 816. Presented at: 2023 European Lung Cancer Congress; March 29-April 1, 2023; Copenhagen, Denmark. Abstract 840.
3. Heymach JV, Harpole D, Mitsudomi T, et al. AEGEAN: a phase 3 trial of neoadjuvant durvalumab + chemotherapy followed by adjuvant durvalumab in patients with resectable NSCLC. Cancer Res. 2023;83(suppl 8):CT005. doi:10.1158/1538-7445.AM2023-CT005
4. Wakelee HA, Liberman M, Kato T, et al. KEYNOTE-671: randomized, double-blind, phase 3 study of pembrolizumab or placebo plus platinum-based chemotherapy followed by resection and pembrolizumab or placebo for early stage NSCLC. J Clin Oncol. 2023;41 (suppl 17):LBA100. doi:10.1200/JCO.2023.41.17_suppl.LBA100
5. Lu S, Wu L, Zhand W, et al. Perioperative toripalimab + platinum-doublet chemotherapy vs chemotherapy in resectable stage II/III non-small cell lung cancer (NSCLC): Interim event-free survival (EFS) analysis of the phase III Neotorch study. Presented at: 2023 April ASCO Plenary Series. Abstract 425126.
6. Herbst RS, Tsuboi M, John T, et al. Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR-mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC). J Clin Oncol. 2023;41(suppl 17):LBA3. doi:10.1200/JCO.2023.41.17_suppl.LBA3
7. 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 3 trial. Ann Oncol. Published online July 17, 2023. doi:10.1016/j.annonc.2023.07.001KEYNOTE-091
8. O’Brien M, Paz-Ares L, Marreaud S, et al. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol. 2022;23(10):1274-1286. doi:10.1016/S1470-2045(22)00518-6