Neoadjuvant vs Perioperative Immune Checkpoint Blockade in Resectable NSCLC: How Do We Choose?

Samuel Rosner, MD

Survival outcomes following curative resection in patients with resectable non–small cell lung cancer (NSCLC) have been poor and, until recently, the main tool oncologists had at their disposal was neoadjuvant or adjuvant chemotherapy. This approach has shown a modest overall survival (OS) benefit, with an absolute benefit of approximately 5% at 5 years.¹

Despite these gaps in care within the NSCLC armamentarium, the emergence of immune checkpoint blockade in the treatment of advanced disease has gained traction in earlier stages of treatment. In the neoadjuvant setting, immunotherapy can be used to treat the tumor while it’s still in place, and with draining lymph nodes intact, potentially stimulate a stronger immune response compared with adjuvant therapy alone.¹

“Neoadjuvant or perioperative immune checkpoint blockade has really revolutionized the treatment of [patients with] early-stage NSCLC,” Samuel Rosner, MD, said in a presentation delivered at the 21st Annual Winter Lung Conference^®. “Perioperative immune checkpoint blockade has shown improvement in overall survival [OS], [although] there may be a promising trend for neoadjuvant only approaches as well.”

In his presentation, Rosner, who is an assistant professor of medicine at the University of Maryland Greenebaum Comprehensive Cancer Center in Baltimore, discussed the current role of neoadjuvant vs perioperative treatment with immune checkpoint blockade in patients with resectable NSCLC, highlighting several key trials within the treatment landscape that have pushed the envelope forward.

Neoadjuvant Nivolumab (Opdivo) and Chemotherapy

In the phase 3 Checkmate-816 trial (NCT02998528), patients with stage IB to IIIA resectable NSCLC were evaluated, excluding those with EGFR or ALK alterations and an ECOG performance score greater than 1. Patients were randomly assigned to receive 3 cycles of nivolumab plus chemotherapy or chemotherapy alone before definitive surgery.1,2

The coprimary end points of the study were pathologic complete response (pCR) and event-free survival (EFS) ].2

The investigation yielded positive results, significantly increasing the rate of pCR and EFS with nivolumab. Moreover, all patient subgroups benefited from the investigational treatment. Notably, patients with stage IIIA disease, nonsquamous histology, and PD-L1–positive disease experienced the greatest benefits, Rosner said. Initially, there were concerns that early use of these agents might lead to surgical complications or delays. However, data from Checkmate-816 showed the opposite, Rosner explained.2

In the 3-year follow-up presentation of data from the Checkmate-816 trial, given at the 2023 ASCO Annual Meeting, investigators shared that patients who received nivolumab were more likely to undergo definitive surgery, with shorter surgical times and lower rates of high-risk surgeries such as pneumonectomy.²

“Checkmate-816 is [also] showing this promising trend towards improvement in overall survival [OS]. In fact, when you look at magnitude of impact, [the nivolumab arm] has a favorable hazard ratio of 0.62,” Rosner said. “I think statistics is also behind this. Checkmate-816 was a small phase 3 study, so it was likely underpowered to detect survival impact.”

Regarding safety, some patients experienced low-grade immune-related adverse effects. However, this did not significantly affect surgical schedules, with primary disease progression or administrative reasons being the main causes of delays, Rosner said.¹

Perioperative Pembrolizumab (Keytruda) Meets Primary End Points

The phase 3 KEYNOTE-671 trial (NCT03425643) evaluated treatment with pembrolizumab and chemotherapy prior to surgery, followed by resection and single-agent pembrolizumab after surgery. Results showed that the combination improved EFS and OS vs neoadjuvant placebo and chemotherapy.³

In this trial, patients with resectable stage II to IIIB disease were randomly assigned in a 1:1 ratio to receive pembrolizumab plus chemotherapy for 4 preoperative cycles or chemotherapy alone. When compared with Checkmate-816, there were notable differences between the studies, Rosner said.¹

First, the chemotherapy regimen used in KEYNOTE-671 was cisplatin-based, unlike the regimen in Checkmate-816, which was selected at the discretion of the provider. Furthermore, patients in KEYNOTE-671 who were treated postoperatively continued pembrolizumab in the adjuvant setting for up to 13 cycles.¹

The primary end points of KEYNOTE-671 were EFS and OS. However, unlike CheckMate-816 patients with EGFR and ALK alterations were not excluded, although they represented a small subset of the total trial population, Rosner said. Regarding treatment disposition, a higher proportion of patients in the pembrolizumab arm underwent surgery, at 82.1% vs 79.4% in the control arm. Although mandated, only 40.4% of patients completed adjuvant therapy with pembrolizumab.¹

Notably, EFS was positive, favoring pembrolizumab, with a hazard ratio of 0.59 (95% CI, 0.48-0.72). Additionally, there were improvements in major pCR and pathologic CR rates. Importantly, all patient subgroups derived some degree of benefit from the addition of perioperative pembrolizumab, particularly those with squamous cell histology (HR, 0.51), Rosner said.1 OS was also improved with the addition of pembrolizumab (HR, 0.72; 95% CI, 0.56-0.93).⁴

Additional Investigations Into Perioperative Immunotherapy

Additional studies within this realm of treatment for patients with resectable NSCLC include the phase 3 AEGEAN trial (NCT03800134).1,5 In May 2023, the first interim analysis of the phase 3 AEGEAN trial was presented at the 2023 AACR Annual Meeting. This trial, which studied the use of perioperative durvalumab (Imfinzi) with neoadjuvant platinum-based chemotherapy in patients with stage II to IIIB disease, favored the use of durvalumab for pCR and EFS, with an absolute improvement of 13.0% (95% CI, 8.7%-17.6%) and a hazard ratio of 0.68 (95% CI, 0.53-0.88), respectively.

“In terms of AEGEAN, patients with invasive T4 disease were excluded as well as patients who required upfront planned pneumonectomy, which is important when we’re thinking about this in the clinical realm,” Rosner said.

More recently, the phase 3 CheckMate 77T trial (NCT04025879) evaluated and confirmed benefit with neoadjuvant nivolumab plus chemotherapy followed by surgery and adjuvant nivolumab. These data were presented at the 2023 ESMO Congress, and looked at 4 preoperative cycles of chemotherapy plus nivolumab, followed by up to 1 year of adjuvant nivolumab in patients with stage II to IIIB disease. Results from the trial showed an improvement in EFS with nivolumab with a hazard ratio of 0.58 (95% CI, 97.36% CI, 0.42-0.81; P =.00025).⁶

“About 30% of patients [in the nivolumab arm] had multi-station N2 disease and despite these patients being high-risk, there were favorable outcomes with the chemotherapy/nivolumab approach with a hazard ratio of 0.43,” Rosner stated.

Rosner also briefly touched on the phase 3 NEOTORCH trial (NCT04158440 ).⁷ Rosner explained that the design of the trial is unique due to the incorporation of 3 preoperative cycles of chemoimmunotherapy with toripalimab-tpzi (Loqtorzi), 1 postoperative cycle of chemoimmunotherapy, and 1 year of toripalimab maintenance. Rosner added that another feature that “makes the [improvement in EFS and major PR] a little hard to interpret in comparison to the other phase 3 studies,” is the significant proportion of patients with squamous cell histology (78%) and PD-L1–positive disease (66%).

“Is perioperative therapy better than neoadjuvant therapy? I’m not ready to say that for sure. It may be, but if so for whom? Are their patients who should be prioritized for surgery? What biomarkers can we use to help guide that decision-making? Should we be basing post resection management on pathologic response? And should we be escalating therapy for patients without a pCR or major PR? I am excited to see trials in that space,” Rosner concluded.

References

1. Rosner S. Impact of perioperative/neoadjuvant therapy. Presented at: 21st Annual Winter Lung Cancer Conference; February 2-4, 2023; Hollywood, FL. Accessed February 6, 2024.
2. Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. 2022;386(21):1973-1985. doi:10.1056/NEJMoa2202170
3. Wakelee H, Liberman M, Kato T, et al; KEYNOTE-671 Investigators. Perioperative pembrolizumab for early-stage non–small-cell lung cancer. N Engl J Med. 2023;389(6):491-503. doi:10.1056/NEJMoa2302983
4. Overall survival in the KEYNOTE-671 study of perioperative pembrolizumab for early-stage non-small-cell lung cancer. Ann Oncol. 2023;34(suppl 2):S1297-S1298. doi:10.1016/j.annonc.2023.10.052
5. 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
6. Cascone T, Awad MM, Spicer JD, et al. CheckMate 77T: phase 3 study comparing neoadjuvant nivolumab plus chemotherapy with neoadjuvant placebo plus chemotherapy followed by surgery and adjuvant nivolumab or placebo for previously untreated, resectable stage II–IIIB NSCLC. Ann Oncol. 2023;34(suppl 2):S1295. doi:10.1016/j.annonc.2023.10.050
7. Lu S, Wu L, Zhang 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. J Clin Oncol. 2023;41(suppl 36):425126. doi:10.1200/JCO.2023.41.36_suppl.425126