Perioperative Immunotherapy Improves EFS, But Clouds Optimal Sequencing in Early NSCLC

Heather Wakelee, MD, FASCO

Positive event-free survival (EFS) data from the phase 3 AEGEAN (NCT03800134), NEOTORCH (NCT04158440), and KEYNOTE-671 (NCT03425643) trials add further evidence to the benefit of perioperative immunotherapy in early-stage non–small cell lung cancer (NSCLC) but have yet to show clear biomarkers of response beyond PD-L1, explained Heather Wakelee, MD, FASCO. She added that pending approvals for these regimens may further complicate treatment decisions with the availability of pure neoadjuvant and adjuvant approaches.

“Perioperative immunotherapy will likely lead to approvals in the near future. We have many options for our patients, but we still need to figure out better biomarkers of response and how to provide benefit to more patients,” Wakelee, professor of medicine (oncology) at Stanford Medicine in Palo Alto, California, said in a presentation delivered during the 24th Annual International Lung Cancer Congress^®.¹

Preliminary EFS Data Spark Hope for Durvalumab in Stage IIA to IIIB NSCLC

The phase 3 AEGEAN trial evaluated treatment-naïve patients with EGFR and ALK wild-type, resectable stage IIA to IIIB NSCLC with an ECOG performance status of 0 or 1 and confirmed PD-L1 status. Eligible patients were randomly assigned 1:1 to 1500 mg of intravenous (IV) durvalumab plus platinum-based chemotherapy (n = 366) or matched placebo (n = 374) every 3 weeks for 4 cycles, followed by surgery, and an additional 12 cycles of durvalumab and placebo, respectively.²

“The investigators tried to exclude patients who were going to require pneumonectomy, so that was one of the differences [between the trials], so it’s a little bit more rigorous from that perspective,” Wakelee said.

Pathologic complete response (pCR) and blinded independent central review–assessed EFS using RECIST v1.1 criteria served as the primary end points of the trial. Patients were randomly assigned between January 2, 2019, and April 19, 2022, with a minimum follow-up of 6.7 months. At the first planned analysis for EFS, median follow-up was 11.7 months (range, 0.0-46.1). A similar proportion of patients in each arm completed 4 cycles of both chemotherapy agents, underwent surgery resulting in R0 resection, and started and are still receiving treatment with durvalumab or placebo.

“We’re talking about what are truths, [but] about 20% of patients don’t go to surgery. This is a number that we have seen consistently,” Wakelee said.

Regarding baseline characteristics, median patient age was 65.0 years (range, 30-88) in both arms, approximately 70% of patients had stage IIIA/B disease and approximately half had squamous histology. Approximately one-third of patients had PD-L1 expression less than 1%, between 1% and 49%, and 50% or greater, and more than 70% of patients in both arms received carboplatin-based chemotherapy.

In the first planned interim analysis, the median EFS was not reached (NR; 95% CI, 31.9-NR) with durvalumab vs 25.9 months (95% CI, 18.9-NR) with placebo (HR, 0.68; 95% CI, 0.53-0.88; P <.003902). With 31.9% maturity, the 12- and 24-month EFS rates with durvalumab were 73.4% and 63.3%, respectively, vs 64.5% and 52.4% with placebo. All patients benefited from durvalumab regardless of age, sex, performance status, race, smoking history, disease stage, PD-L1 expression, and neoadjuvant platinum therapy.

pCR, which was evaluated centrally per IASLC 2020 methodology, was improved with durvalumab at 17.2% vs 4.3% with placebo (difference, 13.0%; 95% CI, 8.7%-17.6%; P =.000036). Major PR (MPR), also evaluated centrally, was 33.3% and 12.3% with durvalumab and placebo, respectively (difference, 21.0%; 95% CI, 15.1%-26.9%; P =.000002).

Adverse effects (AEs) included anemia, nausea, constipation, decreased appetite, neutropenia, alopecia, decreased neutrophil count, rash, diarrhea, fatigue, asthenia, pruritus, vomiting, procedural pain, COVID-19, and insomnia. The most frequent grade 3 or greater AEs included neutropenia, decreased neutrophil count, and anemia.

NEOTORCH: A Stand-Out Option for Squamous, Stage III NSCLC?

The phase 3 NEOTORCH trial enrolled newly diagnosed patients with EGFR and ALK wild-type, resectable stage II and III NSCLC. Patients were randomly assigned 1:1 to 240 mg of toripalimab plus platinum-based chemotherapy (n = 202) or matched placebo (n = 202) plus platinum-based chemotherapy every 3 weeks for 3 cycles before undergoing surgery.² After recovering from surgery, patients received an additional cycle of platinum-based chemotherapy plus toripalimab or placebo depending on randomization, followed by toripalimab or placebo for an additional 13 cycles. Investigator-assessed EFS in the stage III and II/III population, and blinded independent pathologic review (BIPR)–assessed MPR served as primary end points.

The median age of enrolled patients was 62 years, and most patients had stage IIIA disease and squamous histology. Two-thirds of patients had positive PD-L1 expression (tumor cells ≥1%), the rest had negative expression or were not evaluable.

At median follow-up of 18.25 months, median EFS in the stage III population was not evaluable (NE; 95% CI, NE-NE) with toripalimab vs 15.5 months (95% CI, 9.9-NE) with chemotherapy alone (HR, 0.40; 95% CI, 0.271-0.572; P <.0001). The 1- and 2-year EFS rates with toripalimab were 80.7% and 66.7%, respectively, vs 55.7% and 46.1% with chemotherapy alone. As in AEGEAN, there was no subgroup who did not benefit from the addition of the checkpoint inhibitor, Wakelee said.

pCR by BIPR was 24.8% (95% CI, 22.1%-35.0%) with toripalimab vs 1.0% (95% CI, 0.1%-3.5%) with chemotherapy alone (difference, 23.7%; 95% CI, 17.6%-29.8%; P <.0001). Most patients underwent surgery in both arms, achieving R0 resection in 95.8% (95% CI, 91.5%-98.3%) and 92.6% (95% CI, 87.1%-96.2%) of cases in the toripalimab and placebo arms, respectively (difference, 3.2%; 95% CI, -2.0%-8.4%).

Grade 3 or greater treatment-emergent AEs (TEAEs; 63.4% vs 54.0%) and serious AEs (40.6% vs 28.2%) were more common with the addition of toripalimab vs placebo, respectively. Any TEAE leading to treatment interruption or discontinuation occurred in 28.2% and 9.4% of patients in the toripalimab arm vs 14.4% and 7.4% of patients in the placebo arm. Investigator-determined immune-related AEs were twice as common in the toripalimab arm, at 42.1%, 11.9% of which were grade 3 or greater. Infusion-related reactions occurred in 3.5% of patients. Six and four deaths owing to TEAEs occurred in the toripalimab and placebo arms, respectively.

KEYNOTE-671 Hints at Survival Benefit With Pembrolizumab in Resectable Disease

The phase 3 KEYNOTE-671 trial enrolled treatment-naïve patients with pathologically confirmed, resectable stage II, IIIA, or IIIB NSCLC.³ A total of 786 patients were randomly assigned 1:1 to 200 mg of IV pembrolizumab (Keytruda) every 3 weeks plus cisplatin and gemcitabine or cisplatin and pemetrexed (Alimta) for up to 4 cycles, or matched placebo plus the same chemotherapy regimens, followed by surgery, and an additional 13 cycles of pembrolizumab or placebo, respectively. Investigator-assessed EFS and overall survival (OS) served as the primary end points.

Baseline characteristics indicated that most patients were White, not from East Asia, and had nonsquamous histology and stage IIIA disease. Approximately one-third of patients each had negative (<1%), positive (1% to 49%), and high (≥50%) PD-L1 expression by tumor proportion score.

Approximately 74% of patients in both arms completed 4 cycles of pembrolizumab or placebo, and approximately 80% underwent surgery. In the pembrolizumab arm, 73.2% of patients received at least 1 dose of adjuvant therapy, 40.4% of which completed the entire course. In the placebo arm, these rates were 66.9% and 35.3%, respectively.

At median follow-up of 25.2 months (range, 7.5-50.6), median EFS was NR with pembrolizumab (95% CI, 34.1-NR) vs 17.0 months (95% CI, 14.3-22.0) with placebo (HR, 0.58; 95% CI, 0.46-0.72; P <.00001). The 12- and 24-month EFS rates with pembrolizumab were 73.2% and 62.4%, respectively, vs 59.9% and 40.6% with placebo. All subgroups benefited from the addition of pembrolizumab.

mPR by BIPR was 30.2% (95% CI, 25.7%-35.0%) with pembrolizumab vs 11.0% (95% CI, 8.1%-14.5%) with placebo (difference, 19.2%; 95% CI, 13.9%-24.7%; P <.00001). The pCR rates with pembrolizumab and placebo were 18.1% (95% CI, 14.5%-22.3%) and 4.0% (95% CI, 2.3%-6.4%), respectively.

In an exploratory analysis performed by mPR status, mPR was associated with improved EFS regardless of treatment arm. With mPR, the hazard ratio was 0.54 (95% CI, 0.24-1.22) and without mPR was 0.73 (95% CI, 0.58-0.92).

Median OS was NR with pembrolizumab vs 45.5 months with placebo (HR, 0.73; 95% CI, 0.54-0.99; P =.02124), though this was not statistically significant. The 12- and 24-month OS rates were 87.9% and 80.9% with pembrolizumab vs 87.9% and 77.6% with placebo.

Immune-mediated AEs and infusion reactions included hypothyroidism, hyperthyroidism, pneumonitis, severe skin reactions, colitis, infusion reactions, thyroiditis, hepatitis, hypophysitis, and pancreatitis.

References

1. Wakelee H. Update on early-stage perioperative immunotherapy trials in NSCLC. Presented at: 24th Annual International Lung Cancer Congress; July 27-29, 2022; Huntington Beach, CA.
2. 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.
3. 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):42512. doi:10.1200/JCO.2023.41.36_suppl.42512
4. Wakelee H, Liberman M, Kato T, et al. Perioperative pembrolizumab for early-stage non-small-cell lung cancer. N Engl J Med. Published online June 3, 2023. doi:10.1056/NEJMoa2302983