Chemoimmunotherapy Is at the Forefront of the Perioperative NSCLC Paradigm

Mark G. Kris, MD

As a durvalumab (Imfinzi) regimen joins the pembrolizumab (Keytruda) combination in the perioperative treatment paradigm for patients with resectable non–small cell lung cancer (NSCLC), combination therapies with neoadjuvant immune checkpoint inhibitors (ICIs) and chemotherapy followed by an adjuvant ICI have shown that they’re here to stay.¹

“I urge physicians to [give] patients with earlystage lung cancers who are candidates for surgery [checkpoint inhibitors plus chemotherapy] whenever possible; if they don’t have EGFR, ALK, ROS1, RET, or NTRK [alterations], those patients need a checkpoint inhibitor and chemotherapy presurgery. You have the best chance to make a huge impact in patients’ [lives with that approach],” Mark G. Kris, MD, said in an interview with OncologyLive.

The August 15, 2024, addition of neoadjuvant durvalumab plus platinum-based chemotherapy followed by adjuvant durvalumab monotherapy to the treatment paradigm for adult patients with resectable NSCLC and no ALK or EGFR alterations represents one of the most recent advancements in the perioperative setting.¹

Treatment with the PD-L1 checkpoint inhibitor regimen reduced the risk of disease progression, recurrence, or death by 32% vs neoadjuvant platinum-based chemotherapy plus placebo followed by adjuvant placebo in this patient population. The median event-free survival (EFS) was not reached (NR; 95% CI, 31.9-NR) in patients who received the durvalumab regimen (n = 366) vs 25.9 months (95% CI, 18.9-NR) in those who received the placebo regimen (n = 374; HR, 0.68; 95% CI, 0.53-0.88; P = .0039). Additional data from the pivotal phase 3 AEGEAN trial (NCT03800134) revealed that the pathologic complete response (pCR) rate was 17.2% (95% CI, 13.5%-21.5%) compared with 4.3% (95% CI, 2.5%- 6.8%), respectively (P < .0001).²

^{Several Chemoimmunotherapy Strategies Prove Effective}

“In the perioperative space, it is unexpected and amazing how effective checkpoint inhibitors are [when] given before surgery. I don’t think anybody would have suspected that, and it’s been shown [many times],” Kris explained. Kris is a thoracic medical oncologist and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center in New York, New York.

Findings from the phase 3 CheckMate 77T study (NCT04025879) also demonstrated an improvement with the addition of a checkpoint inhibitor—nivolumab (Opdivo)—to chemotherapy (n = 229) for patients with resectable NSCLC, significantly extending EFS vs chemotherapy alone (n = 232; HR, 0.58; 97.36% CI, 0.42-0.81; P < .001). The pCR rate also improved at 25.3% vs 4.7%, respectively (OR, 6.64; 95% CI, 3.40-12.97).³

Kris added, “It is unusual that there would be 8 randomized trials all over the world that reach the same conclusion that immunotherapy [given] preoperatively with chemotherapy is better than chemotherapy alone. [But the data from those trials have shown it is well] tolerated and sometimes yields great results, including the complete eradication of the cancer, something we don’t see with other approaches.”

One of those 8 trials is the phase 3 KEYNOTE-671 trial (NCT03425643). Data from the study led to the FDA approval of neoadjuvant pembrolizumab plus platinum-containing chemotherapy, followed by single-agent adjuvant pembrolizumab for patients with resectable NSCLC.⁴ At a median follow-up of 29.8 months (range, 0.4-62.0), the pembrolizumab regimen significantly improved overall survival (OS) vs placebo plus chemotherapy followed by adjuvant placebo, reducing the risk of death by 28% (HR, 0.72; 95% CI, 0.56-0.93; 1-sided P = .00517).⁵

Although findings from KEYNOTE-671 were from 1 of the 8 randomized clinical trials that demonstrated a significant benefit from combined neoadjuvant chemoimmunotherapy in this patient population, KEYNOTE-671 was the only trial of the 8 where OS was one of the primary end points, according to a systematic review and meta-analysis. Further, data from KEYNOTE-671 confirmed significant prolongation of OS for patients treated with 4 cycles of neoadjuvant pembrolizumab plus cisplatin-based chemotherapy followed by 9 months of adjuvant pembrolizumab.⁶

The systematic review and meta-analysis examined data from the 8 trials in patients with early-stage NSCLC who received neoadjuvant ICIs and chemotherapy; findings also revealed that the improved pCR and EFS rates seen were not significantly modified by main patient characteristics or tumor- or treatment-related factors, including PD-L1 status.

Considerations With Checkpoint Inhibition From Surgery to Oligoprogression

In regard to tolerability when adding an ICI to chemotherapy, overall treatment-related adverse effects (TRAEs) in CheckMate 77T occurred at any grade in 89.0% of patients who received the nivolumab regimen and 87.0% of those who received the chemotherapy/placebo regimen. These events led to treatment discontinuation in 19.3% vs 7.4% of patients, respectively, and 2 patients in the nivolumab group died due to TRAEs in the neoadjuvant period.³

In AEGEAN, serious AEs occurred in 37.7% of patients receiving the durvalumab regimen compared with 31.4% of patients receiving the chemotherapy/placebo regimen. They led to discontinuation in 12.0% vs 6.0% of patients, respectively, and 5.7% compared with 3.8% of patients died due to AEs, respectively.⁷

Furthermore, Kris noted that a newer treatment consideration with ICIs concerns patients who experience oligoprogression. “The concept of treatment beyond progression goes against everything I was taught. [I was taught if a] patient progresses, you have to change therapy. Particularly with targeted therapies, you have situations where there’s millimeter growth over many years and it’s in the patient’s best interest to keep them on the drug, even in the face of progression,” Kris said.

He added that when “you have patients with long disease-free survival, the concept of oligoprogression [is important]. There is growing literature that after [a patient] has a good result with systemic therapy, persisting disease sites in both small cell lung cancer and NSCLC could benefit from a local, targeted therapy, [specifically] with checkpoint inhibition; if a [patient] has single sites of progression, using a local therapy for those single sites even in the face of progression, particularly in the liver, can get a patient back into a disease control state. That’s thinking that we don’t normally have.”

Experts Detail Factors for These Treatment Strategies and More

With new therapies and an array of options opening the door for additional questions surrounding optimal treatments in NSCLC, the 19th Annual New York Lung Cancers Symposium^®, hosted by Physicians’ Education Resource^®, LLC, will serve as an opportunity to have key questions answered (Figure). The conference, which will take place on November 16, 2024, in New York, New York, will parse through the latest data and feature multidisciplinary panel discussions in a tumor board format.⁸

“We make sure that [each] presentation is not just a dry data review—there is a bottom line there, synthesizing the data and saying with what we know today about this area of question or controversy, this is what I think is best. If clinicians come to the New York Lung Cancers Symposium, they’re going to walk away with the expert’s true opinion, and not just a list of possibilities,” said Kris, who is cochair of the meeting with Balazs Halmos, MD, MS, associate director of Clinical Science at Montefiore Einstein Comprehensive Cancer Center in the Bronx, New York.

Kris and colleagues from the tristate area will gather in the city to discuss the perioperative setting and more, homing in on genomic testing strategies and best practices, multidisciplinary considerations in treatment, and approaches to mitigate as well as manage treatment-related toxicities.

“There’s been a huge output of information on how to treat patients with early-stage [disease], particularly those in the perioperative [setting]. A large amount of data on neoadjuvant therapy [have come out, with] a consensus that wherever it’s feasible it should be done and [is more efficacious],” Kris said. “The perioperative space is a big one right now.”

References

1. FDA approves neoadjuvant/adjuvant durvalumab for resectable non-small cell lung cancer. FDA. August 15, 2024. Accessed August 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvantadjuvant-durvalumab-resectable-non-small-cell-lung-cancer
2. Imfinzi. Prescribing information. AstraZeneca; 2024. Accessed August 21, 2024. https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/9496217c-08b3-432b-ab4f-538d795820bd/9496217c-08b3-432b-ab4f-538d795820bd_viewable_rendition__v.pdf
3. Cascone T, Awad MM, Spicer JD, et al; CheckMate 77T Investigators. Perioperative nivolumab in resectable lung cancer. N Engl J Med. 2024;390(19):1756-1769. doi:10.1056/NEJMoa2311926
4. FDA approves neoadjuvant/ adjuvant pembrolizumab for resectable non-small cell lung cancer. FDA. October 16, 2023. Accessed August 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvant-adjuvant-pembrolizumab-resectable-non-small-cell-lung-cancer
5. European Commission approves Merck’s Keytruda (pembrolizumab) plus chemotherapy as neoadjuvant treatment, then continued as monotherapy as adjuvant treatment, for resectable non-small cell lung cancer (NSCLC) at high risk of recurrence in adults. News release. Merck. March 28, 2024. Accessed August 21, 2024. https://www.merck.com/news/european-commission-approves-mercks-keytruda-pembrolizumab-plus-chemotherapy-as-neoadjuvant-treatment-then-continued-as-monotherapy-as-adjuvant-treatment-for-resectable-non-small-ce/
6. Banna GL, Hassan MA, Signori A, et al. Neoadjuvant chemo-immunotherapy for early-stage non-small cell lung cancer: a systematic review and meta-analysis. JAMA Netw Open. 2024;7(4):e246837. doi:10.1001/jamanetworkopen.2024.6837
7. Heymach JV, Harpole D, Mitsudomi T, et al; AEGEAN Investigators. Perioperative durvalumab for resectable non-small-cell lung cancer. N Engl J Med. 2023;389(18):1672-1684. doi:10.1056/NEJMoa2304875
8. 19th Annual New York Lung Cancers Symposium. Physicians’ Education Resource, LLC. Accessed August 21, 2024. https://www.gotoper.com/courses/new-york-lung-cancers-symposium?utm_medium=paid&utm_source=google&utm_campaign=nyl_24_&gad_source=1&gclid=EAIaIQobChMI4qO8gu-DiAMVjzMIBR0S-gt8EAAYASAAEgI6UvD_BwE