Multidisciplinary Collaboration Is Essential in Early-Stage NSCLC

Multidisciplinary Collaboration in Early-Stage NSCLC

| Image by Ashling Wahner & MJH Life Sciences Using AI

In recent years, physicians in the field of early-stage non–small cell lung for patients with resectable disease, such as nivolumab (Opdivo) and durvalumab (Imfinzi), as well as effective targeted agents and combinations for those with unresectable disease. This influx of therapeutic options underscores the need for collaboration with a multidisciplinary team to choose the treatment plan that best suits individual patients.

“My role used to be mainly being a resource at the main site,” Jaspal Singh, MD, said. “I look at my role now as being a resource for the other doctors out there who feel much more comfortable calling me and [asking questions such as] ‘What can I do to expedite things? Can I biopsy this? What’s the best route to start?’ Being a resource for the community physicians is such a privilege, and I enjoy that role.”

In a recent OncLive Peer Exchange, expert investigators convened to discuss the current treatment landscape of early-stage NSCLC from a multidisciplinary perspective. They discussed the importance of molecular testing for determining the optimal treatment approach, notable clinical trial data in resectable and unresectable disease, and highlighted ongoing trials in the early-stage setting.

Neoadjuvant and Perioperative Regimens Enhance Outcomes in Resectable NSCLC

In August 2024, the FDA approved the PD-L1 inhibitor durvalumab in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by adjuvant durvalumab monotherapy after surgery for the treatment of adult patients with resectable NSCLC without EGFR mutations or ALK rearrangements.1 The regulatory decision was supported by data from the phase 3 AEGEAN trial (NCT03800134), which showed that the median event-free survival (EFS) among patients who received durvalumab or placebo, both in combination with platinum-based chemotherapy, was not reached (NR; 95% CI, 31.9-not estimable [NE]) vs 25.9 months (95% CI, 18.9-NE), respectively (HR, 0.68; 95% CI, 0.53-0.88; P = .0039). The pathologic complete response (pCR) rates were 17% (95% CI, 13%-21%) vs 4.3% (95% CI, 2.5%-7%) in the durvalumab (n = 366) and placebo (n = 374) arms, respectively.1,2

Data from an exploratory subgroup analysis of AEGEAN presented during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting demonstrated that the effect of perioperative durvalumab on patients with early-stage NSCLC was maintained among patients with N2 lymph node involvement at baseline.2 In the durvalumab (n = 181) and placebo (n = 185) arms, the respective pCR rates were 16.6% and 4.9%, respectively, representing an 11.7% difference (95% CI, 5.6%-18.4%) in favor of the investigational arm. The median EFS was NR (95% CI, 31.9-NR) vs 19.5 months (95% CI, 12.6-26.2), respectively (HR, 0.63; 95% CI, 0.43-0.90).

“It’s the surgeon who initially sets the tone with the patient, and it’s critical for thoracic surgeons to have awareness of these [perioperative] therapeutic options,” Joshua K. Sabari, MD, commented. “If a surgeon tells the patient they don’t need any therapy, the patient will not listen to anything I say. But if the surgeon tells a patient, ‘We can resect this, but we need therapy that will hopefully prevent this from coming back and increase your rate of cure,’ patients are very willing to consider systemic therapy in the neoadjuvant setting.”

The PD-1 inhibitor, nivolumab, has earned FDA approval as both a neoadjuvant and a perioperative treatment. In March 2022, the FDA approved the agent in combination with platinum-doublet chemotherapy for adult patients with resectable NSCLC in the neoadjuvant setting; the approval was supported by data from the phase 3 CheckMate 816 study (NCT02998528).3 Then, in October 2024, the FDA approved neoadjuvant nivolumab plus chemotherapy followed by adjuvant nivolumab after surgery for the treatment of adult patients with resectable NSCLC without EGFR mutations or ALK rearrangements. The regulatory decision was supported by findings from the phase 3 CheckMate 77T trial (NCT04025879).4

Updated data from the 4-year update of CheckMate 816 presented during the 2024 ASCO Annual Meeting demonstrated that patients who received neoadjuvant nivolumab plus chemotherapy followed by surgery (n = 179) experienced a median EFS of 43.8 months (95% CI, 30.6-NR) compared with 18.4 months (95% CI, 14.0-26.7) among those who received placebo plus chemotherapy before surgery (n = 179; HR, 0.66; 98.36% CI, 0.49-0.90).5 The median overall survival (OS) was NR in either arm. However, a trend in favor of the nivolumab arm was observed (HR, 0.71; 98.36% CI, 0.47-1.07; P = .0451).

“A lot of the neoadjuvant protocols have [had difficulties and] technical challenges, [including] delays and all the different steps [that are involved],” Jessica Donington, MD, MSCR, said. “[These approaches also] have a hard time with attrition; there’s a concept that 20% of patients are not coming back [for surgery]. [Many of] the trials have not done a good job of showing us who didn’t make it. [One of] the only trials that did that was CheckMate 816; it showed which patients didn’t go on to surgery. I’ve gotten better at neoadjuvant therapy because I’ve been doing it for almost 10 years. I now can recognize that patient who’s not going to make it through neoadjuvant [therapy] and surgery. These tend to be patients who have a worse performance status or bad lung function.”

In CheckMate 77T, patients who received perioperative nivolumab (n = 229) achieved a significant EFS benefit compared with those who received perioperative placebo (n = 232; HR, 0.58; 97.36% CI, 0.42-0.81; P = .00025).6 The pCR rates were 25.3% vs 4.7%, respectively.

Moreover, data from an exploratory analysis of the study demonstrated that the clinical benefit with perioperative nivolumab was maintained in patients with both stage III N2 and non-N2 disease. Patients with stage III N2 (n = 70) or non-N2 (n = 45) disease who received nivolumab and underwent resection achieved pCR rates of 28.6% and 31.1%, respectively. These respective rates were 7.6% and 6.7% among patients in the placebo arm with stage III N2 (n = 66) or non-N2 disease (n = 45). In terms of EFS, patients with stage III N2 disease (HR, 0.32; 95% CI, 0.19-0.54) as well as those with stage III non-N2 disease (HR, 0.61; 95% CI, 0.30-1.24) achieved a significant benefit from definitive surgery compared with those who received placebo.

Another FDA-approved perioperative agent is pembrolizumab (Keytruda). The agent was approved in October 2023 in combination with chemotherapy as neoadjuvant treatment, followed by pembrolizumab monotherapy as postsurgical adjuvant treatment in resectable NSCLC.7 The approval was supported by data from the phase 3 KEYNOTE-671 trial (NCT03425643).

At a median follow-up of 41.1 months (range, 0.4-75.3), data from the 4-year update of KEYNOTE-671 showed that patients with early-stage NSCLC who received perioperative pembrolizumab (n = 397) achieved a median OS that was NR (95% CI, NR-NR); median OS also was NR (95% CI, 50.3-NR) among patients who received placebo (n = 400; HR, 0.73; 95% CI, 0.58-0.92).8 The median EFS was 57.1 months (95% CI, 38.0-69.1) vs 18.4 months (95% CI, 14.8-22.1), respectively (HR, 0.57; 95% CI, 0.47-0.69).

Beyond the neoadjuvant and perioperative regimens that have already received FDA approvals in resectable NSCLC, there are several ongoing studies of interest in the space for patients with oncogene-driven disease (Table).9-17

Table. Ongoing Studies of Neoadjuvant and Adjuvant Targeted Therapies in Early-Stage NSCLC9-17

“The ADAURA data [phase 3; NCT02511106] were quite impressive,” Sabari said. “After completion of resection and adjuvant chemotherapy, patients were randomly assigned to receive osimertinib [Tagrisso] vs placebo, and a significant improvement in OS [was observed] in patients receiving osimertinib, from stage IB to III. [This regimen] is something that I offer to all patients. You don’t want that patient to have had prior chemotherapy and immunotherapy [because] in the neoadjuvant setting, there are a lot of complications when we give osimertinib after PD-1/PD-L1 inhibitors. Testing up front, knowing that information, and using it on the back end are very helpful.”

Following the positive data from ADAURA, the phase 3 NeoADAURA trial (NCT04351555) was initiated to compare neoadjuvant osimertinib with or without chemotherapy with chemotherapy before surgery in patients with resectable stage II to IIIB EGFR-mutated NSCLC.18 The primary end point is centrally assessed major pathologic response rate. Secondary end points include EFS, pCR, OS, and safety.

In the phase 3 LIBRETTO-432 trial (NCT04819100), investigators are examining the first-in-class RET kinase inhibitor selpercatinib (Retevmo) as adjuvant therapy in patients with stage IB to IIIA RET fusion–positive NSCLC previously treated with definitive surgery or radiation.19 Approximately 170 patients will be randomly assigned 1:1 to receive selpercatinib or placebo. The primary end point is EFS in the primary analysis population of patients with stage II to IIIA RET fusion–positive NSCLC; secondary end points include other efficacy measures and safety.

Osimertinib Improves PFS in Unresectable NSCLC;Combination Approaches Are Under Development

In patients with unresectable NSCLC, osimertinib represents an FDA-approved option. In September 2024, the agent earned approval for the treatment of adult patients with locally advanced, unresectable NSCLC who did not experience disease progression during or after concurrent or sequential platinum-based chemoradiation therapy and whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations.20 The regulatory decision was supported by findings from the phase 3 LAURA trial (NCT03521154).

Primary data from LAURA shared during the 2024 ASCO Annual Meeting demonstrated that patients with stage III EGFR-mutated NSCLC who received osimertinib after definitive chemoradiotherapy (n = 143) achieved a median progression-free survival (PFS) per blinded independent central review of 39.1 months (95% CI, 31.5-not calculable) vs 5.6 months (95% CI, 3.7-7.4) in those who received placebo (n = 73; HR, 0.16; 95% CI, 0.10-0.24; P < .001).21 Interim OS data also showed a positive trend in favor of the osimertinib arm, despite 81% of patients in the placebo arm crossing over to the investigational arm (HR, 0.81; 95% CI, 0.42-1.56; P = .530).

“Patients are living 5 years [or more] with stage III disease, [and] this is something that we don’t commonly talk with our patients about,” Sabari said. “[These data] are exciting and solidify the role of osimertinib in the resectable EGFR-mutated population.”

Vamsidhar Velcheti, MD, added, “If you look at how the control arm performed in LAURA, the PFS was incredibly short, so I’m not convinced that chemoradiotherapy had much of a contribution. That’s why all of us are eager to see the NeoADAURA data; maybe those patients should be seeing a thoracic surgeon after a robust response to induction.”

Investigators are also examining combination approaches for patients with unresectable disease. In the phase 2 COAST trial (NCT03822351), patients who received durvalumab in combination with oleclumab (n = 60) or monalizumab (n = 62) achieved a median PFS of 21.1 months (95% CI, 10.4-30.9) and 19.8 months (95% CI, 13.6-31.3), respectively.22 Comparatively, patients who received durvalumab monotherapy experienced a median PFS of 7.3 months (95% CI, 4.0-13.8).

The panelists concluded their discussion by touching on 2 ongoing combination studies in unresectable NSCLC: the phase 3 PACIFIC-8 (NCT05211895) and PACIFIC-9 (NCT05221840) trials. Following positive data from COAST, both trials are evaluating durvalumab-containing combinations following concurrent chemoradiotherapy in patients with stage III unresectable NSCLC. PACIFIC-8 is comparing durvalumab plus domvanalimab with placebo.23 PACIFIC-9 is examining durvalumab plus oleclumab or monalizumab vs durvalumab plus placebo.24

“The COAST [data] are exciting, but we don’t have full datasets yet,” Sabari said. “PACIFIC-8 and PACIFIC-9 are also looking at interesting combinations with anti-TIGIT antibodies, which have not been successful in the metastatic setting, but maybe it’s not a biomarker-specific approach [that is needed and] it is selection related. If [a patient has high-risk factors such as [mutations in] STK11 or KEAP1, or low PD-L1 expression or squamous histology, perhaps selecting those groups and considering more aggressive combination strategies [would be effective]. It would be great to have a biomarker in this space, but, if not, at least [identifying] these poor performers where we might want to escalate treatment [could be beneficial].”

Vamsidhar Velcheti, MD, is Director of the Thoracic Medical Oncology Program and a Professor in the Department of Medicine at the NYU Grossman School of Medicine and the NYU Langone Perlmutter Cancer Center in New York, NY.

Jessica Donington, MD, MSCR, is Chief of the Section of Thoracic Surgery and a Professor of Surgery at UChicago Medicine in Chicago, IL.

Jaspal Singh, MD, is a Clinical Professor of Pulmonary, Critical Care, Allergy, and Immunologic Diseases at the Wake Forest University School of Medicine in Winston-Salem, NC.

Joshua K. Sabari, MD, is Director of the High Reliability Organization Initiatives and an Assistant Professor in the Department of Medicine at the NYU Grossman School of Medicine and the NYU Langone Perlmutter Cancer Center.

References

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2. Heymach J, Reck M, Mitsudomi T, et al. Outcomes with perioperative durvalumab (D) in pts with resectable NSCLC and baseline N2 lymph node involvement (N2 R-NSCLC): an exploratory subgroup analysis of AEGEAN. J Clin Oncol. 2024;42(suppl 16):8011. doi:10.1200/JCO.2024.42.16_ suppl.8011
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9. A study of multiple therapies in biomarker-selected patients with resectable stages IB-III non-small cell lung cancer. ClinicalTrials. gov. Updated March 24, 2025. Accessed April 11, 2025. https://clinicaltrials.gov/study/NCT04302025
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15. A study of selpercatinib (LOXO-292) in participants with advanced solid tumors, RET fusion-positive solid tumors, and medullary thyroid cancer (LIBRETTO-001) (LIBRETTO-001). ClinicalTrials.gov. Updated February 28, 2025. Accessed April 11, 2025. https://clinicaltrials.gov/study/NCT03157128
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17. A phase II study of neoadjuvant sotorasib in combination with cisplatin or carboplatin and pemetrexed for surgically resectable stage IIA-IIIB non-squamous non-small cell lung cancer with a KRAS P.G12C mutation. ClinicalTrials.gov. Updated November 1, 2024. Accessed April 11, 2025. https://clinicaltrials.gov/ study/NCT05118854
18. Tsuboi M, Weder W, Escriu C, et al. Neoadjuvant osimertinib with/without chemotherapy versus chemotherapy alone for EGFR-mutated resectable non-small-cell lung cancer: NeoADAURA. Future Oncol. 2021;17(31):4045-4055. doi:10.2217/fon-2021-0549
19. Tsuboi M, Goldman JW, Wu YL, et al. LIBRETTO-432, a phase III study of adjuvant selpercatinib or placebo in stage IB- IIIA RET fusion-positive non-small-cell lung cancer. Future Oncol. 2022;18(28):3133-3141. doi:10.2217/fon-2022-0656
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21. Ramalingam SS, Kato T, Dong X, et al. Osimertinib (osi) after definitive chemoradiotherapy (CRT) in patients (pts) with unresectable stage (stg) III epidermal growth factor receptor- mutated (EGFRm) NSCLC: primary results of the phase 3 LAURA study. J Clin Oncol. 2024;42(suppl 17):LBA4. doi:10.1200/ JCO.2024.42.17_suppl.LBA4
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23. Özgüroğlu M, Levy BP, Horinouchi H, et al. Phase 3 trial of durvalumab combined with domvanalimab following concurrent chemoradiotherapy (cCRT) in patients with unresectable stage III NSCLC (PACIFIC-8). J Clin Oncol. 2023;41(suppl 16):TPS8609. doi:10.1200/JCO.2023.41.16_suppl.TPS8609
24. Barlesi F, Cho BC, Goldberg SB, et al. PACIFIC-9: phase III trial of durvalumab + oleclumab or monalizumab in unresectable stage III non-small-cell lung cancer. Future Oncol. 2024;20(29):2137- 2147. doi:10.1080/14796694.2024.2354160