Immune Therapy, EGFR Inhibition Take Hold of Stage III NSCLC

The treatment of patients with stage III non–small cell lung cancer (NSCLC) requires a multidisciplinary approach that often hinges on the resectability of the disease. Thus, investigators are working to develop targeted therapies that can be used in conjunction with surgery and chemoradiotherapy in patients with unresectable disease and also tease out the added benefit of a perioperative approach, demonstrating beyond doubt that targeted therapy is equally effective in earlier stages of disease.¹

“We know that the question about resectability is a very complicated one,” Aditya Juloori, MD, said. “It’s very dependent on multiple factors, [including] patien-related factors and disease-extent factors. This is a moving target. There are guidelines that exist, but the guidelines might be different in the future [compared with] where we are now. Each…patient deserves a full discussion.”

During a recent OncLive Peer Exchange^®, a panel of clinicians specializing in caring for patients with lung cancer discussed clinical trial updates on agents in stage III NSCLC, many of which had been presented during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting. The panelists talked through pertinent data and therapy selection considerations regarding the treatment of patients with resectable or unresectable stage III disease.

Neoadjuvant and Perioperative Options in Resectable Stage III NSCLC

At the ASCO meeting, investigators presented updated findings from clinical trials that examined neoadjuvant and perioperative treatment approaches for patients with resectable stage III NSCLC. During their discussion, the panelists sought to further elucidate disease factors and treatment considerations that would lead to them choosing one approach over another in a given patient.

“It’s very important [to note] that we have several neoadjuvant/perioperative regimens,” Sandip P. Patel, MD, said. “One important point is that these are for patients who are, at the time…you meet them, resectable. At that point in time, we don’t yet have data around conversion therapy. This is an area of active interest, but discussions around this take place in multidisciplinary tumor boards.”

The phase 3 AEGEAN study (NCT03800134), findings from which informed the July 2024 decision by the FDA’s Oncologic Drugs Advisory Committee to require adequate within trial assessment of contribution of treatment phase in new trial design proposals for perioperative regimens for resectable NSCLC, enrolled patients with treatment-naive stage IIA-IIIB resectable NSCLC.² Patients were randomly assigned 1:1 to receive the anti–PD-L1 antibody durvalumab (Imfinzi) perioperatively with neoadjuvant chemotherapy, or neoadjuvant chemotherapy alone. The coprimary end points were event-free survival (EFS) and pathological complete response (pCR) via blinded independent central review (BICR).³

Primary analysis findings from AEGEAN demonstrated that adding perioperative durvalumab to neoadjuvant chemotherapy significantly improved EFS compared with neoadjuvant chemotherapy alone (HR, 0.68; 95% CI, 0.53-0.88; P = .004); the difference in pCR rate between the 2 arms was 13.0% (95% CI, 8.7%-17.6%) in favor of the durvalumab arm (P < .001). Additionally, results from an exploratory analysis presented during ASCO 2024 showed that patients with baseline N2 nodal status (n = 181) achieved a similar benefit to the overall population with the addition of durvalumab; the difference in pCR rate between the durvalumab and placebo arms was 11.7% (95% CI, 5.6%-18.4%) in favor of durvalumab. EFS benefit in favor of durvalumab was also consistent between the baseline N2 population and the overall population and was seen in patients with single- (n = 273; HR, 0.61; 95% CI, 0.39-0.94) and multistation (n = 74; HR, 0.69; 95% CI, 0.33-1.38) N2 disease.

In another phase 3 study, CheckMate 816 (NCT02998528), investigators examined neoadjuvant treatment with nivolumab (Opdivo) plus chemotherapy in patients with stage IB to IIIA resectable NSCLC with no known EGFR/ALK alterations. Patients were randomly assigned 1:1 to receive nivolumab plus chemotherapy or chemotherapy alone, followed by surgery. EFS and pCR, both per BICR, represented the primary end points; overall survival (OS) was a key secondary end point.⁴

Data from the 4-year update of CheckMate 816 demonstrated that patients who received nivolumab (n = 179) achieved a median EFS of 43.8 months vs 18.4 months among patients who received chemotherapy alone (n = 179; HR, 0.66; 95% CI, 0.49-0.90); the 48-month EFS rates were 49% vs 38%, respectively. The median OS (HR, 0.71; 98.36% CI, 0.47-1.07; P = .0451; unstratified HR, 0.69; 95% CI, 0.49-0.97) and lung cancer–specific survival (unstratified HR, 0.62; 95% CI, 0.41-0.93) significantly favored the nivolumab arm. Notably, the survival benefit with nivolumab vs chemotherapy alone was observed in patients whether they received cisplatin (HR, 0.79; 95% CI, 0.53-1.17) or carboplatin (HR, 0.36; 95% CI, 0.16-0.81), and whether they had undergone lobectomy (HR, 0.71; 95% CI, 0.41-1.21) or pneumonectomy (HR, not calculable). Moreover, pCR appeared to correlate with improved OS in patients in the investigational arm (HR, 0.08; 95% CI, 0.02-0.34).

Findings from CheckMate 816 supported the March 2022 FDA approval of nivolumab plus platinum-doublet chemotherapy for adult patients with resectable NSCLC in the neoadjuvant setting. The decision made the combination the first FDA-approved neoadjuvant therapy for early-stage NSCLC.⁵

“[Previously], in CheckMate 816, the patients [who were] PD-L1 negative weren’t benefiting the way the patients [who were] PD-L1 positive were,” Heather Wakelee, MD, noted. “We’ve had some updates at ASCO 2024 with 4-year results that are looking great. They didn’t do that PD-L1 break down again, but in the perioperative trials, you see patients without PD-L1 expression looking like they’re potentially benefiting, crossing unity [of the survival curves].”

The phase 3 CheckMate 77T study (NCT04025879) built upon the rationale established by CheckMate 816 by evaluating neoadjuvant nivolumab plus chemotherapy followed by adjuvant nivolumab after surgery. Investigators enrolled adult patients with resectable stage IIA to IIIB NSCLC and randomly assigned them 1:1 to receive neoadjuvant nivolumab plus chemotherapy followed by adjuvant nivolumab monotherapy after surgery or placebo in place of nivolumab. The primary end point was EFS by BICR; secondary end points included pCR, major pathologic response (MPR), OS, and safety.⁶

Findings from the primary analysis of CheckMate 77T showed that the median EFS by BICR significantly favored the nivolumab arm (HR, 0.58; 97.36% CI, 0.42-0.81; P = .00025); the addition of nivolumab also led to a 20.5% and 23.2% increase in pCR and MPR, respectively, vs placebo. Additional data from an exploratory analysis of the study demonstrated that perioperative nivolumab led to an EFS benefit over placebo in patients with stage III N2 disease (HR, 0.46; 95% CI, 0.30-0.70) as well as those with stage III non-N2 disease (HR, 0.60; 95% CI, 0.33-1.08) from the time of random assignment. Landmark EFS from definitive surgery also favored the nivolumab arm in patients with stage III N2 disease (HR, 0.32; 95% CI, 0.19-0.54) and those with stage III non-N2 disease (HR, 0.61; 95% CI, 0.30-1.24).

Beyond findings presented during ASCO 2024, the panelists also highlighted data from the phase 3 KEYNOTE-671 study (NCT03425643), which evaluated pembrolizumab (Keytruda) in combination with platinum-doublet chemotherapy in patients with resectable stage II to IIIB NSCLC. The study randomly assigned patients 1:1 to receive neoadjuvant pembrolizumab or placebo with cisplatin-based chemotherapy followed by surgery and adjuvant pembrolizumab or placebo. The coprimary end points were EFS and OS; secondary end points included MPR, pCR, and safety.⁷

At a median follow-up of 25.2 months (range, 7.5-50.6), the 24-month EFS rates in the pembrolizumab and placebo arms were 62.4% (95% CI, 56.8%-67.5%) vs 40.6% (95% CI, 34.8%-46.3%), respectively (HR, 0.58; 95% CI, 0.46-0.72; P < .001). The estimated 24-month OS rates were 80.9% (95% CI, 76.2%-84.7%) vs 77.6% (95% CI, 72.5%-81.9%; ^P = .02). The MPR rates were 30.2% (95% CI, 25.7%- 35.0%) vs 11.0% (95% CI, 8.1%-14.5%), respectively (P < .0001), and the pCR rates were 18.1% (95% CI, 14.5%-22.3%) vs 4.0% (95% CI, 2.3%-6.4%), respectively (P < .0001).

“KEYNOTE-671 [data showed definitive] EFS and OS benefit and [led to an FDA] approval,” Wakelee explained. “We also have [data from] AEGEAN with durvalumab and CheckMate 77T with nivolumab. The questions we have are perioperative vs neoadjuvant and how much does that additional adjuvant piece add. [In terms of] neoadjuvant therapy, you’re considering [administering] immune therapy combined with chemotherapy in that neoadjuvant or perioperative regimen. That’s the standard, except it’s not for everybody. That’s where we need to be aware of who should not get immune therapy. If a patient has a driver mutation, I don’t believe they should receive it, because we know that giving immunotherapy [to these patients] can cause problems. We also know from what we’ve learned in the metastatic [setting] that for a lot of patients who develop lung cancer who don’t have a smoking history and have a driver mutation, immune therapy doesn’t work very well.”

Treatment Advances in Unresectable Stage III NSCLC

Durvalumab has also carved out a significant role in the treatment of patients with unresectable stage III NSCLC, both after concurrent or sequential chemoradiotherapy. The phase 3 PACIFIC study (NCT02125461) examined the agent in patients with stage III unresectable NSCLC who had not experienced disease progression after concurrent chemoradiotherapy. Investigators randomly assigned patients 2:1 to receive durvalumab or placebo. The coprimary end points were progression-free survival (PFS) by BICR and OS; secondary end points included objective response rate (ORR), duration of response (DOR), and safety.⁸

At a January 11, 2021, data cutoff, at a median follow-up of 34.2 months (range, 0.2-74.7), findings from the primary analysis of PACIFIC demonstrated that patients in the durvalumab (n = 476) and placebo (n = 237) arms achieved a median OS of 47.5 months (95% CI, 38.1-52.9) vs 29.1 months (95% CI, 22.1-35.1), respectively (HR, 0.72; 95% CI, 0.59-0.89); the respective 5-year OS rates were 42.9% (95% CI, 38.2%-47.4%) vs 33.4% (95% CI, 27.3%-39.6%). The median PFS was 16.9 months (95% CI, 13.0-23.9) vs 5.6 months (95% CI, 4.8-7.7), respectively (HR, 0.55; 95% CI, 0.45-0.68); the 5-year PFS rates were 33.1% (95% CI, 28.0%-38.2%) vs 19.0% (95% CI, 13.6%-25.2%), respectively.

In February 2018, the FDA approved durvalumab monotherapy for the treatment of patients with unresectable stage III NSCLC who did not experience disease progression after concurrent platinum-based chemotherapy and radiation therapy. The regulatory decision was supported by interim findings from PACIFIC.⁹

Following the establishment of consolidation durvalumab as a standard of care for the treatment of patients with unresectable stage III NSCLC without disease progression following definitive chemoradiotherapy, the observational PACIFIC-R study (NCT03798535) aimed to evaluate the real-world efficacy of the approach. The international retrospective study examined patients with unresectable stage III NSCLC who started receiving durvalumab in an early access program from September 2017 to December 2018 across 290 sites in 11 countries. The coprimary end points were investigator-assessed real-world PFS and OS.¹⁰

In the full analysis set (n = 1399), the median real-world PFS was 21.7 months (95% CI, 19.1- 24.5); the 12-, 18-, and 24-month PFS rates were 62.2% (95% CI, 59.6%-64.6%), 54.1% (95% CI, 51.4%-56.7%), and 48.2% (95% CI, 45.4%-50.9%), respectively. The median OS was not reached, and the estimated 24-month OS rate was 71.2% (95% CI, 68.8%-73.6%).

Due to a significant number of patients being unsuitable for concurrent chemoradiotherapy, the phase 2 PACIFIC-6 trial (NCT03693300) sought to examine the role of durvalumab following sequential chemoradiotherapy in patients with stage III unresectable NSCLC. Investigators enrolled patients who did not experience disease progression after sequential chemoradiotherapy. The primary end point was incidence of grade 3 or 4 adverse effects (AEs) potentially related to treatment occurring within 6 months; secondary end points included investigator-assessed PFS and OS.

At the July 15, 2021, data cutoff, patients who received durvalumab (n = 117) experienced grade 3 or 4 AEs at a rate of 18.8%, and 4.3% (95% CI, 1.4%-9.7%) had grade 3 or 4 AEs possibly related to treatment within 6 months. Although investigators noted that survival data maturity was limited, the median PFS was 10.9 months (95% CI, 7.3-15.6) and the 12-month PFS rate was 49.6% (95% CI, 39.5%- 58.9%). The 12-month OS rate was 84.1% (95% CI, 75.6%-89.9%).

One of the most notable studies in the lung cancer space whose data were presented during ASCO 2024 was the phase 3 LAURA trial (NCT03521154). LAURA was a double-blind, placebo-controlled study that enrolled adult patients with locally advanced, unresectable stage III NSCLC with an EGFR exon 19 deletion or L858R mutation whose disease had not progressed following definitive chemoradiotherapy. Investigators randomly assigned eligible patients 2:1 to receive oral osimertinib (Tagrisso) 80 mg or placebo once daily. The primary end point was PFS by BICR per RECIST 1.1; secondary end points included OS, central nervous system PFS, and safety.¹²

The median PFS per BICR in the osimertinib arm (n = 143) was 39.1 months (95% CI, 31.5-NC) vs 5.6 months (95% CI, 3.7-7.4) in the placebo arm (n = 73), leading to an 84% reduction in the risk of progression or death compared with placebo (HR, 0.16; 95% CI, 0.10-0.24; P < .001). The 12- and 24-month PFS rates were 74% and 65%, respectively, in the investigational arm vs 22% and 13%, respectively, in the control arm.

The ORRs by BICR in the osimertinib and placebo arms were 57% (95% CI, 49%-66%) vs 33% (95% CI, 22%-45%), respectively. The median DOR was 36.9 months (95% CI, 30.1-NC) vs 6.5 months (95% CI, 3.6-8.3), respectively. OS data were only 20% mature at the time of ASCO 2024 but indicated a positive trend in favor of the osimertinib arm, even with 81% of patients in the placebo arm having crossed over to receive osimertinib (HR, 0.81; 95% CI, 0.42- 1.56; P = .530).

“The LAURA [data] are immediately relevant, and I’ve been using [the drug] off-label for a long time,” Joshua K. Sabari, MD, said. “We saw a significant improvement. One thing I’ll [emphasize] is that osimertinib is continuous; it’s lifelong, essentially. There was a lot of excitement about the data, [although] there are toxicity issues. This builds upon [our] understanding [of] the biology of this type of disease; EGFR-mutated lung cancer responds well to an EGFR-[directed] TKI. I don’t believe with the data now [that] anybody…would use durvalumab in this setting.”

Investigators are also examining the potential role of combination regimens in the consolidation setting. The phase 2 COAST trial (NCT03822351) evaluated durvalumab alone or combined with oleclumab or monalizumab in patients with unresectable stage III NSCLC who did not experience disease progression following concurrent chemoradiotherapy. The primary end point was investigator-assessed ORR; key secondary end points included safety, DOR, and investigator-assessed PFS.¹³

At a median follow-up of 11.5 months (range, 0.4-23.4), the confirmed ORRs among patients who received durvalumab plus oleclumab (n = 59) or durvalumab plus monalizumab (n = 61) was 30.0% (95% CI, 18.8%-43.2%) and 35.5% (95% CI, 23.7%-48.7%) vs 17.9% (95% CI, 9.6%-29.2%) among patients who received durvalumab monotherapy (n = 66). The addition of oleclumab (HR, 0.44; 95% CI, 0.26-0.75) or monalizumab (HR, 0.42; 95% CI, 0.24-0.72) to durvalumab led to a significant PFS benefit vs durvalumab monotherapy. The respective 12-month PFS rates were 62.6% (95% CI, 48.1%-74.2%), 72.7% (95% CI, 58.8%-82.6%), and 33.9% (95% CI, 21.2%-47.1%).

“COAST [examined] oleclumab, which is a CD73-targeted monoclonal antibody against the immunosuppressive adenosine monalizumab targeting NKG2A, which targets one of the natural killer cell check points in combination with durvalumab,” Patel said. “Some of the studies [whose data] we are looking forward to in different settings, whether [post]surgical or post radiation, [are] trying to help patients, especially those with lower PD-L1 scores, who may not respond to treatment.”

References

1. Kim F, Borgeaud M, Addeo A, Friedlaender A. Management of stage III non-small-cell lung cancer: rays of hope. Explor Target Antitumor Ther. 2024;5(1):85-95. doi:10.37349/ etat.2024.00206
2. July 25, 2024, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. https://www.youtube.com/live/smUHtK5wdic
3. 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
4. Spicer J, Girard N, Provencio M, et al. Neoadjuvant nivolumab (NIVO) + chemotherapy (chemo) vs chemo in patients (pts) with resectable NSCLC: 4-year update from CheckMate 816. J Clin Oncol. 2024;42(suppl 17):LBA8010. doi:10.1200/ JCO.2024.42.17_suppl.LBA8010
5. FDA approves neoadjuvant nivolumab and platinum-doublet chemotherapy for early-stage non–small cell lung cancer. FDA. March 4, 2022. Accessed July 2, 2024. https://www.fda.gov/ drugs/resources-information-approved-drugs/fda-approves-neoadjuvant-nivolumab-and-platinum-doublet-chemotherapy-early- stage-non-small-cell-lung
6. Provencio M, Awad MM, Spicer J, et al. Clinical outcomes with perioperative nivolumab (NIVO) by nodal status among patients (pts) with stage III resectable NSCLC: results from the phase 3 CheckMate 77T study. J Clin Oncol. 2024;42(suppl 17):LBA8007. doi:10.1200/JCO.2024.42.17_suppl.LBA8007
7. 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
8. Spigel DR, Faivre-Finn C, Gray JE, et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. J Clin Oncol. 2022;40(12):1301-1311. doi:10.1200/JCO.21.01308
9. FDA approves durvalumab after chemoradiation for unresectable stage III NSCLC. FDA. Updated February 20, 2018. Accessed July 2, 2024. https://www.fda.gov/drugs/resources-informationapproved-drugs/fda-approves-durvalumab-after-chemoradiation-unresectable-stage-iii-nsclc
10. Girard N, Bar J, Garrido P, et al. Treatment characteristics and real-world progression-free survival in patients with unresectable stage III NSCLC who received durvalumab after chemoradiotherapy: findings from the PACIFIC-R study. J Thorac Oncol. 2023;18(2):181-193. doi:10.1016/j. jtho.2022.10.003
11. Garassino MC, Mazieres J, Reck M, et al. Durvalumab after sequential chemoradiotherapy in stage III, unresectable NSCLC: the phase 2 PACIFIC-6 trial. J Thorac Oncol. 2022;17(12):1415- 1427. doi:10.1016/j.jtho.2022.07.1148
12. 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
13. Herbst RS, Majem M, Barlesi F, et al. COAST: an open-label, phase II, multidrug platform study of durvalumab alone or in combination with oleclumab or monalizumab in patients with unresectable, stage III non–small-cell lung cancer. J Clin Oncol. 2024;40(29):3383-3385. doi:10.1200/JCO.22.00227