Brahmer's Take: Advancements in 3 Cornerstone Settings of NSCLC

Julie R. Brahmer, MD, MSc, FASCO

As of October 4, 2024, 10 FDA approvals have entered the non–small cell lung cancer (NSCLC) arena in the calendar year, and within the past 2 weeks of the aforementioned date, approvals for those with resectable and nonresectable disease have further added to the paradigm.¹ The practice-changing indications as well as notable data have sparked conversations in not only the early-stage setting but also the neo(adjuvant) and metastatic settings.

Nivolumab (Opdivo) plus platinum-doublet chemotherapy joined durvalumab (Imfinzi) when it received another indication on October 3, 2024, as neoadjuvant treatment followed by single-agent adjuvant nivolumab for adults with resectable (tumors ≥ 4 cm and/or node positive) NSCLC and no known EGFR mutations or ALK rearrangements.² Just a few months earlier, on August 15, 2024, a durvalumabplus platinum-containing chemotherapy regimen received the same indication for this patient population.³

“The most important advances of this year thus far are in early-stage NSCLC with the advent of neoadjuvant immunotherapy plus chemotherapy,” Julie R. Brahmer, MD, MSc, FASCO, said in an interview with OncologyLive. “We know that patients with stage II and stage IIIA disease benefit from neoadjuvant therapy, and there are multiple perioperative paradigms that are now approved for giving neoadjuvant chemotherapy and immunotherapy followed by immunotherapy in the adjuvant setting, as well.”

Durvalumab’s addition to the perioperative treatment paradigm was based on data from the phase 3 AEGEAN trial (NCT03800134), in which the durvalumab regimen reduced the risk of an event-free survival (EFS) event by 32% vs the placebo regimen (HR, 0.68; 95% CI, 0.53-0.88; P = .0039).³ This marked the second approval in the perioperative space; the first was the October 16, 2023, FDA approval of pembrolizumab (Keytruda) plus platinum-containing chemotherapy as neoadjuvant treatment followed by adjuvant pembrolizumab for patients with resectable NSCLC. New data from the phase 3 KEYNOTE-671 study (NCT03425643), which supported the approval, showed a significant overall survival (OS) benefit with perioperative immunotherapy vs neoadjuvant chemotherapy alone.^4,5

Findings from the second interim analysis revealed that the 36-month estimated OS rates were 71% (95% CI, 66%-76%) in the pembrolizumab arm (n = 397) vs 64% (95% CI, 58%-69%) in the placebo arm (n = 400; HR, 0.72; 95% CI, 0.56-0.93; 1-sided P = .0052). Moreover, with a median follow-up of 36.6 months (IQR, 27.6-47.8), the HR for EFS continued to favor the pembrolizumab regimen (HR, 0.59; 95% CI, 0.48-0.72). At the first interim analysis, significantly improved pathologic complete response (pCR) rates occurred among patients treated with pembrolizumab (18%) vs placebo (4%; 1-sided P < .0001).⁵

“The data that have continued to come out on these regimens show that if patients achieve a pCR with neoadjuvant chemotherapy and immunotherapy, they do extremely well for quite some time,” Brahmer said. “[In] most of the studies, we have not seen long-term OS [data], but in the KEYNOTE-671 study [with the pembrolizumab regimen], there was an advantage from the survival standpoint, in addition to having decreased risk of cancer recurrence.”

Early-Stage Setting: Neoadjuvant Chemoimmunotherapy Represents a Key Step Forward

“In the early-stage setting, it is exciting [having] neoadjuvant therapy and trying to move the bar [to figure out] how these types of therapies work for patients, knowing that patients who achieve a pCR do well after treatment. But for practice, the devil is in the details,” Brahmer noted. “Knowing patients’ fusions and driver mutations can help you decide whether neoadjuvant therapy is needed since patients with ALK-positive disease and EGFR mutations don’t do well with single-agent immunotherapy plus chemotherapy. Every practice needs to figure out how to operationalize getting these answers quickly to start the therapy for these patients or take them directly to surgery, depending on those results.”

Brahmer added that with time and more mature data, it will become clearer which combination therapy should be used for select patients. The phase 2 NeoCOAST-2 trial (NCT05061550), which examined 3 different durvalumab-based combinations, was the first global, phase 2 trial to show efficacy and a manageable safety profile of an antibody-drug conjugate in the neoadjuvant setting for patients with resectable NSCLC.⁶

Findings on the 3 different novel combinations, which were given before surgery and following surgery without the chemotherapy component of therapy, were presented at the IASLC 2024 World Conference on Lung Cancer. In the intention-to-treat population, patients with stage IIA to IIIB disease experienced high pCR rates with the following combinations: datopotamab deruxtecan plus durvalumab and single-agent platinum chemotherapy (n = 44; 34.1%), oleclumab plus durvalumab and platinum-doublet chemotherapy (n = 60; 20.0%), and monalizumab plus durvalumab and platinum-doublet chemotherapy (n = 60; 26.7%).

“Trying to increase the pCR rate and assessing toxicities is important,” Brahmer said. “None of these combinations [from NeoCOAST-2] are clear front-runners yet, but over time, we’ll have a better idea [of the efficacy] of different combinations with immunotherapy and/or chemotherapy.”

Perioperative and Adjuvant Therapy: Nivolumab and Alectinib Join the Paradigm

“We are learning about adjuvant therapy—a lot of our patients go straight to surgery. What to do after surgery, depending on the stage [of disease, is important],” Brahmer said. “We know that adjuvant immunotherapy after chemotherapy is also helpful, but now for those patients with targeted mutations, we are learning that adjuvant targeted therapy is also helpful. Adjuvant osimertinib [Tagrisso] for patients with the classic EGFR exon 19 [deletions and] exon 21 mutations is advantageous, but now we have alectinib [Alecensa] in the adjuvant setting for patients who have ALK fusions. These targeted therapies for specific patient populations are helpful after resection.”

The April 18, 2024, approval of adjuvant alectinib for patients with ALK-positive NSCLC was based on data from the phase 3 ALINA trial (NCT03456076), which showed that the agent reduced the risk of a disease-free survival event by 76% vs platinum-based chemotherapy (HR, 0.24; 95% CI, 0.13-0.45; P < .0001) in patients with stage II to IIIA disease, and by 76% (HR, 0.24; 95% CI, 0.13-0.43; P < .0001) in patients with stage IB to IIIA disease.⁷

In addition to the benefit seen with targeted therapies in the adjuvant setting, patients with no known ALK rearrangements or EGFR mutations who received neoadjuvant nivolumab plus platinum-based chemotherapy followed by adjuvant nivolumab in the phase 3 CheckMate 77T trial (NCT04025879) experienced a median EFS of not reached (95% CI, 28.9-not estimable [NE]) in the nivolumab arm (n = 229) vs 18.4 months (95% CI, 13.6-28.1) in the chemotherapy-alone arm (n = 232; HR, 0.58; 95% CI, 0.43-0.78; P = .00025).²

Advanced/Metastatic Setting and Future Directions: Novel Agents Are Emerging

“In the metastatic setting, we are trying to see how best to give immunotherapy in which combinations for which patients. Unfortunately, most of the [anti-]TIGIT combinations are not showing improved progression-free survival [PFS] or OS in combination with immunotherapy. However, there are other compounds being studied,” Brahmer said.

She noted that the bispecific PD-1– and VEGF–targeted antibody ivonescimab is an agent to watch, as frontline treatment with ivonescimab led to a 49% reduction in the risk of disease progression or death vs pembrolizumab in patients with PD-L1–positive advanced NSCLC. Findings from the primary analysis of the phase 3 HARMONi-2 trial (AK112-303; NCT05499390), which was conducted in China and presented at the IASLC 2024 World Conference on Lung Cancer, revealed that the median PFS was 11.14 months (95% CI, 7.33-NE) among patients treated with ivonescimab (n = 198) vs 5.82 months (95% CI, 5.03-8.21) for those treated with pembrolizumab (n = 200; stratified HR, 0.51; 95% CI, 0.38-0.69; P < .0001).⁸

Additionally, HARMONi-2 was the first randomized phase 3 study in patients with advanced NSCLC to demonstrate a clinically significant improvement in efficacy with a novel drug vs pembrolizumab. “It was exciting to see that improvement on pembrolizumab as a single agent. I believe this may change practice in the US down the road, but we eagerly await phase 3 studies to be completed here in the US,” Brahmer said.

With the plethora of data that have been released in 2024, the 22nd Annual Winter Lung Cancer Conference will serve as a way to examine the latest findings. The meeting will occurfromJanuary 31 to February 2, 2025, in Hollywood, Florida, and it will be cochaired by Brahmer; Rogerio C. Lilenbaum, MD, FACP, FASCO, of Jupiter Medical Center in Florida; and Mark A. Socinski, MD, of AdventHealth Cancer Institute in Orlando, Florida.⁹

“I’m most excited about seeing how this conference has evolved into more of a multidisciplinary conference. But also, with the rapidly changing treatment landscape for these patients—all the way from NSCLC and small cell lung cancer with new approvals as well—it’s exciting to be able to bring all these data together from this past year and present it early on in 2025 to help everyone synthesize the data and how to apply it in their own practice. It’s exciting to see all these changes,” Brahmer said.

22nd Annual Winter Lung Cancer Conference

References

1. Oncology (cancer)/hematologic malignancies approval notifications. FDA. Updated October 3, 2024. Accessed October 4, 2024. bit.ly/3Ne3jBO
2. FDA approves neoadjuvant/adjuvant nivolumab for resectable non-small cell lung cancer. FDA. October 3, 2024. Accessed October 4, 2024. bit.ly/3TVfLdi
3. FDA approves neoadjuvant/adjuvant durvalumab for resectable non-small cell lung cancer. FDA. August 15, 2024. Accessed October 4, 2024. bit.ly/3zKL2Jb
4. FDA approves neoadjuvant/adjuvant pembrolizumab for resectable non-small cell lung cancer. FDA. October 16, 2023. Accessed October 4, 2024. bit.ly/3BFXiuY
5. Spicer JD, Garassino MC, Wakelee H, et al; KEYNOTE-671 Investigators. Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone in patients with early-stage non-small-cell lung cancer (KEYNOTE-671): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024;404(10459):1240-1252. doi:10.1016/S0140-6736(24)01756-2
6. Cascone T, Guisier F, Bonanno L, et al. NeoCOAST-2: efficacy and safety of neoadjuvant durvalumab (D) + novel anticancer agents + CT and adjuvant D ± novel agents in resectable NSCLC. Presented at: IASLC 2024 World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA. Abstract PL02.07.
7. FDA approves alectinib as adjuvant treatment for ALK-positive non-small cell lung cancer. FDA. April 18, 2024. Accessed October 4, 2024. bit.ly/47VXGBH
8. Zhou C, Chen J, Wu L, et al. Phase 3 study of ivonescimab (AK112) vs. pembrolizumab as first-line treatment for PD-L1-positive advanced NSCLC: HARMONi-2. Presented at: IASLC 2024 World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA. Abstract PL02.04.
9. 22nd Annual Winter Lung Cancer Conference. Physicians’ Education Resource, LLC. Accessed October 4, 2024.
   bit.ly/3XVcThW