Refining treatment approaches in early-stage lung cancer

NeoCOAST-2: novel perioperative regimens

At WCLC 2024, Cascone et al. reported preliminary efficacy and safety data for several novel perioperative combinations in patients with stage IIA-IIIB resectable non–small-cell lung cancer (NSCLC) included in Arms 1, 2 and 4 of the open-label, phase II NeoCOAST-2 platform study [1]. Arm 1 received the anti-CD73 antibody oleclumab in addition to durvalumab and platinum-doublet chemotherapy prior to surgery (n = 76), while oleclumab and durvalumab were administered in the adjuvant setting. In Arm 2, the neoadjuvant regimen consisted of the anti-NKG2A antibody monalizumab plus durvalumab and platinum-doublet chemotherapy (n = 72); here, surgery was followed by monalizumab plus durvalumab. Arm 4 was treated with the TROP2-targeted antibody drug conjugate datopotamab deruxtecan (Dato-DXd) in addition to durvalumab and single-agent platinum chemotherapy (n = 54). In the adjuvant setting, these patients received durvalumab monotherapy. Neoadjuvant treatment was administered Q3W for 4 cycles across the arms, while the adjuvant regimens were administered for up to one year. Consistent with real-world practice, carboplatin constituted the preferred platinum agent. Most patients had PD-L1–positive tumors (TPS, ≥ 1 %), stage IIIA disease, and adenocarcinoma histology.

NeoCOAST-2 was not powered for direct statistical comparisons between the arms. Instead, the primary intent was to identify preliminary efficacy signals. The combinations indeed displayed promising efficacy, with pathological complete response (pCR) and/or major pathological response (mPR) rates being numerically higher than historical benchmarks. pCR rates ranged from 20.0 % to 34.1 % and mPR rates from 45.0 % to 65.9 % (Figure). Across the arms, higher pCR rates emerged with increasing PD-L1 expression. However, caution should be applied here as the sample sizes were small in the PD-L1 subgroups.

All combinations demonstrated manageable safety profiles and surgical rates comparable to currently approved regimens [2-4]. The analysis revealed low rates of adverse events (AEs) in all phases of treatment. Nausea, anemia, neutropenia and asthenia were among the most common treatment-emergent AEs observed across the arms during the neoadjuvant phase. Grade ≥ 3 treatment-related AEs (TRAEs) occurred in approximately 30 % in Arms 1 and 2 and in 18.5 % in Arm 4, with low rates of AEs leading to discontinuation in each arm. Pertaining to the Dato-DXd–based strategy that had given rise to the highest pCR rate, the authors noted that NeoCOAST-2 is the first global phase II study showing encouraging efficacy and manageable safety of an antibody drug conjugate in the neoadjuvant setting for patients with resectable NSCLC.

Figure: pCR and mPR rates across treatment arms in the NeoCOAST-2 study

Figure: pCR and mPR rates across treatment arms in the NeoCOAST-2 study

Perioperative vs. neoadjuvant nivolumab

The CheckMate 816 study has explored the neoadjuvant use of 3 cycles of nivolumab plus chemotherapy in patients with resectable NSCLC. Building on the findings of CheckMate 816, the CheckMate 77T trial investigated neoadjuvant nivolumab plus chemotherapy for up to 4 cycles followed by adjuvant nivolumab treatment for up to 13 cycles. Both studies have shown benefits regarding event-free survival (EFS) compared to chemotherapy alone [5, 6]. In the absence of a randomized controlled trial, Forde et al. conducted an exploratory patient-level data analysis of the two studies to address the question of which patients derive benefit from adjuvant nivolumab following neoadjuvant nivolumab plus chemotherapy and surgery. While the perioperative nivolumab group contained 139 patients, the neoadjuvant nivolumab plus chemotherapy group comprised 147 individuals. After propensity score weighting, the baseline characteristics of the two cohorts were generally balanced. EFS landmarked from the time of surgery constituted the primary endpoint. This analysis represents the only comparison of perioperative vs. neoadjuvant-only immunotherapy for patients with resectable NSCLC, as the authors pointed out.

According to the weighted analysis, perioperative treatment gave rise to a 39 % risk reduction regarding EFS from definitive surgery compared to the neoadjuvant-only approach (HR, 0.61) [7]. The landmark analysis by pCR status showed a distinct separation of the EFS curves in favor of the perioperative immunotherapy in patients who did not achieve pCR (HR, 0.65). In those with pCR, the perioperatively treated cohort fared better as well, although this group had a low number of events due to its good prognosis and the separation of curves was limited. A greater magnitude of benefit was observed in perioperatively treated patients with tumor PD-L1 expression < 1 % (HR, 0.51) than in those with PD-L1 expression ≥ 1 % that showed merely a trend favoring perioperative treatment. Similar benefits compared to the neoadjuvant-only approach emerged in patients with stage IB-II and stage III disease (HRs, 0.53 and 0.63, respectively).

The safety analysis showed that perioperative nivolumab had a generally manageable safety profile. Any-grade TRAEs leading to treatment discontinuation occurred in 16 % vs. 11 % with the perioperative and neoadjuvant strategies; grade 3/4 TRAEs necessitated discontinuation in 6 % vs. 5 %. In similar vein, any-grade and grade 3/4 surgery-related AEs were balanced across the two groups. These results help inform the potential benefit of adjuvant nivolumab following neoadjuvant nivolumab plus chemotherapy and surgery. Moreover, they further support perioperative nivolumab as a treatment option for eligible patients with resectable NSCLC.

KEYNOTE-671: EFS and pathologic regression

In the randomized, double-blind, phase III KEYNOTE-671 trial, neoadjuvant pembrolizumab combined with platinum-based chemotherapy for up to 4 cycles followed by surgery and adjuvant pembrolizumab for up to 13 cycles has demonstrated efficacy in patients with stage II, IIIA, or IIIB (N2) NSCLC [2]. Patients in the control arm received placebo plus chemotherapy and placebo in the neoadjuvant and adjuvant phases, respectively. EFS was longest in those who had achieved pCR and mPR after neoadjuvant treatment with pembrolizumab. Jones et al. conducted a post-hoc analysis of the KEYNOTE-671 data to assess the association of EFS with the degree of pathologic regression, which was defined as percent residual viable tumor (% RVT) after resection. The patients included in this analysis had undergone in-study surgery and showed pathologically evaluable tumors, which applied to 320 and 300 in the pembrolizumab and placebo arms, respectively.

Based on % RVT, neoadjuvant pembrolizumab plus chemotherapy elicited more pronounced pathologic regression than neoadjuvant chemotherapy only [8]. Median % RVT was 29.5 % vs. 52.0 % for the two cohorts. Within the pembrolizumab-treated group, EFS was longest in patients with % RVT of 0 % to ≤ 5 % and shortest in the group with % RVT > 60 %. In both groups, higher % RVT correlated with poorer EFS, although pembrolizumab-treated patients fared better across the % RVT categories (Table). The authors noted that further studies are needed to validate % RVT for the evaluation of outcomes in this patient population. Taken together, perioperative pembrolizumab demonstrated clinically significant EFS benefits that extend to patients with residual viable tumors after neoadjuvant treatment, which supports the benefit of this regimen.

Table Event-free survival in KEYNOTE-671 according to the degree of residual disease after resection

Safety results for alectinib in ALINA

The global, open-label, randomized ALINA trial comparing adjuvant alectinib with chemotherapy was the first and only positive phase III study investigating an ALK inhibitor in the setting of early-stage ALK-positive NSCLC [9]. A total of 257 patients with resected stage IB (≥ 4 cm) to IIIA ALK-positive NSCLC were ran­domized to either alectinib 600 mg BID for 2 years or platinum-based chemotherapy Q3W for 4 cycles. Alectinib improved disease-free survival (DFS, primary endpoint) compared to chemotherapy in a statistically significant and clinically meaningful manner (HR, 0.24; p < 0.0001). For the exploratory endpoint of DFS in the central nervous system, the analysis revealed a clinically meaningful benefit (HR, 0.22). Horinouchi et al. presented safety results for the ALINA study at WCLC 2024 [10].

The overall incidence of AEs was similar between the two arms despite the difference in median treatment duration, which was ten times longer with alectinib than with chemotherapy (23.9 vs. 2.1 months). Grade 3/4 treatment-related AEs were observed in 18 % vs. 28 %, and treatment-related serious AEs occurred in 2 % vs. 7 %. AEs led to dose reductions in 26 % vs. 10 % and to dose interruptions in 27 % vs. 18 %. Treatment withdrawal was necessary in 5 % vs. 13 %. No patient died due to AEs across the arms. Alectinib showed a tolerable and manageable safety profile. AEs primarily consisted of low-grade laboratory anoma­lies and were in line with the known safety profile of alectinib. Increases in blood creatine phosphokinase were most common, followed by constipation as well as AST, ALT and bilirubin increases. The most frequent AEs emerged within the first month of treatment. AEs of longer duration were mostly grade 1-2, proved manageable and did not lead to treatment discontinuation. Higher-grade AEs were easily amenable to management with dose interruption or reduction.

In all, the safety profile of adjuvant alectinib was consistent with the profile that had previously been observed in patients receiving alectinib in the setting of metastatic ALK-positive NSCLC [11]. The authors concluded that together with the DFS benefit seen in the ALINA trial, these safety data support the adjuvant use of alectinib as an important new treatment strategy.

REFERENCES

  1. Cascone T et al., NeoCOAST-2: efficacy and safety of neoadjuvant durvalumab + novel anticancer agents + CT and adjuvant durvalumab ± novel agents in resectable NSCLC. WCLC 2024, abstract PL02.07
  2. Wakelee H et al., Perioperative pembrolizumab for early-stage non-small-cell lung cancer. N Engl J Med 2023; 389(6): 491-503
  3. Forde PM et al., Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med 2022; 386 (21): 1973-1985
  4. Heymach JV et al., Perioperative durvalumab for resectable non-small-cell lung cancer. N Engl J Med 2023; 389(18): 1672-1684
  5. Forde PM et al., Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med 2022; 386(21): 1973-1985
  6. Cascone T et al., Perioperative nivolumab in resectable lung cancer. N Engl J Med 2024; 390(19): 1756-1769
  7. Forde PM et al., Perioperative vs neoadjuvant nivolumab for resectable NSCLC: patient-level data analysis of CheckMate 77T vs CheckMate 816. WCLC 2024, abstract PL02.08
  8. Jones DR et al., Association of pathologic regression with event-free survival in the KEYNOTE-671 study of perioperative pembrolizumab for early-stage NSCLC. WCLC 2024, abstract OA01.03
  9. Wu et al., Alectinib in resected ALK-positive non–small-cell lung cancer. N Engl J Med 2024; 390(14): 1265-1276
  10. Horinouchi H et al., ALINA safety results: adjuvant alectinib vs chemotherapy in patients with resected ALK+ non-small cell lung cancer. WCLC 2024, abstract OA13.04
  11. Dziadziuszko R et al., Clinical experience and management of adverse events in patients with advanced ALK-positive non-small-cell lung cancer receiving alectinib. ESMO Open 2022; 7(6): 100612

© 2024 Springer-Verlag GmbH, Impressum

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