New developments and updates in non-small cell lung cancer and immunotherapy: adjuvant, neoadjuvant and advanced stages
Recently, the article entitled “Immune checkpoint inhibitors in non-small cell lung cancer: from current perspectives to future treatments-a systematic review” was published (1). This systematic review gave an overview of studies investigating the use of immunotherapy in non-small cell lung cancer (NSCLC). Immunotherapy is currently the mainstay of treatment of NSCLC and researchers are constantly looking into new therapies (2). In the last few months since the publication of the review, three new immune therapies have been introduced (Table 1), which are fundamental to understanding the new treatment of NSCLC, especially in the adjuvant.
Table 1
| Trial | Phase | Stage | Histology | PD-L1 | Trial design | Results | Approved by FDA |
|---|---|---|---|---|---|---|---|
| KEYNOTE-091 | 3 | Adjuvant IB–III | All | All | Pembrolizumab vs. placebo post-surgery and CT | DFS 58.7 vs. 34.9 m | January/2023 stage IB (≥4 cm)–III All PD-L1 |
| DFS in PD-L1 ≥50% NR vs. NR | |||||||
| EMPOWER-Lung 3 | 3 | Advanced stages (1L) | All | All | Cemiplimab + CT vs. CT | OS 21.9 vs. 13.0 m | November/2022 advanced or metastatic NSCLC 1L all PD-L1 |
| PFS 8.2 vs. 5.0 m | |||||||
| POSEIDON | 3 | Advanced stages (1L) | All | All | Durvalumab + tremelimumab + CT vs. CT |
OS 14.0 vs. 11.7 m | November/2022 advanced or metastatic NSCLC 1L all PD-L1 |
| PFS 6.2 vs. 4.8 m | |||||||
| NADIM II | 2 | Perioperative stage III | All | All | Nivolumab + CT (three cycles) → surgery → nivolumab 6 months | pCR 37% vs. 7% | Not yet |
| PFS (24 m) 67.2% vs. 40.9% | |||||||
| KEYNOTE-671 | 3 | Perioperative stage II–III | All | All | Pembrolizumab + CT (four cycles) → surgery → pembrolizumab 1 year | pCR 30.2% vs. 11.0% | Not yet |
| OS (24 m) 80.9% vs. 77.6% |
NSCLC, non-small cell lung cancer; FDA, Food and Drug Administration; PD-L1, programmed death-ligand 1; CT, chemotherapy; 1L, first-line; DFS, disease-free survival; m, months; NR, not reached; OS, overall survival; PFS, progression-free survival; pCR, pathological complete response.
The first study, the PEARLS/KEYNOTE-091 trial, evaluated the efficacy of pembrolizumab in resected stage IB-IIIA (≥4 cm) NSCLC (3). This study showed favourable data for the use of pembrolizumab in this setting after adjuvant chemotherapy, with disease-free survival (DFS) of 58.7 vs. 34.9 months (HR: 0.73; 95% CI: 0.60–0.89). In patients without adjuvant chemotherapy, no difference was observed between the pembrolizumab group and placebo (HR: 1.25; 95% CI: 0.76–2.05). Following these data, the Food and Drug Administration (FDA) approved adjuvant pembrolizumab for use in stage IB (T2a ≥4 cm)-IIIA NSCLC after platinum-based adjuvant therapy in January 2023.
The other two studies (EMPOWER-Lung 3 and POSEIDON) evaluated the efficacy of immunotherapy in metastatic or advanced NSCLC in combination with chemotherapy (4,5). The EMPOWER-Lung 3 evaluated the efficacy of the combination of platinum-doublet chemotherapy with cemiplimab regardless of programmed death-ligand 1 (PD-L1) values (4). The study met its primary endpoint of overall survival (OS) with a median of 21.9 months in the cemiplimab group vs. 13.0 months in the placebo group (HR: 0.71; 95% CI: 0.53–0.93). These data, along with favourable progression-free survival (PFS) and objective response rate (ORR) data, led to FDA approval in November 2022 for the combination of platinum-doublet chemotherapy with cemiplimab in advanced or metastatic NSCLC in first-line NSCLC independent of PD-L1 values.
Finally, the POSEIDON trial evaluated the efficacy of the combination of the anti-PD-L1 durvalumab together with the anti-CTLA4 tremelimumab with platinum-doublet chemotherapy (5). One of the primary endpoints of the study was PFS which showed data for the combination of the immunotherapy doublet plus platinum-doublet of 6.2 vs. 4.8 months for chemotherapy alone (HR: 0.72; 95% CI: 0.60–0.86). The other primary endpoint was OS and this was also met with data of 14.0 vs. 11.7 months (HR: 0.77; 95% CI: 0.65–0.92) respectively. Based on these data, durvalumab, tremelimumab and platinum-doublet chemotherapy in advanced or metastatic NSCLC were approved by the FDA in November 2022 for first-line independent of PD-L1 values.
In addition to the previously mentioned clinical trials, the results of the NADIM II trial have recently been published (6). This study evaluated the efficacy of nivolumab plus chemotherapy in the perioperative treatment of stage III NSCLC. The pathological complete response (pCR) rate after three induction cycles was 37% in the nivolumab group vs. 7% in the placebo group (relative risk, 5.34; 95% CI: 1.34–21.23). Subsequently, PFS at 24 months was 67.2% vs. 40.9% respectively (HR: 0.47; 95% CI: 0.25–0.88). Perioperative treatment with immunotherapy in stage III NSCLC is likely to be approved in the short term. Similarly, the KEYNOTE-671 (7) clinical trial evaluated pembrolizumab treatment in the same indication as NADIM II. This study showed a pCR of 30.2% in the pembrolizumab arm vs. 11.0% for placebo (P<0.001). OS at 24 months was 80.9% vs. 77.6% (P=0.02). This indication will also receive approval in the short term by the main agencies.
In conclusion, immunotherapy in NSCLC is in a constant process of evolution that is radically changing the treatment of these tumours with survival and response rates that were unimaginable less than a decade ago.
Acknowledgments
Funding: None.
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