Dual PD-1/PD-L1 and CTLA-4 inhibition strategies: tailoring immunotherapy for metastatic non-small cell lung cancer
Takayuki Kobayashi1, Taiki Hakozaki1,2
Keywords: Immune checkpoint inhibitors (ICIs); non-small cell lung cancer (NSCLC); programmed death ligand-1 (PD-L1); cytotoxic T-lymphocyte antigen 4 (CTLA-4); dual immunotherapy (dual ITx)
Submitted Feb 21, 2024. Accepted for publication May 06, 2024. Published online Jun 13, 2024.
doi: 10.21037/cco-24-20
Immunotherapy (ITx) has become indispensable for the treatment of non-small cell lung cancer (NSCLC) without driver alterations. Anti-programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) antibodies have improved the prognosis of patients with driver alteration-negative NSCLC. The efficacy of anti-PD-1/PD-L1 antibody monotherapy in PD-L1-positive (≥1%) patients has been demonstrated in KEYNOTE-024, KEYNOTE-042, and IMpower110 trials, which have also importantly improved progression-free survival (PFS) and overall survival (OS) with a long-term survival tail plateau specifically in patients with high PD-L1 (≥50%) (1,2). However, not all the patients are successfully rescued by ITx; a subgroup of patients with non-high PD-L1 (<50%), particularly negative PD-L1 (<1%), tends to have worse clinical outcomes (2-4). Anti-PD-1/PD-L1 antibodies in combination with chemotherapy have improved outcomes in the early phase of the treatment, as demonstrated in several trials, including KEYNOTE-189, KEYNOTE-407, and IMpower150 (1,5). However, the long-term survival benefit conferred by ITx is insufficient for PD-L1-negative patients even when anti-PD-1/PD-L1 antibodies are administered in combination with chemotherapy. In fact, several studies have suggested that the combination with chemotherapy may produce a weaker treatment effect than observed in PD-L1-positive patients (6). Under these circumstances, the efficacy of dual ITx, i.e., a combination of immune checkpoint inhibitors (ICIs) targeting different immune checkpoint molecules, has attracted attention specifically with regard to this subgroup of patients.
Besides PD-1 and PD-L1, cytotoxic T-lymphocyte antigen 4 (CTLA-4) is another major immune checkpoint molecule that plays a key role in the cancer-immune cycle, where anti-PD-1/PD-L1 antibodies activate cancer antigen-specific T cells and enhance their cytotoxicity in the effector phase while anti-CTLA-4 antibodies block the inhibitory regulation of activated T cells and suppress regulatory T cell function in the priming phase (7,8). Previous reports of patients with melanoma and renal cell carcinoma have shown that nivolumab plus ipilimumab was more effective than nivolumab alone regardless of the PD-L1 expression level (9,10). In terms of the underlying mechanism, the combination of anti-PD-1 and anti-CTLA-4 antibodies in the treatment of PD-L1-positive tumors is thought to provide effective, peripheral immunity and the clearance of regulatory T cells from the tumor microenvironment, resulting in enhanced immune activity (11-13). In this context, multiple phase III trials of NSCLC have investigated the benefits of combining anti-PD-1/PD-L1 and anti-CTLA-4 antibodies in dual ITx.
Although some trials have demonstrated the superiority of dual ITx over chemotherapy, differences in primary analysis populations and outcomes make it unclear which populations benefit most from the strategy. The CheckMate 227, CheckMate 9LA, and POSEIDON trials demonstrated the efficacy of dual ITx with or without chemotherapy while the MYSTIC and NEPTUNE trials failed to demonstrate the superiority (14-18). The phase III NEPTUNE trial was a global, randomized, open-label study comparing durvalumab plus tremelimumab (DT) to chemotherapy as the first-line treatment of metastatic NSCLC without driver alterations. The primary endpoint was OS in patients with a high blood tumor mutation burden (bTMB), defined as 20 mut/Mb or greater. This was based on exploratory subgroup analyses from the phase III MYSTIC trial enrolling patients with metastatic NSCLC. The MYSTIC trial failed to statistically demonstrate OS benefit in patients with PD-L1 ≥25%, but optimal OS benefit with first-line DT versus chemotherapy was observed in patients with bTMB ≥20 mut/Mb. A global analysis of the NEPTUNE trial found that DT did not meet the primary endpoint of OS compared to chemotherapy although there was a numerical trend toward improvement. The safety profile of DT was consistent with the findings of previous studies. The efficacy of DT has not been established in any of the populations that were the focus of the MYSTIC and NEPTUNE trials.
For the above reason, Cheng et al. (19) assessed the efficacy of DT in NSCLC patients with negative PD-L1 in a Chinese cohort of the NEPTUNE trial. They performed a prespecified, exploratory analysis of 160 of the 259 patients in the NEPTUNE trial expansion cohort [intention-to-treat (ITT) population] enrolled at ten centers in China. The patients were stratified by PD-L1 expression, histology, and smoking history, then randomized (1:1) to receive DT or standard chemotherapy. While the global NEPTUNE trial focused on patients with bTMB ≥20 mut/Mb, the primary focus of Cheng et al.’s study was patients with negative PD-L1, in whom first-line DT demonstrated a trend toward improved OS than seen with chemotherapy [hazard ratio (HR): 0.60; 95% confidence interval (CI): 0.32–1.11], with the median OS of 15.0 months (95% CI: 10.5–27.4) versus 11.7 months (95% CI: 8.6–20.5). A secondary analysis evaluated OS and PFS in the ITT population and PD-L1 subgroups. In the ITT population, OS tended to be better with DT [HR: 0.70 (95% CI: 0.48–1.02); median OS: 20.0 months (95% CI: 15.0–28.7) versus 14.1 months (95% CI: 9.5–19.4)]. OS benefit with DT versus was also observed in the PD-L1 ≥25% and ≥50% subgroups. In the PD-L1-negative subgroup and ITT population, 24-month OS rates favored DT (PD-L1-negative subgroup: 36.0% versus 17.9%; ITT population: 44.2% versus 30.4%), and 12-month PFS rates were also the same (PD-L1-negative subgroup: 15.6% versus 11.3%; ITT population: 23.9% versus 16.6%). Based on these findings, the authors state that DT demonstrated a benefit in the tail of the survival curve.
However, the results of Cheng et al.’s study differed from those of the comparable analysis population in the global NEPTUNE trial. In contrast to the results found by Cheng et al., no difference in OS between treatment groups was observed in either the PD-L1-negative subgroup [HR: 1.07 (95% CI: 0.79–1.46); median OS: 11.1 months (95% CI: 8.1–14.7) versus 12.5 months (95% CI: 9.9–16.2)] or the ITT population [HR: 1.02 (95% CI: 0.87–1.19); median OS: 10.9 months (95% CI: 9.3–12.6) versus 12.1 months (95% CI: 10.3–13.5)] within the global cohort. The global NEPTUNE trial failed to replicate the findings of the subgroup analysis of the MYSTIC trial because the primary endpoint of the former was originally OS in the ITT population but was changed after randomization, which reduced the sample size. Moreover, there was an imbalance in the patient characteristics, such as more squamous histology and liver metastases in the DT arm. As a result, the survival outcomes of both the DT and chemotherapy arms in the global NEPTUNE trial were generally poorer and the median OS was shorter than in previous trials of dual ITx, including the MYSTIC trial.
Based on the safety profiles in a secondary analysis, the authors concluded that DT was tolerated well and that there were no new safety signals. In their study, the rate of any treatment-related adverse events (TRAEs) in the DT arm was 79.2%, and the rate of any grade 3/4 TRAEs was 31.2%. In the global NEPTUNE trial, on the other hand, the rates of TRAEs were 68.3% and 20.7%, respectively, with the Chinese cohort demonstrating a slightly higher rate. The rates of TRAEs in the global NEPTUNE trial were comparable to those of the MYSTIC trial while the findings of Cheng et al.’s study were comparable to those of the CheckMate 227 trial. Moreover, the rates of TRAEs in the study by Cheng et al. were not as high as those seen with dual ITx for other cancer types (9,10,19).
The study by Cheng et al. still has some major limitations; it was an exploratory analysis that differed from the global NEPTUNE trial in terms of the primary endpoint; OS in patients with negative PD-L1 tended to improve with the DT, but the number of patients was small, and the alpha significance level was not established. Due to the small sample size, there was an imbalance in the patient characteristics between the DT and chemotherapy arms in both the ITT population and the PD-L1-negative subgroup. Nonetheless, their study demonstrated a trend toward improved OS associated with first-line DT than with chemotherapy in the PD-L1-negative subgroup and ITT population. This finding was previously supported by the results of the ARCTIC and MYSTIC trials (16,20). The CheckMate 227 trial also produced similar results. Nivolumab plus ipilimumab has previously been shown to produce a durable, clinical benefit in subgroups with negative PD-L1 or squamous histology. Some meta-analyses demonstrated that nivolumab plus ipilimumab ranked first for OS in PD-L1-negative patients and that the HR of dual ITx trended downward over time compared to other ICI-based combination therapies (21,22). In addition to the differences in the patient characteristics and primary endpoints, there were also differences in the mOS and the median duration of response outcomes between their study and other clinical trials of DT (Tables 1,2). Notably, the results of this study were similar to those of the Checkmate 227 trial. As noted above, the major limitations of this study make it difficult to draw any definitive conclusions.
Table 1
| Trial | Authors/years | Primary endpoint | Agents | Patient number | mPFS (months) (HR) | mOS (months) (HR) | mDoR (months) |
|---|---|---|---|---|---|---|---|
| CM 227, Part 1 | Brahmer JR et al. [2023], (14) | OS | N + I | 396 | 5.1 (0.79) | 17.1 (0.77) | 24.5 |
| N + I vs. C | N | 396 | 4.2 (0.97) | 15.7 (0.92) | 15.5 | ||
| PD-L1 >1% | C (Ref.) | 397 | 5.6 | 14.9 | 6.7 | ||
| CM 9LA | Paz-Ares L et al. [2021], (15) | OS | N + I + C | 361 | 6.7 (0.68) | 15.6 (0.66) | 11.3 |
| N + I + C vs. C | C (Ref.) | 358 | 5 | 10.9 | 5.6 | ||
| PD-L1 all comers | – | ||||||
| MYSTIC | Rizvi NA et al. [2020], (16) | OS, PFS | D + T | 163 | 3.9 (1.05) | 11.9 (0.85) | NR |
| D + T vs. C | D | 163 | 4.7 (0.87) | 16.3 (0.76) | NR | ||
| PD-L1 >25% | C (Ref.) | 162 | 5.4 | 12.9 | 4.4 | ||
| NEPTUNE | de Castro G Jr et al. [2023], (17) | OS | D + T | 69 | 4.2 (0.77) | 11.7 (0.71) | 11.6 |
| D + T vs. C | C (Ref.) | 60 | 5.1 | 9.1 | 4.2 | ||
| bTMB >20 mut/Mb | – | ||||||
| NEPTUNE, China cohort | Cheng Y et al. [2023], (19) | OS | D + T | 78 | 4.2 (0.95) | 20.0 (0.70) | 10.5 |
| D + T vs. C | C (Ref.) | 82 | 6 | 14.1 | 6.1 | ||
| PD-L1 <1% | – | ||||||
| POSEIDON | Johnson ML et al. [2023], (18) | OS, PFS | D + T + C | 338 | 6.2 (0.72) | 14.0 (0.77) | 9.5 |
| D + C vs. C | D + C | 338 | 5.5 (0.74) | 13.3 (0.86) | 7 | ||
| PD-L1 all comers | C (Ref.) | 337 | 4.8 | 11.7 | 5.1 |
PD-1, programmed death receptor-1; PD-L1, programmed death ligand-1; CTLA-4, cytotoxic T-lymphocyte antigen 4; mOS, median overall survival; mPFS, median progression-free survival; HR, hazard ratio; mDoR, median duration of response; CM 227, CheckMate 227; OS, overall survival; N, nivolumab; I, ipilimumab; C, chemotherapy; Ref., reference; CM 9LA, CheckMate 9LA; PFS, progression-free survival; D, durvalumab; T, tremelimumab; bTMB, blood tumor mutation burden; NR, not reached.
Table 2
| Trial | CM 227 (14) | CM 9LA (15) | MYSTIC (16) | NEPTUNE (17) | NEPTUNE, China cohort (19) | POSEIDON (18) |
|---|---|---|---|---|---|---|
| Treatment | N + I vs. C | N + I + C vs. C | D + T vs. C | D + T vs. C | D + T vs. C | D + T + C vs. C |
| ITT | 583 vs. 583 | 361 vs. 358 | 372 vs. 372 | 410 vs. 413 | 78 vs. 82 | 338 vs. 337 |
| mOS (months) | 17.1 vs. 13.9 | 15.6 vs. 10.9 | 11.2 vs. 11.8 | 10.9 vs. 12.1 | 20.0 vs. 14.1 | 14.0 vs. 11.7 |
| HR (95% CI) | 0.73 (0.64–0.84) | 0.66 (0.55–0.80) | 0.94 (0.79–1.10) | 1.02 (0.87–1.19) | 0.70 (0.48–1.02) | 0.77 (0.65–0.92) |
| mPFS (months) | 5.1 vs. 5.5 | 6.7 vs. 5.0 | 2.9 vs. 5.4 | 4.0 vs. 5.6 | 4.2 vs. 6.0 | 6.2 vs. 4.8 |
| HR (95% CI) | 0.79 (0.69–0.91) | 0.68 (0.57–0.82) | 1.25 (1.05–1.49) | 1.08 (0.92–1.25) | 0.95 (0.66–1.36) | 0.72 (0.60–0.86) |
| mDoR (months) | 19.6 vs. 5.8 | 11.3 vs. 5.6 | – | – | 12.9 vs. 6.1 | 9.5 vs. 5.1 |
| PD-L1 <1% | 187 vs. 186 | 135 vs. 129 | 76 vs. 83 | 91 vs. 104 | 26 vs. 29 | 125 vs. 130 |
| mOS (months) | 17.4 vs. 12.2 | 16.8 vs. 9.8 | 11.9 vs. 10.3 | 11.1 vs. 12.5 | 15.0 vs. 11.7 | – |
| HR (95% CI) | 0.65 (0.52–0.81) | 0.62 (0.45–0.85) | 0.73 (0.51–1.04) | 1.07 (0.79–1.46) | 0.60 (0.32–1.11) | 0.77 (0.58–1.00) |
| mPFS (months) | 5.1 vs. 4.7 | 5.8 vs. 4.6 | – | – | 5.1 vs. 6.0 | – |
| HR (95% CI) | 0.75 (0.59–0.95) | 0.71 (0.53–0.94) | – | – | 1.13 (0.59–2.14) | 0.78 (0.59–1.03) |
| mDoR (months) | 19.4 vs. 4.8 | NR vs. 4.3 | – | – | 10.5 vs. 6.1 | – |
ITT, intention to treat; PD-L1, programmed death ligand-1; CM 227, CheckMate 227; CM 9LA, CheckMate 9LA; N, nivolumab; I, ipilimumab; C, chemotherapy; D, durvalumab; T, tremelimumab; mOS, median overall survival; HR, hazard ratio; CI, confidence interval; mPFS, median progression-free survival; mDoR, median duration of response; NR, not reached.
There is still an unmet need to identify patients requiring combination therapy with anti-PD-1/PD-L1 antibodies and anti-CTLA-4 antibodies to achieve the optimal, therapeutic benefit. The primary evaluation populations for both the MYSTIC and NEPTUNE trials were modified from their original configuration, resulting in the loss of statistical power due to the smaller sample size. The Checkmate 227 trial suggested that dual ITx may be effective in PD-L1-negative patients and those diagnosed with squamous histology. However, the efficacy of the treatment in PD-L1-negative patients was only a secondary endpoint; the exploratory analysis of its efficacy in the squamous histology subgroup had insufficient statistical power, making it difficult to conclude that dual ITx had any benefit for these populations. In previous clinical trials, including Cheng et al.’s study, dual ITx is not directly compared with chemoimmunotherapy regardless of PD-L1 expression. At present, dual ITx does not exclusively represent a clinical option in the treatment of PD-L1-negative metastatic NSCLC. Further prospective studies with adequate statistical power are warranted to identify the patient population that would benefit most from dual ITx.
Acknowledgments
We thank Mr. James R. Valera for his assistance with editing this manuscript.
Funding: None.
Footnote
Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.
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Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-20/coif). T.H. received personal fees from Chugai Pharmaceutical, Ono Pharmaceutical, and Eisai outside the submitted work. The other author has no conflicts of interest to declare.
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