IMpower, CASPIAN, and more: exploring the optimal first-line immunotherapy for extensive-stage small cell lung cancer

The life expectancy of extensive-stage small cell lung cancer (ES-SCLC) patients has not improved in the last 2–3 decades until two recent trials (CASPIAN [1] and IMpower133 [2]) showing the addition of anti-programmed death ligand (PD-L1) therapy to chemotherapy has survival benefit over chemotherapy alone. However, such benefit is relatively small and was not even observed in some other immunotherapy trials, e.g., CA184-156 study using anti-cytotoxic T cell lymphocyte antigen-4 (CTLA-4) agent ipilimumab [3], raising the question of optimal chemoimmunotherapy combination in the 1st-line setting for ES-SCLC.

Both IMpower133 and CASPIAN were multi-center, phase III randomized studies that reached their primary endpoint of overall survival (OS) benefit. In both studies, the median OS (mOS) was significantly longer in the immunotherapy plus platinum-etoposide group compared to the platinum-etoposide alone group (CASPIAN: 13 [95% CI 11.5–14.8] vs. 10.3 [95% CI 9.3–11.2] months; IMpower133: 12.3 [95% CI 10.8–15.9] vs. 10.3 [95% CI 9.3–11.3] months) (Table 1). Similarly, the progression-free survival (PFS) benefit was observed. The IMpower133 demonstrated that the median PFS (mPFS) was longer in the combined therapy arm (5.2 months [95% CI 4.4–5.6]) compared to the chemotherapy alone arm (4.3 months [95% CI 4.2–4.5]). In the CASPIAN trial, although the mPFS was insignificant, the 1-year progression-free survival rate in the combined treatment group (18% [95% CI 13.1–22.5]) was much higher over the chemotherapy alone group (5% [95% CI 2.4–8.0]), suggesting additional follow-up time for patient events is necessary. It is interesting to notice that IMpower133 reported higher immune-related adverse events (irAEs; Table 1). One reason for this may be reflected in the trial design: while IMpower133 was a double-blinded study, CASPIAN was an open-label trial, which could affect how patients and/or clinicians attribute irAEs.

Despite the survival benefit observed in both studies, the absolute improvement in OS remains quite small, and not even statistically significant in the recent KEYNOTE-604 using anti-PD-1 agent pembrolizuamb in combination with platinum-etoposide (not yet published, from Merck’s press release [4]). This is in sharp contrast to the significant OS benefit using anti-PD-1/L1 agents in NSCLC patients [5], suggesting the PD-1/L1 axis may not be the major T cell co-inhibitory pathway, which is consistent with low PD-L1 expression reported in SCLC [6, 7], and co-suppression of other immune checkpoints is likely needed to exert the maximal benefit from immunotherapy. In fact, two recent studies have demonstrated that PD-L1 can bind in cis (same cell) to CD80 [8, 9], which interact with both the co-inhibitory receptor CTLA-4 and co-stimulatory receptor CD28. By disrupting PD-L1:CD80 heterodimers, anti-PD-L1 could license high-avidity CD80:CTLA-4 interactions to unleash regulatory T cell-mediated depletion of CD80 from antigen-presenting cells, thereby inhibiting CD28 co-stimulation—this rationalizes the combination of anti-PD-L1 with anti-CTLA-4 for a maximal anti-tumor effect [9]. In consistent with this, CASPIAN has a 4-drug arm including the anti-CTLA-4 agent tremelimumab (in addition to durvalumab plus platinum-etoposide) that is currently ongoing. Comparison of this arm to the other two (platinum-etoposide with or without durvalumab) will be highly anticipated despite the earlier negative result from the CA184-156 study [3]. Furthermore, co-targeting other co-inhibitory receptors such as the T cell immunoreceptor with Ig and ITIM domains (TIGIT) is also of great interest (there is an ongoing study SKYSCRAPER-02, ClinicalTrials.​gov Identifier: NCT04256421), especially considering its ligand CD155 (or poliovirus receptor (PVR)) is broadly expressed in both the SCLC cell lines and patient tumor tissue [10], and co-blockade of TIGIT and PD-1/L1 was found synergistic [11]. Finally, consolidative thoracic radiotherapy (CTRT) may further improve the survival benefit since 75% of patients with ES-SLCC could have persistent intrathoracic disease following induction chemotherapy [12], and CTRT has been shown to provide an OS benefit in patients who respond to initial chemotherapy [13]. It is hoped that radiation could enhance the immunogenicity of these tumors through promoting the release of tumor antigens [14], therefore enhance immunotherapy response. Importantly, a recent phase 1 trial of pembrolizumab in combination with thoracic radiation after induction chemotherapy for ES-SCLC demonstrated this combination was well tolerated [15].

In summary, these two studies provided strong evidence to support the use of immune checkpoint blockade in ES-SCLC. However, questions remain regarding whether anti-PD-1/L1 in combination with other immune checkpoint inhibitors could further enhance the overall survival, and whether radiotherapy should be combined with chemoimmunotherapy in ES-SCLC.