POSEIDON: Dual ICIs plus chemo up survival in first-line mNSCLC

Adding two immune checkpoint inhibitors, tremelimumab (T) and durvalumab (D), to platinum-based chemotherapy (CT) significantly improves overall survival (OS) and progression-free survival (PFS) vs CT alone in first-line treatment of metastatic non-small-cell lung cancer (mNSCLC), without causing a meaningful increase in toxicity, according to results of the phase III POSEIDON trial.  

“Immunotherapies targeting PD-1 and its ligand [PD-L1], administered as monotherapy or in combination with established CTs, have transformed the first-line treatment of mNSCLC,” wrote the researchers. “However, patients with PD-L1–low or –negative tumours are less likely to respond to anti–PD-L1 therapy, underlining the need for new therapeutic strategies with immunotherapy combinations in this setting.”

 

POSEIDON was a three-arm randomized controlled trial comparing two ICI-based regimens, T + D + CT (n=338; median age, 63.0 years) and D + CT (n=338; median age, 64.5 years), with CT alone as control (n=337; median age, 64 years), in 1,013 patients with EGFR or ALK wild-type mNSCLC. [J Clin Oncol 2022;doi:10.1200/JCO.22.00975]

 

At a median follow-up of 10.3 months, D + CT significantly improved PFS vs CT alone (median, 5.5 months vs 4.8 months; hazard ratio [HR], 0.74; 95 percent confidence interval [CI], 0.62–0.89; p=0.0009), with a positive trend of OS improvement that did not reach statistical significance (median, 13.7 months vs 11.7 months; HR, 0.86; 95 percent CI, 0.72–1.02). The 24-month OS rates were 29.6 percent vs 22.1 percent.

 

Importantly, T + D + CT demonstrated significant and clinically meaningful improvements in both PFS (median, 6.2 months vs 4.8 months; HR, 0.72; 95 percent CI, 0.60–0.86; p=0.0003) and OS (median, 14.0 months vs 11.7 months; HR, 0.77; 95 percent CI, 0.65–0.92; p=0.003) vs CT alone at a median follow-up of 34.9 months. At 24 months, OS rate was higher with T + D + CT vs CT alone (32.9 percent vs 22.1 percent).

 

With currently available treatments, patients with PD-L1 tumour cells <1 percent can have suboptimal outcomes. In these difficult-to-treat patients, T + D + CT also demonstrated OS benefit vs CT alone (HR, 0.77; 95 percent CI, 0.58–1.00).

“Although not formally assessed in the statistical analysis plan, T + D + CT led to more durable responses vs D + CT [median duration of response, 9.5 months vs 7.0 months], and a notable separation of the survival curves was observed, particularly at later landmarks,” pointed out the researchers.

 

Anti–CTLA-4 therapy can diversify T-cell responses and lead to increased tumour infiltration, whereas continuous anti–PD-L1 therapy may enhance T-cell function and support a sustained antitumour response. “Given their complementary mechanisms of action, the T + D + CT regimen is expected to broaden clinical activity, potentially overcoming primary resistance to PD-L1 blockade by enabling novel T-cell responses,” explained the researchers.

 

Grade 3/4 treatment-related adverse events (TRAEs) were reported in 51.8 percent, 44.6 percent, and 44.4 percent of patients receiving T + D + CT, D + CT, and CT alone, respectively. Rates of treatment discontinuation due to TRAEs were similar between the T + D + CT and D + CT groups (15.5 percent vs 14.1 percent), and numerically lower in the CT alone group (9.9 percent), suggesting no meaningful additional tolerability burden with the addition of anti–CTLA-4 therapy.

 

In summary, T + D + CT provided survival benefits with a manageable tolerability profile, representing a potential new first-line treatment option in mNSCLC, especially in patients with PD-L1–negative tumours.