Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non–Small-Cell Lung Cancer: The Phase III POSEIDON Study

Abstract

PURPOSE The open-label, phase III POSEIDON study evaluated tremelimumab plus durvalumab and chemotherapy (T + D + CT) and durvalumab plus chemotherapy (D + CT) versus chemotherapy alone (CT) in first-line metastatic non–small-cell lung cancer (mNSCLC). METHODS Patients (n = 1,013) with EGFR/ ALK wild-type mNSCLC were randomly assigned (1:1:1) to tremelimumab 75 mg plus durvalumab 1,500 mg and platinum-based chemotherapy for up to four 21-day cycles, followed by durvalumab once every 4 weeks until progression and one additional tremelimumab dose; durvalumab plus chemotherapy for up to four 21-day cycles, followed by durvalumab once every 4 weeks until progression; or chemotherapy for up to six 21-day cycles (with or without maintenance pemetrexed; all arms). Primary end points were progression-free survival (PFS) and overall survival (OS) for D + CT versus CT. Key alpha-controlled secondary end points were PFS and OS for T + D + CT versus CT. RESULTS PFS was significantly improved with D + CT versus CT (hazard ratio [HR], 0.74; 95% CI, 0.62 to 0.89; P = .0009; median, 5.5 v 4.8 months); a trend for improved OS did not reach statistical significance (HR, 0.86; 95% CI, 0.72 to 1.02; P = .0758; median, 13.3 v 11.7 months; 24-month OS, 29.6% v 22.1%). PFS (HR, 0.72; 95% CI, 0.60 to 0.86; P = .0003; median, 6.2 v 4.8 months) and OS (HR, 0.77; 95% CI, 0.65 to 0.92; P = .0030; median, 14.0 v 11.7 months; 24-month OS, 32.9% v 22.1%) were significantly improved with T + D + CT versus CT. Treatment-related adverse events were maximum grade 3/4 in 51.8%, 44.6%, and 44.4% of patients receiving T + D + CT, D + CT, and CT, respectively; 15.5%, 14.1%, and 9.9%, respectively, discontinued treatment because of treatment-related adverse events. CONCLUSION D + CT significantly improved PFS versus CT. A limited course of tremelimumab added to durvalumab and chemotherapy significantly improved OS and PFS versus CT, without meaningful additional tolerability burden, representing a potential new option in first-line mNSCLC.

New Approaches in Early-Stage NSCL Management: Potential Use of PARP Inhibitors and Immunotherapy Combination

“…New anti-CLTA-4 molecules (e.g., tremelimumab) are being studied in several oncologic settings (e.g., NCSCL, SCLC, hepatocarcinoma, etc.) [ 40 , 41 , 42 ]. The other key immune checkpoint mediator, PD-L1/PD-1, is responsible for the suppression of T cell migration, proliferation, and secretion of cytotoxic mediators, hence restricting tumor cell attack [ 27 , 28 , 43 ].…”

Lung Cancer Immunotherapy: Beyond Common Immune Checkpoints Inhibitors

“…Very recently, FDA approved tremelimumab in combination with durvalumab and platinum-based chemotherapy for patients with metastatic NSCLC with no sensitizing EGFR, ALK genomic tumor aberrations. The phase III POSEIDON study, enrolled patients to receive the following: tremelimumab plus durvalumab and platinum-based chemotherapy for four cycles, followed by durvalumab until progression and one additional tremelimumab dose; durvalumab plus chemotherapy for four cycles, followed by durvalumab; or chemotherapy for up to six cycles ± maintenance pemetrexed [ 55 ]. Durvalumab plus tremelimumab and chemotherapy significantly improved PFS (6.2 v 4.8 months) and OS (14.0 v 11.7 months) compared to chemotherapy alone.…”

“…TIGIT is a protein composed of an extracellular Ig variable domain, a transmembrane domain and a short intracellular domain endowed with one immunoreceptor tyrosine-based inhibitory motif (ITIM) and one immunoglobulin tyrosine tail (ITT)-like motif [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , …”

“…TIGIT belongs to the family of Poliovirus Receptor (PVR)-like proteins and shares sequence homology with other members of the PVR-like family [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , ...…”

The POSEIDON Trial: Will Secondary End Points Change Our Clinical Practice?

“…In the article that accompanies this editorial, Johnson et al 6 presented the results of the phase III POSEIDON trial, in which 1,013 patients with advanced EGFR/ ALK-negative NSCLC were randomly assigned to tremelimumab (T, anti-CTLA4) plus durvalumab (D, an anti-PD-L1) and platinum-based CT every 3 weeks for up to four cycles, followed by D (every 4 weeks) until progression and one additional T dose; D plus CT every 3 weeks for up to four cycles, followed by D every 4 weeks until progression or CT every 3 weeks for up to six cycles. Pemetrexed maintenance was allowed for nonsquamous histology in all investigational arms.…”