Addition of Tremelimumab to Durvalumab/Chemo Continues to Improve OS in Metastatic NSCLC

Following approximately 4 years of follow-up, the addition of a limited course of tremelimumab to durvalumab (Imfinzi) plus chemotherapy continued to yield durable, long-term overall survival (OS) outcomes in patients with frontline metastatic non–small cell lung cancer (mNSCLC), according to an updated exploratory analysis of OS from the phase 3 POSEIDON study (NCT03164616) that was presented at ESMO Congress 2022.¹

Melissa L. Johnson, MD, program director of lung cancer research at Sarah Cannon Cancer Institute in Tennessee, presented the long-term follow-up (median, 46.5 months [range, 0.0-56.5] at the congress.

The triplet combination induced a median OS of 14.0 months (95% CI, 11.7-16.1), compared with 11.7 months (95% CI, 10.5-13.1) with chemotherapy alone (HR, 0.75; 95% CI, 0.63-0.88), reducing the risk for death by 25%. The 36-month OS rates were 25% vs 13.6%, respectively.

Similarly, durvalumab plus chemotherapy showed a median OS of 13.3 months (95% CI, 11.4-14.7), compared with 11.7 months (95% CI, 10.5-13.1) with chemotherapy alone (HR, 0.84; 95% CI, 0.71-0.99). The 36-month OS rates were 20.7% vs 13.6%, respectively.

According to the subgroup analysis, all patients who were treated with immunotherapy plus chemotherapy had improved OS, according to Johnson. In particular, there was a trend that favored OS in patients with low or no levels of PD-L1 who were treated with the triplet regimen, she added.

In addition, investigators explored OS by histology and mutation status—all of which demonstrated an OS benefit that was consistent with the intent-to-treat population.

The OS benefit was greater in patients with nonsquamous mNSCLC, compared with squamous disease, when they were treated with the triplet regimen (median OS, 17.2 months; 95% CI, 14.9-21.8) vs chemotherapy alone (median OS, 13.1 months; 95% CI, 10.6-15.1), reducing the risk for death by 32% (HR, 0.68; 95% CI, 0.55-0.85). At 3 years, OS rates were 31.4% vs 17.3%, respectively. Without the addition of tremelimumab, patients with nonsquamous histology demonstrated a median OS of 14.8 months (95% CI, 11.8-18.3), with a 3-year OS rate of 25.0% (HR, 0.80; 95% CI, 0.64-0.98).

OS by mutation status continually favored treatment with tremelimumab plus durvalumab and chemotherapy. In those who harbor a STK11 mutation, the triplet reduced the risk for death by 38% (HR, 0.62; 95% CI, 0.34-1.12), with a median OS of 15.0 months (95% CI, 8.2-23.8), compared with 10.7 months (95% CI, 6.0-14.9) with chemotherapy alone. At 3 years, the OS rates were 25.8% vs 4.5%, respectively.

Similarly, those with a KEAP1 mutation saw a 57% reduction in the risk for death (HR, 0.43; 95% CI, 0.16-1.25) with the triplet regimen, demonstrating a median OS of 13.7 months (95% CI, 7.2-26.5), vs 8.7 months (95% CI, 5.1-not evaluable) with chemotherapy alone. The 36-month OS rates were 30.0% vs 0.0%, respectively; however, Johnson noted this was a small sample size.

Lastly, patients with a KRAS mutation experienced a 45% reduction in the risk for death (HR, 0.55; 95% CI, 0.36-0.85) with tremelimumab plus durvalumab and chemotherapy, with a median OS of 25.7 months (95% CI, 9.9-36.7), compared with 10.4 months (95% CI, 7.5-13.6) with chemotherapy alone. The 36-month OS rates were 40.0% vs 15.8%, respectively.

During the long-term follow-up, serious adverse events (AEs) were collected; however, other safety data were not collected after the final analysis of the trial. Johnson reported 1 new serious AE/death in the durvalumab plus chemotherapy arm; however, it was not considered treatment related.

In the randomized, open label, global, multicenter phase 3 study, patients with treatment-naïve, EGFR/ALK wild-type mNSCLC were randomized 1:1:1 to receive either of the following regimens:

• 1500 mg durvalumab plus chemotherapy every 3 weeks for 4 cycles followed by 1500 mg durvalumab every 4 weeks until disease progression;
• 1500 mg durvalumab plus a limited course of 75 mg tremelimumab concurrently with chemotherapy every 3 weeks for up to 4 cycles, followed by 1500 mg durvalumab every 4 weeks as maintenance until progression, with 1 additional dose of tremelimumab after chemotherapy (week 16); or
• Chemotherapy every 3 weeks for up to 6 cycles.

Patients were eligible if they had stage IV NSCLC; EGFR/ALK wild type mutations; an ECOG performance status of 0 or 1; were treatment-naïve for metastatic disease; and had a tumor biopsy and baseline plasma samples for circulating tumor DNA.

Progression-free survival (PFS) per RECIST v1.1 by blind independent review committee and OS of durvalumab plus chemotherapy vs chemotherapy served as the primary end points. Secondary end points were triggered by results from the primary end points and included PFS by BICR and OS for durvalumab plus tremelimumab and chemotherapy vs chemotherapy.

Of the 1013 patients randomly assigned to the 3 treatment arms, 28.8% had PD-L1 TC ≥ 50%, 49.6% had stage IVB disease, and 36.9% had squamous histology.

Results were presented at the IASLC 2021 World Conference on Lung Cancer.²

The combination of durvalumab with tremelimumab and chemotherapy demonstrated a median OS of 14.0 months, compared with 11.7 months with chemotherapy alone, reducing the risk for death by 23% (HR, 0.77; 95% CI, 0.65-0.92; P = .00304). Similarly, the triplet regimen induced a median PFS of 6.2 months vs 4.8 months with chemotherapy, reducing the risk for disease progression or worsening by 28% (HR, 0.72; 95% CI, 0.60-0.86; P = .0003).

Treatment with durvalumab plus chemotherapy demonstrated a median PFS of 5.5 months, compared with 4.8 months with chemotherapy alone (HR, 0.74; 95% CI, 0.62-0.89; P = .0009), as well as median OS of 13.3 months vs 11.7 months (HR, 0.86; 95% CI, 0.72-1.02; P = .0758).

To conclude, Johnson noted that the data support the use of a limited course of tremelimumab in combination with durvalumab plus chemotherapy as a first-line treatment for those with mNSCLC, “including hard-to-treat subgroups.”

_Reference:

_{1. Johnson ML, Cho BC, Luft A, et al. Durvalumab (D) ± tremelimumab (T) + chemotherapy (CT) in 1L metastatic (m) NSCLC: Overall survival (OS) update from POSEIDON after median follow-up (mFU) of approximately 4 years (y). Ann Oncol. 2022;33(suppl_7):S808-S869. doi:10.1016/annonc/annonc1089}

_{2. Johnson ML, Cho BC, Luft A, et al. Durvalumab ± tremelimumab + chemotherapy as first-line treatment for mNSCLC: results from the phase 3 POSEIDON Study. J Thorac Oncol. 2021;16(10):S844. doi:10.1016/j.jtho.2021.08.029}