Durvalumab and Chemotherapy, Plus or Minus Tremelimumab Yields Survival Benefit in Frontline Treatment of Advanced NSCLC

The phase 3 POSEIDON trial indicated that patients with metastatic non–small cell lung cancer who were treated with first-line durvalumab and chemotherapy with or without tremelimumab experienced a statistically significant survival benefit.

A statistically significant improvement in progression-free survival (PFS) was noted with use of the first-line combination of durvalumab (Imfinzi) and chemotherapy plus or minus tremelimumab in patients with metastatic non–small cell lung cancer (NSCLC), according findings from the phase 3 POSEIDON trial (NCT03164616) that were presented during the International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer.

The median PFS with durvalumab plus chemotherapy was 5.5 months (95% CI, 4.7-6.5) compared with 4.8 months (95% CI, 4.6-5.8) for chemotherapy alone, leading to a 26% reduction in the risk of disease progression or death (HR, 0.74; 95% CI, 0.62-0.89; P = .00093).

However, the median overall survival (OS) was 13.3 months (95% CI, 11.4-14.7) with durvalumab/chemotherapy and 11.7 months (95% CI, 10.5-13.1) with chemotherapy alone—a difference that was not found to be statistically significant (HR, 0.86; 95% CI, 0.72-1.02; P = .07581).

When tremelimumab was added to the durvalumab/chemotherapy regimen, the median PFS was 6.2 months (95% CI, 5.0-6.5) vs 4.8 months (95% CI, 4.6-5.8) with chemotherapy alone (HR, 0.72; 95% CI, 0.60-0.86; P = .00031). The median OS was 14.0 months (95% CI, 11.7-16.1) and 11.7 months (95% CI, 10.5-13.1) in the 3-drug and chemotherapy-alone arms, respectively (HR, 0.77; 95% CI, 0.65-0.92; P = .00304).

Both the PFS and OS benefits with durvalumab/tremelimumab and chemotherapy were statistically significant, explained lead study author Melissa L. Johnson, MD, who presented the data virtually in a press briefing during the meeting.

“We noticed an improved separation of the curves with the addition of tremelimumab, and improvement in both the 12-month PFS as well as the 24-month OS landmark analysis over what was seen with durvalumab plus chemotherapy,” Johnson, program director of Lung Cancer Research at Sarah Cannon Research Institute, said. “Durvalumab plus tremelimumab plus chemotherapy represents a potential new frontline treatment option for patients with metastatic NSCLC.”

Although PD-1/PD-L1 inhibitors have transformed the treatment paradigm of advanced NSCLC, both as single agents and in combination with chemotherapy, an unmet need remains for this population. The addition of CTLA-4 inhibition to PD-L1 antibodies and chemotherapy, however, could confer further clinical and long-term survival benefit in select patient subgroups.

In the international, open-label, multicenter phase 3 POSEIDON trial, investigators explored durvalumab with or without tremelimumab in combination with investigator’s choice of chemotherapy in the frontline treatment of patients with squamous or nonsquamous metastatic NSCLC (n = 1013). Patients were randomized 1:1:1 to receive durvalumab at 1500 mg plus chemotherapy every 3 weeks for 4 cycles, followed by maintenance durvalumab at 1500 mg every 4 weeks plus pemetrexed until disease progression (n = 330); durvalumab at 1500 mg plus tremelimumab at 75 mg and chemotherapy every 3 weeks for 4 cycles, followed by maintenance durvalumab at 1500 mg every 4 weeks plus tremelimumab at 75 mg at week 16 only, and pemetrexed until disease progression (n = 335); or platinum-based chemotherapy every 3 weeks for up to 6 cycles, followed by maintenance pemetrexed until disease progression (n = 332).

Chemotherapy regimens consisted of gemcitabine plus carboplatin or cisplatin for those with squamous histology, pemetrexed plus carboplatin or cisplatin for those with nonsquamous disease, or nab-paclitaxel (Abraxane) plus carboplatin for either histology.

To be eligible for enrollment, patients had to have stage IV NSCLC without EGFR or ALK alterations, an ECOG performance status of 0 or 1, and must not have received prior systemic therapy for metastatic disease. Patients were stratified by PD-L1 expression (tumor cells ≥50% vs <50%), disease stage (stage IVA vs IVB), and histology.

The primary end points of the trial were PFS by blinded independent central review (BICR) and OS, both for durvalumab plus chemotherapy vs chemotherapy alone. Secondary outcome measures were PFS by BICR and OS, as well as OS in patients with blood tumor mutational burden ≥20 mutations/megabase, all for durvalumab/tremelimumab plus chemotherapy vs chemotherapy alone.

Additional outcome measures included objective response rate (ORR), duration of response (DOR), and best objective response by BICR, as well as 1-year PFS rate, health-related quality of life, safety, and tolerability.

Further findings showed that in the durvalumab/chemotherapy and chemotherapy-alone arms, the 1-year PFS rates were 24.4% and 13.1%, respectively, and the 2-year OS rates were 29.6% and 22.1%, respectively. With the addition of tremelimumab, the 1-year PFS rate was 26.6% and the 2-year OS rate was 32.9%.

Johnson added that the addition of tremelimumab to durvalumab/chemotherapy appeared to have the highest benefit in patients with nonsquamous histology and in those with a PD-L1 expression of less than 1%.

The confirmed ORRs were 41.5% with durvalumab plus chemotherapy, 38.8% with durvalumab/tremelimumab plus chemotherapy, and 24.4% with chemotherapy alone. The odds ratio was 2.26 (95% CI, 1.61-3.19) between durvalumab/chemotherapy and chemotherapy alone and 2.00 (95% CI, 1.43-2.81) between durvalumab/tremelimumab plus chemotherapy and chemotherapy alone.

Additionally, the DOR was 7.0 months (95% CI, 5.7-9.9), 9.5 months (95% CI, 7.2–not estimable), and 5.1 months (95% CI, 4.4-6.0) for durvalumab/chemotherapy, durvalumab/chemotherapy plus tremelimumab, and chemotherapy alone, respectively. At 12 months, 38.9%, 49.7%, and 21.4% of these patients, respectively, remained in response.

Importantly, the addition of tremelimumab did not seem to affect the exposure of patients to chemotherapy or durvalumab, Johnson noted.

Regarding safety, no unexpected safety signals were observed, and most effects were driven by chemotherapy.

All-grade, all-cause AEs occurred in 96.1%, 97.3%, and 96.1% of patients on durvalumab/chemotherapy, durvalumab/chemotherapy plus tremelimumab, and chemotherapy alone, respectively; the grade 3/4 AE rates in these groups were 54.8%, 53.3%, and 51.7%, respectively. Serious AEs occurred in 40.1% of patients on durvalumab/chemotherapy, 44.2% of those on durvalumab/chemotherapy plus tremelimumab, and 35.1% of those on chemotherapy alone.

Treatment discontinuation (20.4%, 22.1%, and 15.3%, respectively) and death rates (10.2%, 12.4%, and 9.0%, respectively) due to adverse effects (AEs) were similar across all 3 arms, Johnson noted.

All-grade treatment-related AEs (TRAEs) occurred in 88.6% of patients on durvalumab/chemotherapy, 92.7% who received the addition of tremelimumab, and 89.5% of patients on chemotherapy. Grade 3/4 TRAEs occurred in 44.6%, 51.8%, and 44.4% of patients, respectively.

Serious TRAEs were experienced by 19.5% of durvalumab/chemotherapy-treated patients, 27.6% of those on durvalumab/tremelimumab plus chemotherapy, and 17.7% of those on chemotherapy alone. TRAEs that led to drug discontinuation occurred in 14.4%, 15.5%, and 9.9% of patients, respectively; TRAEs that led to death were reported in 2.1%, 3.3%, and 2.4% of patients, respectively.

Reference

Johnson ML, Cho BC, Luft A, et al. Durvalumab + tremelimumab + chemotherapy as first-line treatment for mNSCLC: results from the phase 3 POSEIDON study. Presented at: International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer; September 8-14, 2021; Virtual. Abstract PL02.01.