FDA Approves Tremelimumab Plus Durvalumab and Chemo for Metastatic NSCLC

FDA

The FDA has approved tremelimumab-actl (Imjudo) plus durvalumab (Imfinzi) and platinum-based chemotherapy for adult patients with metastatic non–small cell lung cancer (NSCLC) without sensitizing EGFR mutation or ALK aberrations.^1-3

The regulatory decision was supported by findings from the pivotal phase 3 POSEIDON trial (NCT03164616). To be eligible for enrollment, patients were required to have an ECOG performance status of 0 or 1. They could not have previously received chemotherapy or another systemic treatment for metastatic disease.

Exclusion criteria included active and/or untreated brain metastases, a history of active primary immunodeficiency, autoimmune disorders, or the use of systemic immunosuppressants within 2 weeks before the first dose of study treatment.

Study participants were randomly assigned to 1 of the following 3 treatment arms: tremelimumab plus durvalumab and platinum-based chemotherapy (arm 1), durvalumab plus platinum-based chemotherapy (arm 2), or platinum-based chemotherapy (arm 3). The evaluation of efficacy relied on a comparison between the 675 patients enrolled to arms 1 (n = 338) and 3 (n = 337):

• Tremelimumab at 75 mg or 1 mg/kg in those <30 kg plus durvalumab at 1500 mg and platinum-based chemotherapy every 3 weeks for 4 cycles, followed by durvalumab monotherapy at 1500 mg every 4 weeks. A fifth dose of tremelimumab at 75 mg was given at week 16 in combination with the six dose of durvalumab.
• Platinum-based chemotherapy given every 3 weeks as monotherapy for 4 cycles. Patients were allowed to receive an additional 2 cycles for a total of 6 cycles following randomization per investigator discretion.

Treatment continued until patients experienced progressive disease or intolerable toxicity. Patients were stratified based on PD-L1 expression on tumor cells (≥50% vs <50%), disease stage (stage IVA vs stage IVB), and histology (nonsquamous vs squamous).

The primary outcome measures for the trial included overall survival (OS) and progression-free survival (PFS) by blinded independent central review and in accordance with RECIST v1.1 criteria. Additional outcome measures comprised overall response rate (ORR) and duration of response (DOR).

The median age of patients in arms 1 and 3 was 63 years (range, 27-87), and 46% of patients were aged 65 years or older. Seventy-seven percent of patients were male, 57% were White, and 79% were former or current smokers. Regarding performance status, 34% had a status of 0, and the remaining 66% had a status of 66%. In terms of histology, 36% of patients had squamous disease and 63% had nonsquamous disease. In terms of PD-L1 expression, 29% had tumor cell expression of at least 50% and 50% had expression of less than 50%.

The combination of tremelimumab, durvalumab, and chemotherapy significantly improved OS over chemotherapy alone, at 14 months (95% CI, 11.7-16.1) vs 11.7 months (95% CI, 10.5-13.1), respectively; this translated to a 23% reduction in the risk of death (HR, 0.77; 95% CI, 0.65-0.92; 2-sided P = .00304).

Moreover, those in arm 1 also experienced improved PFS over those in arm 3, at 6.2 months (95% CI, 5.0-6.5) and 4.8 months (95% CI, 4.6-5.8), respectively; this correlated to a 28% reduction in the risk of disease progression or death (HR, 0.72; 95% CI, 0.60-0.86; 2-sided P = .00031).

Tremelimumab plus durvalumab and platinum-based chemotherapy elicited an ORR of 39% (95% CI, 34%-44%) vs 24% (95% CI, 20%-29%) with platinum-based chemotherapy alone. The median DOR in arm 1 was 9.5 months (95% CI, 7.2–not reached) vs 5.1 months (95% CI, 4.4-6.0) in arm 3.

A total of 330 patients in arm 1 were evaluable for safety. The most common toxicities reported with the regimen, that were reported in at least 20% of patients, were nausea, fatigue, musculoskeletal pain, decreased appetite, rash, and diarrhea. Grade 3 or 4 laboratory abnormalities experienced by at least 10% of patients comprised neutropenia, anemia, leukopenia, lymphocytopenia, lipase increased, hyponatremia and thrombocytopenia.

Serious toxicities were reported in 44% of patients who received the combination. The most common serious adverse effects included pneumonia (11%), anemia (5%), diarrhea (2.4%), thrombocytopenia (2.4%), pyrexia (2.4%), and febrile neutropenia (2.1%).

Moreover, 4.2% of patients experienced fatal adverse reactions, which included hepatitis, nephritis, myocarditis, pancreatitis (all in the same patient); death (n = 2); sepsis (n = 2); pneumonitis (n = 2); acute kidney injury (n = 2); febrile neutropenia (n = 1); chronic obstructive pulmonary disease (n = 1); dyspnea (n = 1); sudden death (n = 1); and ischemic stroke (n = 1).

Forty-one percent of patients required dose interruptions or delays of tremelimumab or durvalumab due to toxicity; these effects included anemia, leukopenia/white blood cell count decreased, pneumonia, pneumonitis, colitis, diarrhea, hepatitis, rash, asthenia, amylase increased, alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased, neutropenia/neutrophil count decreased, and thrombocytopenia/platelet count decreased.

Seventeen percent of patients discontinued tremelimumab or durvalumab because of an adverse effect. The toxicity that resulted in permanent treatment discontinuation of either agent in more than 2% of patients was pneumonia.

References

1. FDA approves tremelimumab in combination with durvalumab and platinum-based chemotherapy for metastatic non-small cell lung cancer. News release. FDA. November 10, 2022. Accessed November 10, 2022. http://bit.ly/3Ej7yIx
2. Imjudo (tremelimumab-actl). Prescribing information; AstraZeneca Pharmaceuticals; 2022. Accessed November 10, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761270s000lbl.pdf
3. Imfinzi (durvalumab). Prescribing information; AstraZeneca Pharmaceuticals; 2022. Accessed November 10, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761069s033lbl.pdf