FDA Approves New Immunotherapy Combo for mNSCLC

Sharon Worcester and Zosia Chustecka

November 11, 2022

The US Food and Drug Administration (FDA) has approved a new combination of immunotherapies for use together with platinum-based chemotherapy for the treatment of adults with metastatic non–small cell lung cancer (NSCLC) whose tumors do not have EGFR mutations or ALK aberrations.

The new combination comprises two drugs that act at different immune checkpoints: the CTLA-4 inhibitor tremelimumab (Imudo) and the anti-PDL1 antibody durvalumab (Imfinzi).

This combination was recently approved for the first time for use in liver cancer, and durvalumab is already approved for use in lung cancer, bladder cancer, and biliary tract cancers.

The new approval was based on results showing significantly improved overall survival (OS) with the immunotherapy combination and chemotherapy, in comparison with chemotherapy alone, from the phase 3 POSEIDON study, which involved patients with metastatic NSCLC who had not received prior systemic treatment, according to an FDA announcement.

This study was presented at the 2021 World Conference on Lung Cancer and was reported at the time by Medscape Medical News. At the conference, lead researcher Melissa L. Johnson, MD, from the Sarah Cannon Research Institute, Nashville, Tennessee, said the new immunotherapy combination with chemotherapy "represents a potential new frontline treatment option for metasatic non–small cell lung cancer."

However, the discussant for the paper, Julie R. Brahmer, MD, from Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medicine, Baltimore, Maryland, pointed out that several first-line treatment choices were already available for advanced NSCLC. The options include a similar combination of immunotherapies ― the CTLA-4 inhibitor ipilimumab (Yervoy) and the PD-1 blocker nivolumab (Opdivo), used in conjunction with chemotherapy, that has already been approved for use in some patients with lung cancer.

Reacting to the reports from the meeting on Twitter, several lung cancer experts emphasized that many choices are now available for first-line treatment of mNSCLC, but there is no clear guidance as to which therapy would be best for which patient.

Improved Survival in POSEIDON

The results that led to the new approval come from an analysis of 675 patients from two arms of the POSEIDON trial. The group of patients who received tremelimumab, durvalumab, and platinum-based chemotherapy for four cycles, followed by durvalumab and maintenance chemotherapy every 4 weeks, was compared to the group that received platinum-based chemotherapy for six cycles followed by maintenance chemotherapy.

This trial also had a third arm in which only durvalumab was added to chemotherapy, but the FDA ignored this third arm in its announcement.

The FDA said that adding the immunotherapy combination to chemotherapy achieved a statistically significant and clinically meaningful improvement in OS in comparison with chemotherapy alone.

Median OS was 14 months, vs 11.7 months (hazard ratio [HR], 0.77; 95% CI: 0.65 – 0.92).

There was also a significant improvement in progression-free survival (PFS). Median PFS was 6.2 months and 4.8 months (HR, 0.72; 95% CI: 0.60 – 0.86).

In the two treatment arms, the overall response rate was 39% and 24%, and the median duration of response was 9.5 months and 5.1 months.

The most common adverse reactions (occurring in ≥20% of patients) were nausea, fatigue, decreased appetite, musculoskeletal pain, rash, and diarrhea. Grade 3 or 4 laboratory abnormalities (≥10%) were neutropenia, anemia, leukopenia, lymphocytopenia, lipase increased, hyponatremia, and thrombocytopenia, the FDA noted.

Additional data from exploratory analyses of the POSEIDON study showing an ongoing OS benefit with continued follow-up were presented in September 2022 at the annual meeting of European Society of Medical Oncology and were published in the Journal of Clinical Oncology.

These new data, which came from an analysis at a median follow-up of about 4 years, "demonstrate the durable long-term OS benefit of adding a limited course of tremelimumab and durvalumab to 4 cycles of chemotherapy," the trialists, again led by Johnson, reported.

They estimated that 25.0% of patients treated with the combination were still alive at 3 year, vs 13.6% of those treated with chemotherapy alone.

They also noted that the OS benefit with the combination appeared to be more pronounced in patients with disease of nonsquamous histology (vs squamous histology), and that there was a trend for OS benefit in nonsquamous subgroups with mutations in STK11, KEAP1 or KRAS, which represent harder-to-treat subtypes.

"These data support the use of this regimen as a first-line treatment option for patients with mNSCLC, including harder-to-treat mutational subgroups such as STK11m, KEAP1m or KRASm," they concluded.

Commenting now on the new approval, Johnson said in an AstraZeneca press release: "Metastatic non–small cell lung cancer remains a significant treatment challenge because many patients' tumours do not respond well to standard therapies, including checkpoint inhibitors. The approval of this dual immunotherapy regimen with chemotherapy introduces a new, generally well-tolerated treatment option for patients with this devastating disease and gives them the chance to benefit from the long-term survival advantage seen with CTLA-4 inhibition."

Dosing for the newly approved regimen is based on patient weight: For those weighing 30 kg or more, the recommended tremelimumab dose is 75 mg IV every 3 weeks with durvalumab 1500 mg IV and platinum-based chemotherapy for four cycles, then durvalumab 1500 mg with maintenance chemotherapy every 4 weeks. A fifth tremelimumab dose (75 mg) should be given at week 16. For patients weighing less than 30 kg, the recommended tremelimumab dose is 1 mg/kg, and the recommended durvalumab dose is 20 mg/kg.

Full prescribing information is available on the data sheets for Imjudo and Imfinzi.

The POSEIDON study was sponsored by AstraZeneca, the manufacturer of tremelimumab (Imjudo) and durvalumab (Imfinzi).

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