Durvalumab Regimens Improve PFS in Frontline Metastatic NSCLC

Jose Baselga, MD, PhD, executive vice president, Oncology R&D, AstraZenec

José Baselga, MD, PhD

The addition of durvalumab (Imfinzi) to platinum-based chemotherapy demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with chemotherapy alone in patients with previously untreated metastatic non—small cell lung cancer (NSCLC), according to topline findings of the final PFS analysis from the phase III POSEIDON trial (NCT03164616).

Additionally, the triplet regimen of durvalumab, tremelimumab, and chemotherapy also led to a statistically significant and clinically meaningful improvement in PFS compared with chemotherapy alone, which was a key secondary endpoint of the study. The safety and tolerability of durvalumab was found to be consistent with the PD-L1 inhibitor’s known safety profile, and the triplet regimen with tremelimumab did not result in an increased discontinuation of therapy.

The data will be submitted for presentation at an upcoming medical meeting, and AstraZeneca, the developer of both durvalumab and tremelimumab, stated in a press release that it plans to share the results with regulatory authorities. Investigators will continue to assess the additional primary endpoint of overall survival (OS), with data anticipated in 2020.

“The POSEIDON trial provides evidence of the efficacy of Imfinzi in patients with stage IV non—small cell lung cancer,” José Baselga, executive vice president, Oncology R&D, of AstraZeneca, stated in the press release. “Clinical benefit was observed in a trial population that included a high proportion of patients with squamous disease and multiple choices of chemotherapy regimens. Additionally, the potential to add tremelimumab to Imfinzi and chemotherapy may present an important treatment approach in this challenging setting, especially taking into consideration the favorable safety profile.”

In the international, multicenter, open-label, phase III POSEIDON trial, approximately 1000 patients with previously untreated metastatic NSCLC were randomized 1:1:1 to receive either durvalumab plus tremelimumab and standard chemotherapy or durvalumab plus chemotherapy versus standard chemotherapy.

To be eligible for enrollment, patients must have been ≥18 years old, have confirmed PD-L1 status, received no prior chemotherapy or any other systemic therapy for their metastatic disease, have a World Health Organization (WHO)/ECOG performance status of 0 or 1, and had no prior exposure to immune-mediated therapy, excluding therapeutic anticancer vaccines. Those with mixed small cell lung cancer and NSCLC histology or sarcomatoid variant, had active autoimmune or inflammatory disorders, brain metastases, or active tuberculosis, hepatitis B, C, or HV disease were excluded from the trial. Patients could also not harbor EGFR mutations or ALK fusions to be eligible for enrollment.

Durvalumab was administered as a fixed dose of 1500 mg every 3 weeks in combination with chemotherapy, and then every 4 weeks until disease progression.

Additionally, tumor evaluation scans would be performed until disease progression, and an independent data monitoring committee would confirm the safety and tolerability of the proposed dose and schedule.

The coprimary endpoints are PFS by blinded independent central review according to RECIST v1.1 criteria and OS. Secondary endpoints include PFS in the triplet arm, objective response rate, duration of response, PFS2, 12-month PFS rate, best objective response, pharmacokinetics, immunogenicity, health-related quality of life, disease-related symptoms, and changes in WHO/ECOG performance status. Safety of both combination regimens are a clinical outcome measure.

In August 2019, the combination of durvalumab and tremelimumab did not improve OS compared with standard platinum-based chemotherapy in previously untreated patients with stage IV metastatic NSCLC who have tumor mutational burden ≥20 mutations/megabase, therefore missing the primary endpoint of the phase III NEPTUNE trial (NCT02542293).² Full findings are slated to be presented at an upcoming medical meeting.

Additionally, in November 2018, the PD-L1 and CTLA-4 inhibitor combination did not elicit a statistically significant improvement in OS compared with standard chemotherapy in patients with metastatic NSCLC in the phase III MYSTIC trial (HR, 0.85; 98.77% CI, 0.611-1.173; P =.202) in patients with PD-L1 expression ≥25% who received durvalumab/tremelimumab versus standard platinum-based chemotherapy.³ While the hazard ratio for OS was improved with single-agent durvalumab versus standard chemotherapy, the benefit was still not statistically significant (HR, 0.76; 97.54% CI, 0.564-1.019; P = .036).

Frontline durvalumab is also being evaluated as a single agent versus platinum-based chemotherapy in patients with stage IV NSCLC, who are EGFR and ALK wild-type and have high PD-L1 expression, in the phase III PEARL trial (NCT03003962).

References

1. Imfinzi and Imfinzi plus Tremelimumab Delayed Disease Progression in Phase III POSEIDON trial for 1st-line Treatment of Stage IV Non-Small Cell Lung Cancer. AstraZeneca. Published October 28, 2019. https://bit.ly/2oq3oup. Accessed October 28, 2019.
2. Update on the Phase III NEPTUNE trial of Imfinzi plus tremelimumab in stage IV non-small cell lung cancer. AstraZeneca. Published August 21, 2019. https://bit.ly/2TPGs2Y. Accessed August 21, 2019.
3. Rizvi NA, Cho BC, Reinmuth N, et al. Durvalumab with or without tremelimumab vs platinum-based chemotherapy as first-line treatment for metastatic non-small cell lung cancer: MYSTIC. Ann Oncol. 2018;29(10). doi: 10.1093/annonc/mdy511.005.