Frontline Durvalumab/Tremelimumab Misses OS Endpoint in Metastatic NSCLC

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

José Baselga, MD, PhD

The combination of durvalumab (Imfinzi) and tremelimumab did not improve overall survival (OS) compared with standard platinum-based chemotherapy in previously untreated patients with stage IV metastatic non—small cell lung cancer (NSCLC) who have tumor mutational burden (TMB) ≥20 mutations/megabase (mut/mB), missing the primary endpoint of the phase III NEPTUNE trial (NCT02542293).¹

The safety and tolerability profile of the combination was consistent with what was presented in prior clinical trials. Full findings of the NEPTUNE study will be presented at an upcoming medical meeting, AstraZeneca, the developer of the PD-L1 and CTLA-4 inhibitors, stated in a press release.

“We are fully committed to a deep analysis of the vast clinical and biomarker data from this trial to gain further insights to improve immuno-oncology approaches for patients with metastatic non—small cell lung cancer,” José Baselga, MD, PhD, executive vice president, Oncology R&D, AstraZeneca, stated in the press release.

In the international, open-label, multicenter NEPTUNE study, investigators evaluated durvalumab plus tremelimumab versus platinum-based chemotherapy as a first-line treatment in 955 patients with stage IV metastatic NSCLC. The patient population included all-comers, comprising nonsquamous and squamous histologies, no EGFR or ALK abnormalities, and a full range of PD-L1—expression levels.

Patients were randomized 1:1 to receive the immunotherapy combination or chemotherapy. Chemotherapy regimens included carboplatin/paclitaxel, gemcitabine/cisplatin, gemcitabine/carboplatin, pemetrexed/cisplatin, and carboplatin/pemetrexed.

To be eligible for enrollment, patients also had to have a World Health Organization performance status of 0 or 1, and must have had no prior exposure to immune-mediated therapy, chemotherapy, or any other systemic therapy for recurrent/metastatic NSCLC. Those with mixed small cell lung cancer and NSCLC histology or sarcomatoid variant, had brain metastases or spinal cord compression, or autoimmune or inflammatory disorders were excluded from enrollment.

The primary endpoint was patients with high blood TMB, which was defined as ≥20 mut/Mb. Secondary endpoints included: progression-free survival (PFS); OS; objective response rate; duration of response; 12-, 18-, and 24-month OS rates; 12-month PFS rate; and PFS2—all in additional TMB-defined populations, those with PD-L1—negative disease, and all-comers. Investigators also evaluated the pharmacokinetics and immunogenicity of the combination, and treatment-related adverse events (TRAEs).

Similar findings with the combination were previously reported in the phase III MYSTIC trial, which compared the PD-L1/CTLA-4—inhibitor combination with standard chemotherapy in patients with stage IV metastatic NSCLC. In the open-label study, patients with EGFR/ALK wild-type locally advanced or metastatic NSCLC were randomized to durvalumab monotherapy, durvalumab/tremelimumab, or standard chemotherapy. The primary endpoints were OS for the durvalumab arms in patients with PD-L1 expression on ≥25% of their tumor cells, which was measured by the VENTANA PD-L1 (SP263) assay.

Final OS data showed that there was a 15% reduction in the risk of death with durvalumab/tremelimumab versus chemotherapy in patients with PD-L1 expression, which was not found to be statistically significant (HR, 0.85; 98.77% CI, 0.611-1.173; P =.202).² The median OS was 11.9 months with the immunotherapy combination versus 12.9 months for chemotherapy.

OS was also improved with single-agent durvalumab versus chemotherapy, but it was still not statistically significant (HR, 0.76; 97.54% CI, 0.564-1.019; P = .036). Here, the median OS was 16.3 months and 12.9 months for durvalumab and chemotherapy, respectively. The incidence of grade 3/4 TRAEs was 14.6% with single-agent durvalumab, 22.1% with durvalumab/tremelimumab, and 33.8% with chemotherapy.

Durvalumab is also being explored as a single agent in the phase III PEARL trial (NCT03003962), as well as in combination with chemotherapy with or without tremelimumab in the phase III POSEIDON trial (NCT03164616).

In February 2018, the PD-L1 inhibitor was approved by the FDA for the treatment of patients with locally advanced, unresectable stage III NSCLC who have not progressed following chemoradiotherapy.

References

1. 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.
2. 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.