Durvalumab Plus Oleclumab or Monalizumab Induces Increased Response Rates in NSCLC

Consolidation therapy with durvalumab (Imfinzi) and either oleclumab or monalizumab showed increased clinical benefits in patients with unresectable stage III non–small cell lung cancer (NSCLC), according to interim data from the phase 2 COAST study (NCT03822351) that were published in the Journal of Clinical Oncology.¹

At a median follow-up of 11.5 months, the objective response rates (ORRs) were higher in patient subgroups treated with durvalumab plus oleclumab (30.0%; n = 18; 95% CI, 18.8%-43.2%) and durvalumab plus monalizumab (35.5%; n = 22; 95% CI, 23.7%-48.7%) vs durvalumab alone (17.9%; n = 12; 95% CI, 9.6%-29.2%).

Safety was similar across all 3 arms, with no notable new safety signals arising in either combination group.

“These new data have the potential to change the standard of care for patients with advanced non–small cell lung cancer, providing us with new treatment options with the ability to make a major impact on our patients’ lives,” lead study author Roy S. Herbst, MD, PhD, professor of medicine and pharmacology, deputy director for Clinical Affairs, and chief of Medical Oncology at Yale Cancer Center, said in a press release.²

Durvalumab, a human immunoglobulin G1 monoclonal antibody (mAb), has previously been shown to improve overall survival (OS) in patients with unresectable stage III NSCLC when administered after concurrent chemoradiotherapy (CRT). The COAST study seeks to expand on this current standard of care by investigating the effects of durvalumab alone vs combined with the anti-CD73 mAb oleclumab or the anti-NKG2A mAb monalizumab in patients with NSCLC who have undergone concurrent CRT.

The global, open-label, randomized, multidrug platform study enrolled patients who were at least 18 years of age, with a median age of 65 years (range, 37-87) who had histologically/cytologically documented unresectable, stage III NSCLC and who had not progressed following concurrent CRT. Eligible patients had an ECOG performance status (PS) of 0 or 1, at least 1 previously irradiated tumor lesion measurable per RECIST v1.1 criteria, adequate marrow and organ function, and a life expectancy of at least 12 weeks.

Patients who were excluded included those with mixed small cell and non–small cell histology, prior exposure to PD-1/PD-L1 or CTLA-4 inhibitors, history of venous thrombosis within 3 months of randomization, any unresolved grade 3 or greater toxicity from prior CRT, and current or prior use of immunosuppressants within 14 days of the first dose of study drug.

Between January 2019 and July 2020, 189 patients were randomized 1:1:1 to receive 1 of 3 intravenous (IV) treatments. A total of 186 patients received at least 1 dose of study drug. The control arm consisted of 66 patients who received 1500 mg of durvalumab once every 4 weeks (Q4W) on day 1 of each treatment cycle. Arm A consisted of 59 patients who received 1500 mg of durvalumab Q4W on day 1 of each cycle and 3,000 mg of oleclumab every 2 weeks (Q2W) on days 1 and 15 during cycles 1 and 2, and Q4W starting in cycle 3. Arm B consisted of 61 patients who received 1500 mg of durvalumab Q4W on day 1 of each cycle and 750 mg of monalizumab Q2W on days 1 and 15 of each cycle.

The primary end point of this study was ORR by investigator assessment per RECIST v1.1 criteria. Secondary end points included safety, disease control rate, progression-free survival (PFS) by investigator assessment, duration of response, 12-month PFS rate, and OS.

At data cutoff on May 17, 2021, the median follow-up in patients was 11.5 months (range, 0.4-23.4).

Additional results demonstrated that the disease control rate at 16 weeks was 81.7% (95% CI, 69.6%-90.5%) in arm A, 77.4% (95% CI, 65.0%-87.1%) in arm B, and 58.2% (95% CI, 45.5%-70.2%) in the control arm.

Both combination arms exhibited prolonged PFS compared with the control arm. In arm A, the stratified hazard ratio (HR) was 0.44 (95% CI, 0.26-0.75). In arm B, the stratified HR was 0.42 (95% CI, 0.24-0.72).

The 12-month PFS rate was higher in both investigative arms than in the control arm. In arm A, the 12-month PFS rate was 62.6% (95% CI, 48.1%-74.2%). In arm B, the 12-month PFS rate was 72.7% (95% CI, 58.8%-82.6%). In the control arm, the 12-month PFS rate was 33.9% (95% CI, 21.2%-47.1%).

The median PFS for arm B was 15.1 months (95% CI, 13.6-not estimable) compared with 6.3 months (95% CI, 3.7-11.2) in the control arm. The median PFS was not reached in arm A.

An exploratory subgroup analysis reflected PFS benefit with both combinations across several clinically significant subgroups, including those based on type of prior chemotherapy, histology, and ECOG PS. Although this analysis was limited by small subgroup patient numbers, results from exploratory biomarker analyses also showed greater PFS benefit in patients receiving either of the combinations than those receiving durvalumab alone.

In terms of safety, all 3 arms exhibited similar rates of any-cause treatment-emergent adverse effects (AEs) and grade 3 or higher treatment-emergent AEs. The most common grade 3 or 4 treatment-emergent AEs in arms A and B were cough (30.5% in arm A; 44.3% in arm B), dyspnea (25.4% in arm A; 23.0% in arm B), pneumonitis (18.6% in arm A; 16.4% in arm B), pruritus (16.9% in arm A; 24.6% in arm B), and asthenia (16.9% in arm A; 23.0% in arm B). The most common grade 3 or 4 treatment-emergent AEs in the control arm were dyspnea (25.8%), cough (18.2%), pneumonitis (16.7%), and arthralgia (16.7%).

Regarding grade 3/4 durvalumab-related AEs, hypothyroidism was the most common across all 3 arms, occurring in 13.6%, 18.0%, and 15.2% of patients in arms A, B, and the control arm, respectively. Other grade 3 or 4 durvalumab-related AEs in the combination arms included pneumonitis (16.9% in arm A; 9.8% in arm B) and pruritus (16.9% in arm A; 16.4% in arm B).

Overall, both combinations had manageable safety profiles, although additional research with a larger patient population is necessary to better determine differences in AEs of special interest and immune-related AEs across the 3 treatment options.

These interim data indicate that combining durvalumab with either oleclumab or monalizumab provides an increase in ORR and sustained PFS vs durvalumab alone in patients with unresectable, stage III NSCLC who did not progress following concurrent CRT. Additionally, these results support efforts to target CD73 and NKG2A pathways with oleclumab and monalizumab when treating other tumor types.

Going forward, a phase 3 trial is needed for further evaluation of these combinations in a larger, registration-intent setting.

“I look forward to seeing the launch of the phase 3 trial to help gather more insight on these combination therapies and better determine which patients will benefit from each combination treatment to help personalize effective treatments,” Herbst concluded.

References

1. Herbst RS, Majem M, Barlesi F, et al. COAST: an open-label, phase II, multidrug platform study of durvalumab alone or in combination with oleclumab or monalizumab in patients with unresectable, stage III non–small-cell lung cancer. J Clin Oncol. Published online April 22, 2022. doi:10.1200/JCO.22.00227
2. Combination immunotherapy improves outcomes for patients with non-small cell lung cancer. Yale Cancer Center. Published April 22, 2022. Accessed April 26, 2022. https://bit.ly/3xX68Ra