Dinutuximab Misses Survival Endpoint in Small Cell Lung Cancer

lung cancer

The addition of dinutuximab (Unituxin) injection to irinotecan did not improve overall survival (OS) compared with irinotecan or topotecan alone in patients with relapsed/refractory small cell lung cancer (SCLC), missing the primary endpoint of the phase II/III DISTINCT trial (NCT03098030).¹

Additionally, the safety profile of the combination was consistent with prior trials and the current label for dinutuximab. Full results will be presented at an upcoming medical meeting and will also be included in peer-reviewed publications.

"We thank the principal investigators, patients and their families for participating in the DISTINCT study," Gil Golden, MD, PhD, chief medical officer of United Therapeutics, the developer of dinutuximab, stated in a press release. "We're clearly disappointed with the DISTINCT results but we'll continue to seek out underappreciated avenues in our core therapeutic areas addressing rare diseases in oncology and pulmonary hypertension."

Dinutuximab is a GD2-binding monoclonal antibody that is approved for use in combination with granulocyte-macrophage colony-stimulating factor, interleukin-2, and 13-cis-retinoic acid, for the treatment of pediatric patients with high-risk neuroblastoma who achieve a ≥partial response to prior induction therapy.

In the 2-part, open-label, international, multicenter, phase II/III DISTINCT trial, investigators evaluated the combination of dinutuximab and irinotecan or topotecan compared with irinotecan as a second-line treatment for patients with relapsed/refractory SCLC.

The phase II portion of the trial, which included 12 patients, was completed in October 2017. The international enrollment of the phase III portion, which was completed in October 2018, comprised 471 patients.

Patients were randomized 2:2:1 to receive irinotecan (n = 190), irinotecan and dinutuximab (n = 187), or topotecan (n = 94). The trial was conducted in 198 centers from 22 countries in North America, Europe, and Asia-Pacific. A total 312 deaths were observed between the combination and irinotecan-alone arms, data of which were extracted for the analysis.

Dinutuximab was administered at 10 mg/m² intravenously (IV) in combination with irinotecan at 350 mg/m² IV on day 1 every 21 days. The dinutuximab dose was escalated in 2 mg/m² increments per cycle, if any pain was grade <2 and did not require opioids. The maximum-tolerated dose of dinutuximab was 17.5 mg/m². In the topotecan arm, the drug was administered at 1.5 mg/m² on days 1 to 5 every 21 days.

To be eligible for enrollment, patients must have had histologically or cytologically confirmed SCLC with documented relapse or disease progression during or after frontline platinum-based therapy, had no available curative therapy, had a life expectancy of ≥12 weeks, had an ECOG performance status of 0 or 1, had adequate bone marrow and hepatic function, and had calculated creatinine clearance ≥30 mL/minute or serum creatinine ≤1.5 times below the upper limit of normal.

Those who were candidates for re-treatment with an original platinum-based regimen in the second-line setting; had prior treatment with irinotecan, topotecan, or dinutuximab; had active brain metastases; had mixed small cell and non—small cell histologic features; had a prior or concurrent cancer distinct in primary site or histology from the cancer being evaluated on the trial; a history or current evidence of uncontrolled cardiovascular disease; did not recover from prior surgery, trauma, or anticancer therapy; had organ allograft or hematopoietic transplantation; or were HIV-positive were not permitted to enroll on the study.

The primary endpoint was OS in patients treated with dinutuximab and irinotecan versus those who received irinotecan alone. Secondary endpoints include progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR) with the combination versus irinotecan; safety; pharmacokinetics; and PFS, ORR, and CBR with the combination versus topotecan alone. An exploratory endpoint was the relationship between selected biomarkers and survival of patients treated with the dinutuximab regimen.

Earlier findings of the phase II portion of the study, which looked at the feasibility of this regimen, showed that dinutuximab plus irinotecan is well tolerated with no unanticipated adverse events (AEs) when dinutuximab is given at a dose up to 16 mg/m².² Of the 12 patients enrolled, 8 were male and the mean age was 68 years old (range, 47-79). The median number of completed cycles per patient was 3, and the median dose of dinutuximab was 14 mg/m².

Safety data showed that pain was mostly grade 1 (80%) and most cases resolved within hours of infusion; while 1 patient experienced grade 3 pain, they received the same dose of dinutuximab in the following cycle. Pain did not lead to dose reductions, discontinuations, or hospitalizations from dinutuximab, and no grade 5 AEs were observed. Gastrointestinal AEs were likely attributable to irinotecan, the investigators noted.

United Therapeutics stated in the press release that it is also pursuing a label expansion for dinutuximab in combination with irinotecan and temozolomide for the treatment of pediatric patients with relapsed/refractory neuroblastoma. The expansion is based on results from the ANBL1221 study, which was conducted by the Children's Oncology Group. The company plans to meet with the FDA to discuss the proposed label expansion in the first half of 2020 and subsequently file a supplemental biologics license application.&#8239;

References

1. United Therapeutics Announces Study of Unituxin (dinutuximab) for Small Cell Lung Cancer Did Not Meet Primary Endpoint [news release]: Silver Spring, MD and Research Triangle Park, NC. United Therapeutics Corporation. Published February 3, 2020. https://yhoo.it/31onggh. Accessed February 3, 2020.
2. Edelman MJ, Juan O, Navarro A, et al. Feasibility of outpatient dinutuximab (D) and irinotecan (I) for second-line treatment of relapsed or refractory small cell lung cancer (RR SCLC): Part 1 of an open-label, randomized, phase 2/3 study. J Thor Oncol. 2018;13(4):S48-S49. doi: 10.1016/S1556-0864(18)30363-0.