Rova-T Delivers Disappointing Results in Phase II SCLC Trial

Mike Severino, MD

Mike Severino, MD

In preliminary findings from the single-arm, phase II TRINITY trial investigating Rovalpituzumab Tesirine (Rova-T) in the third-line setting for patients with relapsed/refractory small cell lung cancer (SCLC) demonstrating high DLL3 expression, the DLL3-targeted antobody-drug conjugate delivered disappointing results.

Per investigator assessment, the best overall response (BOR) rate was 29% (95% CI, 22-36). BOR was defined in the study by a complete response (CR) or partial response (PR) any time before receieving a subsequent therapy.¹

According to an assessment from the independent review committee (IRC), the objective response rate (ORR) was 16% (95% CI, 11-22). ORR was defined in the study as CR or PR prior to receiving any subsequent anticancer therapy, with confirmation of CR or PR at least 28 days from the initial determination per RECIST v1.1. The median duration of response was found by the IRC as 4.1 months (95% CI, 3.0-4.2). Median overall survival (OS) was 5.6 months (95% CI, 4.9-6.8), while there was an estimated 12-month OS rate of 17.5% (95% CI, 10.8-25.5).

The full results of the TRINITY trial were submitted to be presented at the 2018 ASCO Annual Meeting. AbbVie, manufacturer of the antibody-drug conjugate, is not looking for accelerated approval by the FDA for use of its drug in the third-line setting for treatment of SCLC.

Mike Severino, MD, executive vice president of research and development and chief scientific officer at AbbVie, said in a statement, “We continue to believe Rova-T has potential for patients with small cell lung cancer and other DLL3-expressing cancers. Although the results from the study were not what we hoped for, we look forward to receiving data from the ongoing phase III studies in the first- and second-line settings and remain committed to developing Rova-T for the treatment of patients with small cell lung cancer.”

The TRINITY trial, a multicenter, open-label, single-arm trial, enrolled 177 patients with DLL3-expressing SCLC who had undergone at least 2 prior treatment regimens, where at least 1 of which was a platinum-based regimen. The primary objective was an assessment of Rova-T’s efficacy of Rova-T as third-line and later treatment.

Additionally, secondary objectives included assessment of safety and tolerability, pharmacokinetics, RECIST-assessed progression-free survival (PFS), duration of response, and clinical benefit rate.

According to IRC, the most common treatment-emergent adverse events (TRAEs) reported were fatigue (38%), photosensitivity reaction (36%), pleural effusion (32%), edema peripheral (31%), decreased appetite (30%), nausea (26%), dyspnea (25%), thrombocytopenia (25%), constipation (22%), vomiting (17%), anemia (17%), hypoalbuminemia (16%), and cough (16%).

The most common (≥5%) grade ≥3 severe toxicities were thrombocytopenia (11%), photosensitivity reaction (7%), and pleural effusion (5%).

The MERU study (NCT03033511), an ongoing phase III trial, is investigating Rova-T as a maintenance therapy to follow first-line platinum-based chemotherapy in patients with extensive stage SCLC. The phase III TAHOE trial (NCT03061812), currently ongoing, is also comparing Rova-T with topotecan in patients with advanced or metastatic SCLC with high levels of DLL3 who have first disease progression during or following frontline platinum-based chemotherapy.

Rova-T has shown promise in a first-in-human, first-in-class, open-label phase I study.²From July 2013 to August 2015, 82 patients enrolled in this study at 10 US centers. There was a toal of 74 patients with SCLC and 8 with large-cell neuroendocrine carcinoma in this patient population, all of which received at least 1 dose of Rova-T. The whole study cohort was given a median of 2 doses (IQR 1-3; range 1-14).

Overall, 11 of the 60 assessable patients (18%) who had received an active dose of Rova-T (0.2 mg/kg or 0.4 mg/kg every 3 weeks or 0.3 mg/kg or 0.4 mg/kg every 6 weeks) reached a confirmed objective response. Thirty patients (50%) had stable disease. Median PFS was 2.8 months (95% CI, 2.5-4.0).

According to an exploratory analysis of available tumor tissue samples (n = 34), an overall response rate of 38% (n = 10) was found among 26 DLL3-high patients (tumor expression levels ≥50%) compared with 0% in DLL3-low patients. The median PFS was 4.3 months (95% CI, 2.8-5.6) in DLL3-high patients versus 2.2 months (95% CI, 1.3-2.5) in DLL3-low patients.

Of 65 patients with SCLC who were assessable for activity analyses and received any dose of Rova-T, 11 (17%) achieved a confirmed objective response, and 35 (54%) had stable disease. Forty-six patients (71%) achieved disease control.

Samples were provided by 39 patients for exploratory analysis of DLL3 expression in tumor tissue. Of the 29 assessable DLL3-high patients, 10 (35%) had a confirmed objective response and 26 (90%) achieved disease control. Of those 10 assessable patients defined as DLL3-low, none reached a confirmed objective response. However, 6 (60%) patients had disease control.

Median PFS found in an exploratory analysis was 4.5 months (95% CI, 3.0-5.4) for DLL3-high patients (based on 26 of 29 patients who had disease progression or died) and 2.3 months (95% CI, 1.3-3.3) for DLL3-low patients (based on 9 of 10 patients who had disease progression or died).

OF the 68 patients treated with active dose levels of Rova-T, OS was 4.6 months (95% CI, 3.9-7.1). Exploratory analysis of DLL3 expression led to the conclusion of 29 patients in the DLL3-high subset with a median OS of 5.8 months (95% CI, 4.4-11.6); in the 10 patients in the DLL3-low subset, median OS was 2.7 months (95% CI, 1.2-10).

The 1-year OS rate was 18% (95% CI, 9-29) in patients treated at the active dose levels, 32% (95% CI, 15-49) in DLL3-high patients, and 0% in DLL3-low patients. A posthoc analysis of chemotherapy-sensitive versus refractory or resistant patients showed a 1-year OS rate of 21% in patients with resistant/refractory disease; the rates were 29% in DLL3-high patients and 0% in DLL3-low patients.

Overall, 28 (38%) patients reported ≥grade 3 TRAEs. The most often reported ≥grade 3 TRAE was thrombocytopenia (11%) , followed by pleural effusion (8%) and increased lipase (7%).

References:

1. AbbVie. AbbVie announces results from phase 2 study evaluating rovalpituzumab tesirine (rova-t) for third-line treatment of patients with Dll3-expressing relapsed/refractory small cell lung cancer. Available at: https://bit.ly/2ubjnOS. Accessed March 22, 2018.
2. Rudin CM, Pietanza MC, Bauer TM, et al. Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study. Lancet Oncol. 2017;18(1):42-51. doi:10.1016/S1470-2045(16)30565-4.