Jeffrey R. Infante, MD
A combination regimen of the PD-L1 inhibitor atezolizumab (Tecentriq) and the investigational OX40 agonist MOXR0916 was well tolerated and showed early signs of of antitumor activity in solid tumors, according to results from a phase Ib dose escalation study presented at the 2016 ASCO Annual Meeting.
At the data cutoff, there were 2 partial responses, 1 in urothelial cancer and 1 in renal cell carcinoma (RCC). The patient with RCC had previously received MOXR0916 in a single-agent study; had metastases to the lung, liver, and pancreas; and had received prior sunitinib (Sutent), everolimus (Afinitor), and a Notch inhibitor.
“MOXR0916 was well tolerated at saturating exposures in combination with atezolizumab with no maximum-tolerated dose [MTD] reached,” lead study author Jeffrey R. Infante, MD, said when presenting the data at ASCO.
“The phase Ib study showed evidence of immune activation, including induction of PD-L1, in some paired tumor biopsies in a heterogeneous, all-comer population. PD-L1 modulation was observed in patients whose immediate prior therapy was single-agent anti-OX40 or anti–PD-1,” added Infante, who is director of the Drug Development Program at the Sarah Cannon Research Institute.
MOXR0916 is an agonist, effector-competent humanized IgG1 antibody against OX40. Preclinical models have shown that agonist anti-OX40 antibodies, such as MOXR0916, have a dual mechanism of action. When engaging OX40, the antibodies can attack the tumor through both costimulation of effector T cells and reduction of regulatory T cells.
Infante et al hypothesized that there would be a synergistic benefit between this dual mechanism of action and PD-L1 blockade. “OX40 promotes T-cell priming and generation of T-cell memory,” explained Infante. “OX40 signaling leads to PD-L1 induction via IFN-γ-upregulation.
The all-comer study enrolled 51 patients who had incurable or metastatic solid tumors of any type. Patients had either progressed on standard therapy or a clinical trial of a novel agent was a standard treatment for their tumor type and setting. There was no biomarker-based selection. Individuals with untreated brain metastases or a history of autoimmune disease were excluded from the study.
The most common tumor types were non–small cell lung cancer (NSCLC; n = 6), RCC (n = 5), ovarian cancer (n = 4), gastroesophageal junction cancer (n = 3), and soft tissue sarcoma (n = 3). The median patient agent in the trial was 58 years (range, 21-84). Fifty-one percent of patients were male, 43% (n = 22) had an ECOG PS of 0, and 57% (n = 29) had an ECOG PS of 1.
Patients were allowed to have prior treatment with a checkpoint inhibitor or costimulatory agonist. Thirty-five percent of patients (n = 18) had received 3 prior regimens for advanced disease. Eighteen percent (n = 9) had received prior PD-1/PD-L1 inhibition and 8% (n = 4) had prior therapy with an OX40 agonist. Both treatments were administered once every 3 weeks on the same day. MOXR0916 was given at escalating doses, with atezolizumab always administered at the standard dose of 1200 mg.
“The study employed a standard 3+3 dose escalation design,” said Infante. “We began with escalating doses of MOXR0916 of 0.8 mg. This was a very low dose because this combination study was initiated in parallel with a single-agent monotherapy study of the OX40 agonist. There were also concerns at the time with giving an OX40 agonist with a checkpoint inhibitor
Infante said the researchers quickly escalated the dose. The maximum dose administered was 1200 mg IV every 3 weeks. The pharmacokinetics of both agents were similar to results with their single-agent use, suggesting there is no negative effect from the interaction. The median number of treatment cycles, regardless of the MOXR0916 dose was approximately 4.
The primary objective of the phase Ib trial was to evaluate the safety and tolerability of the atezolizumab/MOXR0916 combo. Secondary endpoints included establishing a recommended phase II dose, pharmacokinetics and immunogenicity, and preliminary assessment of antitumor activity. Initial assessment of biomarkers was an exploratory objective.
“I think you’ll find that this combination is well tolerated overall. There were no dose-limiting toxicities and no maximum-tolerated dose was reached. There were no deaths or grade 4 adverse events attributed to the medication and no treatment discontinuations attributed to the study drugs,” said Infante.
The incidence and type of AEs was similar across the various MOXR0916 doses. In the overall population, the most common all-grade AEs were nausea (14%), pyrexia (10%), fatigue (8%), rash (8%), and chills (6%).
The single occurrence of a grade ≥3 serious AE was grade 3 pneumonitis in a patient with NSCLC who received 4 cycles of MOXR0916 at 40 mg. The pneumonitis was resolved with methylprednisolone and antibiotics. Of the 31 discontinuations, 30 were due to disease progression and 1 was due to patient withdrawal.
The efficacy assessment is continuing in ongoing expansion cohorts for patients with melanoma, RCC, NSCLC, urothelial carcinoma, and triple-negative breast cancer. The expansion regimen dose of MOXR0916 is 300 mg every 3 weeks.
Infante JR, Hansen AR, Pishvaian MJ, et al. A phase Ib dose escalation study of the OX40 agonist MOXR0916 and the PD-L1 inhibitor atezolizumab in patients with advanced solid tumors. J Clin Oncol. 34, 2016 (suppl; abstr 101).
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