Giovanni Caforio, MD
Bristol-Myers Squibb and Nektar Therapeutics have announced plans to jointly develop and market combinations of the CD122-biased cytokine NKTR-214 with nivolumab (Opdivo) or nivolumab plus ipilimumab (Yervoy) across for 20 indications in 9 tumor types. Under the terms of the agreement, Bristol-Myers Squibb will pay $1.85 billion to Nektar.
Currently, NKTR-214 is being examined in combination with the PD-1 inhibitor nivolumab in a phase I/II study for patients with a variety of advanced or metastatic cancers (NCT02983045). Additionally, a separate phase II study is already looking at the agent in combination with nivolumab for patients with locally advanced or metastatic sarcoma (NCT03282344).
In addition to these existing trials, pivotal studies looking at NKTR-214 with nivolumab or nivolumab and the CTLA-4 inhibitor ipilimumab are planned for patients with melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), bladder cancer, and triple-negative breast cancer. Studies for RCC and melanoma are expected to open in the middle of this year, according to the companies. Most of the costs associated with these trials (78%) will be paid by Bristol-Myers Squibb.
“We are excited to bring our leading capabilities and expertise in developing cancer therapies together with Nektar’s innovative science to jointly develop and commercialize NKTR-214 in combination with Opdivo and Opdivo plus Yervoy,” Giovanni Caforio, MD, chairman and CEO, Bristol-Myers Squibb, said in a statement.
“Bristol-Myers Squibb has established Opdivo plus Yervoy as the only approved immunotherapy combination for cancer patients and built a robust oncology pipeline,” Caforio continued. “With this commitment to the development of NKTR-214, an investigational therapy designed with a unique approach to harnessing the full potential of the interleukin-2 pathway, we now have a third validated I-O mechanism that has demonstrated a clinical benefit in patients, and holds significant potential to expand the benefits that these immuno-oncology agents can bring to patients with cancer.”
Early findings for the combination of NKTR-214 and nivolumab from the phase Ib PIVOT-02 trial were presented in November at the 2017 SITC Annual Meeting. This dose escalation trial included patients in the first- or second-line setting with advanced NSCLC (n = 5), RCC (n = 22), and melanoma (n = 11). Across all cohorts, the median age of patients was 61 years, 68.4% were treated in the frontline setting, and most had an ECOG performance status of 0 (65.8%).
Across all groups, the combination of NKTR-214 and nivolumab resulted in a reduction of target lesions for 72% of patients with advanced cancers. In treatment-naive patients with melanoma (n = 11), the objective response rate (ORR) by RECIST was 64% and by irRECIST it was 73%. In the efficacy-evaluable treatment-naive RCC group (n = 13), the ORR by RECIST was 46% in those with ≥1 post baseline scan (n = 13) and it was 60% for those with ≥2 post baseline scans (n = 10). In the NSCLC group (n = 4), the ORR was 75%.
This study, which was the basis for future clinical trials, identified a recommended phase II dose for NKTR-214 of 0.006 mg/kg with nivolumab at 360 mg. Both medications were given every 3 weeks. At this dose, just 1 patient experienced grade 3 or 4 treatment-related AEs (TRAE; 4%). The most common grade 1 and 2 TRAEs were fatigue (68%), flu like symptoms (60%), rash (52%), pruritus (32%), headache (32%), diarrhea (32%), arthralgia (24%), and decreased appetite (12%).
“NKTR-214’s ability to grow tumor infiltrating lymphocytes (TILs) in vivo and replenish the immune system is critically important as many patients battling cancer lack sufficient TIL populations to benefit from approved checkpoint inhibitor therapies,” Howard Robin, president and CEO of Nektar, said in a statement. “This strategic collaboration allows us to very quickly develop NKTR-214 with the leading approved PD-1 immune checkpoint inhibitor in numerous registrational trials. We look forward to our continued relationship with Bristol-Myers Squibb as we work together to advance cancer treatment for patients around the world.”
In addition to trials of NKTR-214 in combination with nivolumab, the agent is also being explored with the PD-L1 inhibitor atezolizumab (Tecentriq) or the PD-1 inhibitor pembrolizumab (Keytruda) for patients with advanced or metastatic solid tumors. This phase I study, known as PROPEL, plans to enroll 60 patients, with an estimated completion date of December 2018 (NCT03138889).
In preclinical research, NKTR-214 is being examined in combination with agents from Takeda Oncology. This collaboration, which was entered in May 2017, was focused on the exploration of NKTR-214 with 5 different Takeda compounds, including a SYK inhibitor and proteasome inhibitor, in tumor models for lymphoma, melanoma and colorectal cancer.
Diab A. Pivot-02: Preliminary safety, efficacy and biomarker results from dose escalation of the Phase 1/2 study of CD-122-biased agonist NKTR-214 plus nivolumab in patients with locally advanced/metastatic melanoma, renal cell carcinoma and non-small cell lung cancer. Presented at: SITC 32nd Annual Meeting; National Harbor, MD; November 8-12, 2017. Session 207.7.