Bempegaldesleukin/Nivolumab Combo Misses Mark in RCC and Urothelial Cancer

Nektar Therapeutics and Bristol Myers Squibb have announced the decision to end the global clinical development program for the combination of bempegaldesleukin (NKTR-214) and nivolumab (Opdivo) based on findings from preplanned analyses of 2 late-stage clinical trials evaluating the regimen in patients with renal cell carcinoma (RCC) and urothelial cancer.¹

Data from the final analysis of objective response rate (ORR) in the phase 3 PIVOT-09 trial (NCT03729245) indicated that the doublet did not meet the prespecified boundary for statistical significance compared with investigator’s choice of TKI therapy per blinded independent central review (BICR) in patients with previously untreated advanced or metastatic RCC. This was true for both the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate-/poor-risk and all-risk populations.

Moreover, findings from an interim analysis of overall survival (OS) also did not meet the prespecified boundary for statistical significance in either of the patient populations. Based on these findings, the trial has been unblinded and no additional analyses for this end point will be performed.

Findings from the final analysis of ORR in the phase 2 PIVOT-10 trial (NCT03785925) showed that bempegaldesleukin plus nivolumab did not reach the efficacy threshold to support continued examination in patients with cisplatin-ineligible, locally advanced or metastatic urothelial carcinoma.

Data from both studies will be reviewed by the companies and shared with the scientific community.

“As a leader in developing innovative therapies for patients with cancer, we are committed to continuing to explore novel combinations and pathways and advancing research that may help cancer patients achieve better outcomes,” Jonathan Cheng, senior vice president and head of oncology development at Bristol Myers Squibb, stated in a press release. “We are immensely grateful to the patients and investigators who participated in these studies.

PIVOT-09

The global, multicenter, randomized, open-label, phase 3 PIVOT-09 trial set out to examine the combination of bempegaldesleukin and nivolumab vs investigator’s choice of sunitinib (Sutent) or cabozantinib (Cabometyx) in patients with previously untreated advanced or metastatic RCC with a clear-cell component.²

To be eligible for enrollment, patients needed to have measurable disease per RECIST v1.1 criteria, a Karnofsky performance status of at least 70%, and left ventricular ejection fraction of greater than 45%. Patients could have any IMDC risk score, but they could not have previously received systemic therapy, including neoadjuvant, adjuvant, or vaccine treatment for RCC. Previous palliative radiotherapy needed to be completed at least 2 weeks prior to randomization.

If patients had active autoimmune disease or requirement for systemic immune suppressive agents, an additional malignancy that was progressing or required active treatment, underwent major surgery within 28 days of randomization, had tumor invading major blood vessels or the gastrointestinal tract, they were excluded. Patients also could not have any evidence of endotracheal or endobronchial tumor within 30 days of randomization, nor could they have active infection requiring systemic therapy within 2 weeks of randomization.

A total of 623 patients were randomized 1:1 to receive intravenous (IV) bempegaldesleukin at 0.006 mg/kg every 3 weeks plus IV nivolumab at 360 mg every 3 weeks in an outpatient setting or investigator’s choice of TKI treatment, which could have been oral sunitinib at 50 mg once daily for 4 weeks followed by 2 weeks off or oral cabozantinib at 60 mg once daily.

Treatment was administered until disease recurrence, intolerable toxicity, withdrawn consent, or up to 24 months. Randomization was stratified by IMDC prognostic score and choice of TKI.

The co-primary end points of the trial were ORR by BICR and modified RECIST v1.1 criteria in those with IMDC intermediate- or poor-risk scores, and in those with IMDC all-risk scores, and well as OS in both populations. A key secondary end points was progression-free survival (PFS) by BICR per mRECIST v1.1 criteria in both populations.

Other secondary end points comprised adverse effects; PD-L1 expression as a predictive biomarker for ORR, PFS, and OS; and quality of life.

PIVOT-10

The global, multicenter, single-arm, phase 2 PIVOT-10 trial set out to evaluate the combination of bempegaldesleukin and nivolumab in patients with locally advanced or metastatic urothelial cancer who were not eligible to receive cisplatin.³

The trial included those with measurable disease per RECIST v1.1 criteria and an ECOG performance status ranging from 0 to 2. They needed to be ineligible for cisplatin, which was defined as having 1 or more of the following: impaired renal function, grade 2 or higher hearing loses, grade 2 or higher peripheral neuropathy, and a performance status of 2. Patients could not have previously received systemic chemotherapy or an investigational agent for inoperable disease.

Key exclusion criteria included having active autoimmune disease or a need for systemic immune suppressive agents; having previously received a PD-1/PD-L1, PD-L2, or CTLA-4 antibody, or any other agent designed to target T-cell costimulation or immune checkpoint pathways; and active brain metastases.

A total of 192 patients were enrolled and received IV bempegaldesleukin at 0.006 mg/kg every 3 weeks plus IV nivolumab at 360 mg every 3 weeks. Patients received treatment until disease recurrence, intolerable toxicity, withdrawn consent, or up to 24 months.

The primary objective of the trial was to examine the antitumor activity of the doublet in the form of ORR per RECIST v1.1 criteria and BICR in those with low PD-L1 expression. Secondary objectives included ORR per BICR by RECIST v1.1 criteria in all treated patients, duration of response (DOR) per BICR by RECIST v1.1 criteria in both populations, and ORR and DOR per investigator assessment in both populations, as well as safety and tolerability.

Other Studies Evaluating Bempegaldesleukin/Nivolumab Combo

The pivotal phase 3 CA045-009 trial (NCT04209114), which was launched to examine whether the doublet or nivolumab monotherapy, before and after surgery to remove the bladder, would be more effective than surgery alone in patients with high-risk urothelial cancer, including those with muscle-invasive bladder cancer who are not able to receive cisplatin, is also being discontinued.⁴

Other trials slated for discontinuation include the phase 1/2 PIVOT IO 011 trial (NCT04540705) which was evaluating the safety of nivolumab plus bempegaldesleukin and a TKI, as well as nivolumab plus bempegaldesleukin and cabozantinib vs nivolumab and cabozantinib in patients with previously untreated kidney cancer that has advanced or spread,⁵ and the phase 1/2 PIVOT IO 020 trial (NCT04730349), which was examining bempegaldesleukin plus nivolumab in children, adolescents, and young adults with recurrent or treatment-resistant cancer.⁶

References

1. Nektar and Bristol Myers Squibb announce update on clinical development program for bempegaldesleukin (BEMPEG) in combination with Opdivo (nivolumab). News release. Bristol Myers Squibb; April 14, 2022. Accessed April 15, 2022. https://bit.ly/3KGLwQN
2. Tannir NM, Agarwal N, Pal SK, et al. PIVOT-09: a phase III randomized open-label study of bempegaldesleukin (NKTR-214) plus nivolumab versus sunitinib or cabozantinib (investigator’s choice) in patients with previously untreated advanced renal cell carcinoma (RCC). J Clin Oncol. 2020;38(suppl 6):TPS763. doi:10.1200/JCO.2020.38.6_suppl.TPS763
3. Huddart RA, Siefker-Radtke AO, Balar AV, et al. PIVOT-10: a phase II study of bempegaldesleukin (NKTR-214) in combination with nivolumab (NIVO) in cisplatin (cis) ineligible patients with previously untreated locally advanced or metastatic urothelial cancer (mUC). J Clin Oncol. 2020;38(suppl 6):TPS589. doi:10.1200/JCO.2020.38.6_suppl.TPS589
4. A study of nivolumab plus bempegaldesleukin (Bempeg/NKTR-214) vs nivolumab alone vs standard of care in participants with bladder cancer that may have invaded the muscle wall of the bladder and who cannot get cisplatin, a type of medicine given to treat bladder cancer. ClinicalTrials.gov. Updated March 21, 2022. Accessed April 15, 2022. https://clinicaltrials.gov/ct2/show/NCT04209114
5. A study to compare bempegaldesleukin (BEMPEG: NKTR-214) combined with nivolumab and tyrosine kinase inhibitor (TKI) to nivolumab and TKI alone in participants with previously untreated kidney cancer that is advanced or has spread (PIVOT IO 011). ClinicalTrials.gov. Updated March 21, 2022. Accessed April 15, 2022. https://clinicaltrials.gov/ct2/show/NCT04540705
6. A study of bempegaldesleukin (BEMPEG: NKTR-214) in combination with nivolumab in children, adolescents and young adults with recurrent or treatment-resistant cancer (PIVOT IO 020). ClinicalTrials.gov. Updated January 5, 2022. Accessed April 15, 2022. https://clinicaltrials.gov/ct2/show/NCT04730349