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NKTR-214 and COSMIC-313 for Previously Untreated RCC

Panelists: Daniel J. George, MD, Duke Cancer Center; Robert S. Alter, MD, Hackensack University Medical Center; Chung-Han Lee, MD, PhD, Memorial Sloan Kettering Center; Nizar M. Tamir, MD, FACP, The University of Texas MD Anderson Cancer Center
Published: Friday, Sep 06, 2019



Transcript: 

Daniel J. George, MD:
There’s another company out there, Nektar Therapeutics in San Francisco, California, that’s making a pegylated interleukin 2 [IL-2] formulation in NKTR-214, and it’s got some ambitious plans. Tell us a little about that.

Nizar M. Tannir, MD, FACP: NKTR-214 has a name now that’s many letters: bempegaldesleukin. High-dose IL-2 was aldesleukin, so this is bempegaldesleukin, or NKTR-214. This is a PIVOT-09 trial, a phase III trial. It’s going to be in the US but mostly outside the US: China, Russia, Latin America, Mexico, and Australia. I think, Dan, you’re on the steering committee with me. It is comparing NKTR-214 with pegylated IL-2 plus nivolumab based on already positive results in the PIVOT-02 trial, a phase I/II trial, versus a TKI [tyrosine kinase inhibitor], dealer’s choice, cabozantinib or sunitinib. In the US and other counties, where cabozantinib is approved for first-line therapy, the TKI of choice would obviously be cabozantinib. In countries like Russia and China, where the cabozantinib is not approved for first line, it will be sunitinib. The 2 coprimary endpoints for this 600-patient phase III trial is ORR [objective response rate] and OS [overall survival], and you start with ORR first and then OS would be the second interim analysis.

I think it is a novel mechanism of action because it’s different from the high-dose IL-2. In the phase I trial—PIVOT-02—that we have conducted in many cohorts of different tumor types—melanoma, RCC [renal cell cancer], bladder, lung, and others—what we have seen doing biopsies on these patients in the phase I pretreatment, so baseline and 3 weeks after 1 infusion of the drug, is that this drug is the best T-cell recruiter. It brings T cells CD8 into the tumor microenvironment, and in many patients, it converts PD-L1 [programmed death-ligand 1]–negative tumors to PD-L1–positive tumors. So I think it is definitely a new mechanism-of-action agent, so we’ll see if the trial would be positive in RCC. I hope it will for the sake of our patients. We’ll have new therapies for them.

At this ASCO [American Society of Clinical Oncology] 2019 Annual Meeting, there is a poster. Michael Hurwitz and colleagues presented data on biomarker with NKTR-214 plus nivolumab. In metastatic melanoma, this combination of NKTR-214 and nivolumab produced 34% CR [complete response] rate. I think this is an impressive CR rate with a very favorable safety profile, so it is a deliverable combination. It may have efficacy comparable with nivolumab-ipilimumab but probably with a better safety profile. This is an exciting phase III trial that is in the first-line setting. And it has opened, and we have already enrolled a few patients. I’m looking forward to really seeing it complete its target accrual of 600 patients and then many sites joining.

Daniel J. George, MD: Probably more versions of that drug in combination with other strategies in the future. And then there’s 1 other study, I’m told, similar to the PEDIGREE study—nivolumab-ipilimumab study plus or minus cabozantinib—COSMIC study.

Nizar M. Tannir, MD, FACP: That’s the COSMIC-313 study.

Daniel J. George, MD: Yeah.

Nizar M. Tannir, MD, FACP: It’s a sponsored trial by industry, by Exelixis, Inc, and it actually builds on nivolumab-ipilimumab as the backbone. It’s for patients with intermediate risk and poor risk. Patients are randomized to nivolumab-ipilimumab plus cabozantinib at the dosage of 40 mg per day, and nivolumab-ipilimumab is given at the standard dosing schedule like CheckMate-214 versus the comparator, which is nivolumab-ipilimumab plus placebo. The primary endpoint for this 676-patient phase III trial is PFS [progression-free survival]. The trial has just launched and already enrolled a few patients. Those 2 trials will be going in parallel, and we’ll probably have results in 2021 from COSMIC-313 and the PIVOT-09 trials.

Daniel J. George, MD: There’s a lot to do. Obviously, to Bob’s point, we are going to need patients to fill all these trials. And I think we’re not going to get it done without the community helping and hopefully opening these studies up in more and more community research centers. I hope we can get it all done.


Transcript Edited for Clarity 

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Transcript: 

Daniel J. George, MD:
There’s another company out there, Nektar Therapeutics in San Francisco, California, that’s making a pegylated interleukin 2 [IL-2] formulation in NKTR-214, and it’s got some ambitious plans. Tell us a little about that.

Nizar M. Tannir, MD, FACP: NKTR-214 has a name now that’s many letters: bempegaldesleukin. High-dose IL-2 was aldesleukin, so this is bempegaldesleukin, or NKTR-214. This is a PIVOT-09 trial, a phase III trial. It’s going to be in the US but mostly outside the US: China, Russia, Latin America, Mexico, and Australia. I think, Dan, you’re on the steering committee with me. It is comparing NKTR-214 with pegylated IL-2 plus nivolumab based on already positive results in the PIVOT-02 trial, a phase I/II trial, versus a TKI [tyrosine kinase inhibitor], dealer’s choice, cabozantinib or sunitinib. In the US and other counties, where cabozantinib is approved for first-line therapy, the TKI of choice would obviously be cabozantinib. In countries like Russia and China, where the cabozantinib is not approved for first line, it will be sunitinib. The 2 coprimary endpoints for this 600-patient phase III trial is ORR [objective response rate] and OS [overall survival], and you start with ORR first and then OS would be the second interim analysis.

I think it is a novel mechanism of action because it’s different from the high-dose IL-2. In the phase I trial—PIVOT-02—that we have conducted in many cohorts of different tumor types—melanoma, RCC [renal cell cancer], bladder, lung, and others—what we have seen doing biopsies on these patients in the phase I pretreatment, so baseline and 3 weeks after 1 infusion of the drug, is that this drug is the best T-cell recruiter. It brings T cells CD8 into the tumor microenvironment, and in many patients, it converts PD-L1 [programmed death-ligand 1]–negative tumors to PD-L1–positive tumors. So I think it is definitely a new mechanism-of-action agent, so we’ll see if the trial would be positive in RCC. I hope it will for the sake of our patients. We’ll have new therapies for them.

At this ASCO [American Society of Clinical Oncology] 2019 Annual Meeting, there is a poster. Michael Hurwitz and colleagues presented data on biomarker with NKTR-214 plus nivolumab. In metastatic melanoma, this combination of NKTR-214 and nivolumab produced 34% CR [complete response] rate. I think this is an impressive CR rate with a very favorable safety profile, so it is a deliverable combination. It may have efficacy comparable with nivolumab-ipilimumab but probably with a better safety profile. This is an exciting phase III trial that is in the first-line setting. And it has opened, and we have already enrolled a few patients. I’m looking forward to really seeing it complete its target accrual of 600 patients and then many sites joining.

Daniel J. George, MD: Probably more versions of that drug in combination with other strategies in the future. And then there’s 1 other study, I’m told, similar to the PEDIGREE study—nivolumab-ipilimumab study plus or minus cabozantinib—COSMIC study.

Nizar M. Tannir, MD, FACP: That’s the COSMIC-313 study.

Daniel J. George, MD: Yeah.

Nizar M. Tannir, MD, FACP: It’s a sponsored trial by industry, by Exelixis, Inc, and it actually builds on nivolumab-ipilimumab as the backbone. It’s for patients with intermediate risk and poor risk. Patients are randomized to nivolumab-ipilimumab plus cabozantinib at the dosage of 40 mg per day, and nivolumab-ipilimumab is given at the standard dosing schedule like CheckMate-214 versus the comparator, which is nivolumab-ipilimumab plus placebo. The primary endpoint for this 676-patient phase III trial is PFS [progression-free survival]. The trial has just launched and already enrolled a few patients. Those 2 trials will be going in parallel, and we’ll probably have results in 2021 from COSMIC-313 and the PIVOT-09 trials.

Daniel J. George, MD: There’s a lot to do. Obviously, to Bob’s point, we are going to need patients to fill all these trials. And I think we’re not going to get it done without the community helping and hopefully opening these studies up in more and more community research centers. I hope we can get it all done.


Transcript Edited for Clarity 
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