I've been reporting on NKTR-214 (bempegaldesleukin) since 2013, the PIVOT trial in particular. The drug was also discussed at ASCO this year, with my report on that (with links to prior reports) here: New Stuff!! Treatment options and current trials for melanoma patients! The first installment of this year's ASCO review.
Here's most of what I wrote from ASCO:
I first reported on NKTR in 2013. Click here for that report as well as abstracts and analysis from 2018. After examining the Phase 1 and Phase 2 reports of the PIVOT trial I wrote:
"...back to NKTR-214 combined with nivo. Like many drugs/trials in cancer/melanoma world, the Phase 1 trials were super promising. Phase II results were a little less so. Responses as noted in the article were "(ORR) of 50% in treatment-naïve patients with melanoma, including an ORR of 42% in PD-L1–negative patients". We have already determined that treatment naive patients tend to have the best responses. But even so, 50% beats 40%. Additionally, we also know that PD-L1 status has not been particularly definitive in attaining responses to anti-PD-1 drugs, but it is still good to note a 42% ORR in PD-L1 negative patients and that side effects were really no worse in this combo than when anti-PD-1 is taken alone. So....
I still hold out hope ~ for vaccines, for IDO-inhibitors, and the current responses to NKTR-214 combined with nivo to hold. BUT! Unlike Melanoma Big Dogs in their ivory towers....we canaries in the coalmines...the ratties...you and me...can't afford to pontificate on the hypothetical. We have to deal with the real live results that are happening for real. Today. To us."
That's how I look at melanoma research!!!! ALWAYS! Now....this from ASCO:
CA045-001: A phase III, randomized, open label study of bempegaldesleukin (NKTR-214) plus nivolumab (NIVO) versus NIVO monotherapy in patients (pts) with previously untreated, unresectable or metastatic melanoma (MEL). 2019 ASCO. Nikhil, Khushalani, Diab, .... Sznol, Long.
Background: Standard of care for pts with previously untreated, unresectable or metastatic MEL includes checkpoint inhibitors.Bempegaldesleukin is a CD122-preferential IL-2 pathway agonist designed to provide sustained signaling through the IL-2 βγ receptor to activate and proliferate effector CD8+ T and NK cells over T-regulatory cells in the tumor (Hurwitz ME et al. ASCO GU 2017). In the dose-expansion phase of the phase 1/2 PIVOT-02 trial, bempegaldesleukin + NIVO was well tolerated at the recommended phase 2 dose (RP2D; bempegaldesleukin 0.006 mg/kg IV Q3W + NIVO 360 mg IV Q3W), and previously untreated pts with MEL receiving the RP2D achieved an objective response rate (ORR) of 20/38 (53%) and a complete response of 9/38 (24%) by independent radiology review (Diab A et al. SITC 2018). Presented is the design of the first phase 3 trial in the bempegaldesleukin + NIVO development program in pts with previously untreated, unresectable or metastatic MEL. Methods: Thisphase 3, randomized, open-label study aims to evaluate the effectiveness, safety, and tolerability of bempegaldesleukin + NIVO (NCT03635983).Eligible pts are greater that/= to 2 y with histologically confirmed stage III (unresectable) or stage IV MEL and ECOG PS less that/= to 1 or Lansky PS greater than/= to 80% (minors 12-17 y). Pts are ineligible if they have active brain or leptomeningeal metastases, uveal MEL, or a recurrence within 6 mo of completing adjuvant treatment with any approved agent. Pts will be stratified by PD-L1 status (measured using PD-L1 IHC 28-8 pharmDx), BRAF mutation status, and lactate dehydrogenase level, and will be randomized to receive bempegaldesleukin 0.006 mg/kg IV Q3W + NIVO 360 mg IV Q3W or NIVO 360 mg IV Q3W up to 24 mo, or until progression or unacceptable toxicity (N ~ 764). Primary endpoints are ORR and progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints include ORR and PFS by investigator, ORR and PFS by BICR in biomarker population, OS in biomarker population, and safety. Additional endpoints include pharmacokinetics and quality-of-life assessment. Clinical trial information: NCT03635983
So, this is an open and recruiting trial. It is randomized. Some folks will be getting the NKTR-214 drug with nivo, some will get nivo only. Prior ORR of 53% is better than the usual of about 40% to anti-PD-1 products given alone, but about equal to the ipi/nivo combo. If the side effects of this combo is less than those caused by ipi/nivo, that could be a good thing. Lots of the usual melanoma peeps are excluded. But, there you go.
So that's where I thought I'd left bempegaldesleukin and nivo. Seriously, who names this shit??? Anyhow ~ there's more, and it seriously falls in a GOOD NEWS/BAD NEWS category. Here's a link to the report:
From FiercePharma, August 2019: Faulty manufacturing trips up Nektar's Bristol-partnered cancer drug in crucial trial
Which states in part:
Could a manufacturing mix-up be as detrimental as the fact that a drug simply doesn’t work? Nektar learned the answer the hard way with its Bristol-Myers Squibb-partnered experimental cancer therapy. On Thursday, Nektar CEO Howard Robin went to great lengths to explain why response rates dropped in the second stage of a clinical trial testing NKTR-214 (bempegaldesleukin) in tandem with Bristol's Opdivo. But in a nutshell, some patients received substandard batches of the Nektar drug, he told analysts during a conference call. And unsurprisingly, those bad batches didn't work as well.
According to Robin, Nektar ran an analysis of all 22 lots of bempeg it had produced and found that two lots—lots 2 and 5—were out of specification, though they had passed release controls under old assays. The team noted correlations between patients who started treatment with the two problematic lots and a lower response rate during the PIVOT-02 trial as compared with the other two lots used in the study. Specifically, newly diagnosed melanoma patients who started with lots 2 and 5 saw 36% of their tumors respond to the treatment at best, with a complete response rate of 27%. The others posted response rates at 75% and 44%, respectively, Nektar’s R&D chief Stephen Doberstein said during the call. In the trial's first-line urothelial cancer cohort and first-line renal cell carcinoma cohort, similar differences were observed. Management attributed the mess-up to a single suboptimal batch of intermediate that was used to produce only lots 2 and 5. The company found that bad batch using new quality control assays, Robin said. And Robin promised that Nektar now has the problem under control. “As a result of this discovery, we have developed a comprehensive control strategy to limit variances in raw materials, intermediates and the final product in our manufacturing, and this is being validated for commercial-scale manufacturing,” he said, adding that the company has also shaken up its CMC leadership.
The BAD NEWS: Seriously, Nektar and Mr. Robin CEO man??????? We didn't ask you to change a light fixture or install brakes in our car. We didn't count on you to do brain surgery, cook us a meal, teach our children to read, repair a computer or put a satellite into space. We EXPECTED you to do what you SAID you knew how to do. Make a specific drug, that you eff'n named bempegaldesleukin, they way you said you would, in the strength you said it would be, in a consistent and safe manner for use in HUMAN BEINGS!!!!!!!!!!!!! We didn't FORCE you to do that job! YOU SIGNED UP FOR IT!!!!!!!!!!! Good grief! WTF??????????????!!!!!!!!!!!!!!
On the GOOD NEWS side, perhaps ~ if Mr. Robin CEO man can get his Nektar shit together, and actually make NKTR-214 as it should be - in a safe, consistent, reproducible manner - response rates in melanoma and renal cell carcinoma patients may be much improved on the nivo combo. To the tune of: "Newly diagnosed melanoma patients who started with lots 2 and 5 saw 36% of their tumors respond to the treatment at best, with a complete response rate of 27%. The others posted response rates at 75% and 44%, respectively" per the report above.
It is one crazy world. Being sick should be enough - but no!!! Hang in there ratties. You are the best and we thank you. - c
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