The combination of Bristol-Myers Squibb Co.'s PD-1 inhibitor Opdivo with Nektar Therapeutics's IL-2 agent NKTR-214 yielded deepening responses over time and demonstrated signs of being able to turn immunologically "cold" tumors "hot" – making them susceptible to immuno-oncology approaches, specialists reported at the American Society of Clinical Oncology (ASCO) annual meeting June 2.
Bristol and Nektar have been partnered since February on NKTR-214's development in nine tumor types and 20 indications, under a massive development deal signed in February worth $1.85bn. (Also see "Bristol Goes In Big On New Valentine Nektar" - Scrip, 14 Feb, 2018.)
NKTR-214 is a CD-122 agonist, meaning it binds with and activates CD-122, one of three components of IL-2 receptors found on the surface of T-cells. Nektar's pegylated product adds polyethylene glycol to human recombinant IL-2, which has the effect of delaying breakdown, allowing more convenient dosing and hopefully a better safety profile.
At the time the agreement was announced, the companies said they planned to move rapidly with development, starting pivotal trials in melanoma and renal cell carcinoma and intending to begin all registration-enabling studies within 14 months. (Also see "Nektar/Bristol Deal May Shake Up Immuno-Oncology Landscape" - Scrip, 14 Feb, 2018.)
Nektar reported very impressive data for the drug in the dose escalation stage of the Phase I/II PIVOT study of immunotherapy-naïve cancer patients at the Society for Immunotherapy and Cancer (SITC) meeting in November 2017, with response rates in the 60% range, though the dataset was small – just 38 patients. In March, the company reported that the data from the dose-escalation phase looked even better. For example, in first-line metastatic renal cell carcinoma (RCC), the objective response rate (ORR) improved to 71% from the time data was reported at SITC. (Also see "Nektar's NKTR-214 IO Deal With Bristol Looks Even Sweeter With More Data" - Scrip, 2 Mar, 2018.)
The PIVOT study is set to enroll more than 400 patients with melanoma, urothelial, non-small cell lung cancer and triple-negative breast cancer.
According to updated data presented at ASCO by Adi Diab, University of Texas MD Anderson Cancer Center, responses in the dose-escalation phase continued to deepen over time, as of a data cut-off on May 29.
In first-line metastatic melanoma, for example, 11 out of 13 had a partial response or complete response, an objective response rate of 85%.
Diab reported increased lymphocyte proliferation in blood and CD8 T-cells in tumors. Investigators also noted that some patients who were PD-L1 negative at the study start converted to PD-L1 positive after treatment.
If a certain level of efficacy was shown relative to historical controls with monotherapy in a particular tumor type, the study advanced to the next phase, where additional patients were evaluated. For this stage, Bristol and Nektar reported data for 94 evaluable patients: 37 with melanoma, 47 with RCC and 10 with urothelial cancer.
Relative to the initial dose escalation phase, the objective response rates were lower. Out of 28 patients with melanoma, for example, 14 responded (ORR 50%). Importantly, the combination was very effective in 25 patients with known PD-L1 status; the ORR was 42% (five of 12) in those who had been negative and 62% in those who were positive (eight of 13).
In metastatic renal cell carcinoma, the response rate was 46% (12 of 26). The ORR in those who had been PD-L1 negative was 53% (nine of 17) and 29% in those positive for PD-L1.
In advanced urothelial cancer, six of 10 had a response (60%). The ORR in the PD-L1 negative patients was 60% (3/5) and 60% in those who were positive (3/5).
With safety data for 283 patients, the most common treatment-related adverse events for the combination were Grade 1/2 flu-like symptoms (58.7%), rash (44.5%), fatigue (42%) and pruritus (31.4%). The rate of treatment related Grade 3+ adverse events was 14.1% and the dropout rate was 2.1%. The rate of Grade 3 or higher immune-mediated adverse events was 3.5%, including one death due to pneumonitis.
While acknowledging the hazards of cross-trial comparisons, ASCO discussant Heather McArthur said that the 50% ORR for advanced melanoma patients in the second phase of the study compared well to monotherapy data in this indication. Opdivo (nivolumab) as a monotherapy demonstrated an ORR of 44% and 40%, respectively, in the CheckMate 067 studies and CheckMate 066 studies in melanoma, she noted. A small improvement in response rate for immunotherapies can translate into an overall survival benefit, said McArthur, who is medical director of breast oncology at the Cedars-Sinai Medical Center in Los Angeles.
McArthur also noted that it is remarkable to see that the drug works in PD-L1 positive and negative tumors, with some converting from negative to positive status after treatment. Those who were PD-L1 positive at the start or who had converted from PD-L1 negative to positive status were more likely to derive benefit from clinical treatment, McArthur said, adding that "you have to be patient as responses happen over time."
This shows the potential of the combination for turning "cold" tumors "hot" – meaning they become primed for IO treatment – and raises the question of whether conventional biomarkers still matter, McArthur said.
McArthur also noted that the toxicity compares well to IL-2 historically, including lower rates of immune-related adverse events.
The pegylation of NKTR-214 helps with tolerability. The PEG chains slowly and irreversibly dissociate from NKTR-214 to gradually reveal biological activity, according to Nektar. This slow release of PEG chains in the blood allows less frequent dosing, stops over-activation of the immune system and overcomes traditional IL-2 toxicity such as capillary leak syndrome, the company explains.
With NKTR-214, regulatory T-cells are still generated in the periphery, where they can play a positive role without interfering with the drug's activity.
Data for the NKTR-214/Opdivo combination reported in an ASCO abstract ahead of the conference disappointed investors, as the response rates were lower in the second phase of the trial. (Also see "Immuno-Oncology: What To Watch At ASCO 2018" - Scrip, 17 May, 2018.)
Citeline analyst Maria Berezina commented, however, that the deepening of responses from the dose escalation phase at the time of SITC to ASCO strongly suggests that the latest data will also improve.
The ORR in metastatic melanoma was 85% in the first phase versus 50% in the second, with a disease control rate of 71%. The ORR in RCC was 64% in the first phase versus 46% in the second, with a disease control rate of 77%. The disease control rates show that there is room for the response rates to improve.
"All in all, the ORRs are very impressive when compared to nivolumab alone," Berezina added.
Some investors may understandably be skittish though, given the recent failure of the combination of Merck & Co. Inc.'s PD-1 inhibitorKeytruda(nivolumab) with Incyte Corp.'s IDO inhibitor epacadostat and the termination of IDO combination development programs across the board. This followed glowing reports of efficacy for IDO/PD-1 inhibitors based on comparisons of response rate data to historical monotherapy data and a fast move from Phase I to Phase III. (Also see "A Wake For IDO: Bristol Ends Registrational Trials Of High-Priced Flexus Drug" - Scrip, 30 Apr, 2018.)