Meeting NewsPerspective

Novel nivolumab combination shows efficacy for advanced solid tumors

CHICAGO — The combination of the CD122-based agonist NKTR-214 with nivolumab appeared well tolerated with promising efficacy among patients with a variety of advanced tumor types, according to preliminary results of the phase 1/phase 2 open-label PIVOT trial presented at ASCO Annual Meeting.

Prespecified efficacy criteria were achieved in three tumor types — first-line melanoma, first-line renal cell carcinoma and first-line urothelial cancer.

NKTR-214 (Nektar) as monotherapy increases newly proliferative CD8+ T cells in tumors and increases cell surface PD-1 and PD-L1 expression, suggesting it may be synergistic with anti-PD-1 therapy such as nivolumab (Opdivo, Bristol-Myers Squibb).

“NKTR-214 is a novel cytokine that enhances signaling through the IL-2 pathway with a unique prodrug design that provides a safety profile that avoids rapid and hyperactive immune stimulation and inflammation that usually is associated with toxicity when giving high-dose IL-2,” Adi Diab, MD, assistant professor in the department of melanoma medical oncology in the division of cancer medicine at The University of Texas MD Anderson Cancer Center, said during his presentation. “The unique prodrug design also allows for administration every 3 weeks, which is very convenient for the patients.”

The trial includes cohorts of patients in various lines of treatment with melanoma, non-small cell lung cancer, urothelial carcinoma, triple-negative breast cancer and renal cell carcinoma.

In the stage 1 dose escalation portion of the trial, patients received NKT-214 in 0.003-mg/kg, 0.006-mg/kg or 0.009-mg/kg doses concurrently with 360 mg nivolumab every 3 weeks.

In the stage 2 expansion, patients received the recommended phase 2 dose of 0.006 mg/kg NKT-214 concurrently with nivolumab.

The study uses a Fleming 2-stage design, which incorporates separate predefined efficacy targets for each tumor type using a historical objective response rate for a single-agent checkpoint inhibitor. Diab presented data from the three cohorts that met the prespecified efficacy criteria, meaning the cohorts could advance to registrational studies. The other cohorts are at various stages of enrollment and have not yet met futility or efficacy criteria.

The analysis included 41 patients with melanoma, 48 with renal cell carcinoma and 16 with cisplatin-ineligible urothelial carcinoma. All patients were immunotherapy naive and receiving first-line treatment.

In the melanoma cohort, overall response rate was 85% (n = 11 of 13) for stage 1 and 50% (n = 14 of 28) for stage 2, with a disease control rate of 71% for stage 2.

In the renal cell carcinoma cohort, the ORR was 64% (n = 7 of 11) for stage 1 and 46% (n = 12 of 26) for stage 2, with a disease control rate of 77% in stage 2.

In the urothelial cohort, ORR in stage 1 was 60% (n = 6 of 10) and disease control rate was 70% (n = 7 of 10).

Safety data were evaluable from 283 patients, 14.1% of whom experienced a treatment-related grade 3 or worse adverse event.

Common treatment-related grade 1 to grade 2 events included flu-like symptoms (58.7%), rash (44.5%), fatigue (42%) and pruritus (31.4%).

Discontinuation due to a treatment-related adverse event occurred among six (2.1%) patients.

The combination of NKTR-214 and nivolumab appeared to convert PD-L1-negative tumors to PD-L1-positive tumors. This occurred among nine of 17 (53%) of patients.

Patients who were PD-L1 positive at baseline, or who converted to PD-L1 positivity, had the greatest clinical benefit, Diab said.

A phase 3 registrational trial in first-line advanced melanoma in planned for this year, and pivotal studies also are being designed in renal cell carcinoma and urothelial cancer, Diab said.

“Researching IL-2 pathway agonism and anti-PD-1 in combination may be a key strategy to more effectively activate an antitumor immune response,” Fouad Namouni, MD, head of oncology development at Bristol-Myers Squibb, said in a press release. “These preliminary results from PIVOT are encouraging, particularly in the PD-L1-negative population, and support our belief that that NKTR-214, a CD122 biased IL-2 agonist, in combination with Opdivo can potentially expand the treatment benefits we can bring to patients with cancer.” – by Alexandra Todak

Reference:

Diab A, et al. Abstract 3006. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.

Disclosures: Diab reports consulting/advisory roles with Celgene, CureVac and Nektar, research funding from Celgene, Idera, Nektar and Pfizer, and travel accommodations from Nektar.

CHICAGO — The combination of the CD122-based agonist NKTR-214 with nivolumab appeared well tolerated with promising efficacy among patients with a variety of advanced tumor types, according to preliminary results of the phase 1/phase 2 open-label PIVOT trial presented at ASCO Annual Meeting.

Prespecified efficacy criteria were achieved in three tumor types — first-line melanoma, first-line renal cell carcinoma and first-line urothelial cancer.

NKTR-214 (Nektar) as monotherapy increases newly proliferative CD8+ T cells in tumors and increases cell surface PD-1 and PD-L1 expression, suggesting it may be synergistic with anti-PD-1 therapy such as nivolumab (Opdivo, Bristol-Myers Squibb).

“NKTR-214 is a novel cytokine that enhances signaling through the IL-2 pathway with a unique prodrug design that provides a safety profile that avoids rapid and hyperactive immune stimulation and inflammation that usually is associated with toxicity when giving high-dose IL-2,” Adi Diab, MD, assistant professor in the department of melanoma medical oncology in the division of cancer medicine at The University of Texas MD Anderson Cancer Center, said during his presentation. “The unique prodrug design also allows for administration every 3 weeks, which is very convenient for the patients.”

The trial includes cohorts of patients in various lines of treatment with melanoma, non-small cell lung cancer, urothelial carcinoma, triple-negative breast cancer and renal cell carcinoma.

In the stage 1 dose escalation portion of the trial, patients received NKT-214 in 0.003-mg/kg, 0.006-mg/kg or 0.009-mg/kg doses concurrently with 360 mg nivolumab every 3 weeks.

In the stage 2 expansion, patients received the recommended phase 2 dose of 0.006 mg/kg NKT-214 concurrently with nivolumab.

The study uses a Fleming 2-stage design, which incorporates separate predefined efficacy targets for each tumor type using a historical objective response rate for a single-agent checkpoint inhibitor. Diab presented data from the three cohorts that met the prespecified efficacy criteria, meaning the cohorts could advance to registrational studies. The other cohorts are at various stages of enrollment and have not yet met futility or efficacy criteria.

The analysis included 41 patients with melanoma, 48 with renal cell carcinoma and 16 with cisplatin-ineligible urothelial carcinoma. All patients were immunotherapy naive and receiving first-line treatment.

In the melanoma cohort, overall response rate was 85% (n = 11 of 13) for stage 1 and 50% (n = 14 of 28) for stage 2, with a disease control rate of 71% for stage 2.

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In the renal cell carcinoma cohort, the ORR was 64% (n = 7 of 11) for stage 1 and 46% (n = 12 of 26) for stage 2, with a disease control rate of 77% in stage 2.

In the urothelial cohort, ORR in stage 1 was 60% (n = 6 of 10) and disease control rate was 70% (n = 7 of 10).

Safety data were evaluable from 283 patients, 14.1% of whom experienced a treatment-related grade 3 or worse adverse event.

Common treatment-related grade 1 to grade 2 events included flu-like symptoms (58.7%), rash (44.5%), fatigue (42%) and pruritus (31.4%).

Discontinuation due to a treatment-related adverse event occurred among six (2.1%) patients.

The combination of NKTR-214 and nivolumab appeared to convert PD-L1-negative tumors to PD-L1-positive tumors. This occurred among nine of 17 (53%) of patients.

Patients who were PD-L1 positive at baseline, or who converted to PD-L1 positivity, had the greatest clinical benefit, Diab said.

A phase 3 registrational trial in first-line advanced melanoma in planned for this year, and pivotal studies also are being designed in renal cell carcinoma and urothelial cancer, Diab said.

“Researching IL-2 pathway agonism and anti-PD-1 in combination may be a key strategy to more effectively activate an antitumor immune response,” Fouad Namouni, MD, head of oncology development at Bristol-Myers Squibb, said in a press release. “These preliminary results from PIVOT are encouraging, particularly in the PD-L1-negative population, and support our belief that that NKTR-214, a CD122 biased IL-2 agonist, in combination with Opdivo can potentially expand the treatment benefits we can bring to patients with cancer.” – by Alexandra Todak

Reference:

Diab A, et al. Abstract 3006. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.

Disclosures: Diab reports consulting/advisory roles with Celgene, CureVac and Nektar, research funding from Celgene, Idera, Nektar and Pfizer, and travel accommodations from Nektar.

    Perspective
    Martin E. Gutierrez

    Martin E. Gutierrez

    From this study, two key pieces of information were acquired. One deals with the basic science of immunology. Researchers observed an upregulation of CD8 and natural killer cells in these patients who participated in the trial. Also, PD-L1-negative patients were converted to PD-L1 positive.

    The second important learning is that there was still a differential between PD-L1-positive and PD-L1-negative patients in terms of the response rate. Seemingly, response rates in PD-L1-negative patients rose sequentially with regards to the response rates in the first line of the PD-L1-positive group. Evidently, there is an improvement in response for a checkpoint inhibitor like nivolumab, when combined with the Nektar compound, which makes those patients who were maybe more resistant, perhaps more sensitive to checkpoint inhibition. We do not know if this trend will occur for the other cohorts, where the data has yet to be evaluated, since varying histologies may lead to intrinsic difference in tumor behavior. There are three histologies reported, and they have been trending the same way — with a higher response than typically observed among PD-L1 negative patients. However, it is premature to make this prediction for the other cohorts without definitive data. Also exciting is that even though the response rate has improved, the immune-mediated adverse events are similar to that of monotherapy, which is great for many reasons primarily for patient’s quality of life. Normally, when immunotherapies are combined there is an increase in immune-related adverse events.

    The field has changed tremendously in the last 3 years. Checkpoint inhibitors were being evaluated in the second-line and subsequently first-line therapy for inflamed tumors between 2012 and 2015. There has been rapid development from 2015 to 2018.  The science is focusing directly on finding combinations to manipulate patients with disease that has not responded to checkpoint inhibition. There are different interventions and tactics under evaluation, from combinations with chemotherapy, radiation therapy or molecularly targeted drugs, to manipulating the microenvironment or other immune cells such as the macrophages and natural killer cells, with the goal of overcoming the resistance to checkpoint inhibitors.

    Overall, it is phenomenal to see the Nektar compound in combination with nivolumab enhancing T-cell activity and expression, and it’s fascinating and exciting to witness the shift in expression from PD-L1 negative to positive to potentially improve patient outcomes.

    • Martin E. Gutierrez, MD
    • John Theurer Cancer Center Hackensack University Medical Center

    Disclosures: Gutierrez reports stock and other ownership interests in COTA, consulting/advisory roles with Bayer, Eli Lilly and Karyopharm Therapeutics; speakers bureau roles with Bristol-Myers Squibb, Eli Lilly, Foundation One and Merck; and research funding to his institution from AbbVie, Acceleron Pharma, Bayer, Bayer, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Eisai, EMD Serono, Esanex, Genentech/Roche, Gilead Sciences, Incyte, Karyopharm Therapeutics, Loxo, MedImmune, Merck, Mirati Therapeutics, Moderna Therapeutics, Novartis, Regeneron, Rexahn Pharmaceuticals, Sanofi, Seattle Genetics, Tesaro and TG Therapeutics.

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