In alignment with a new development partner (BMS), the study design, including objectives and endpoints, was modified to evaluate NKTR-214 and nivolumab only. Thus, treatment regimens were revised (eg, removed pembrolizumab and atezolizumab [never opened for enrollment], added an NKTR-214 every 2 week dosing schedule, nivolumab dosing changed from weight-based to a flat 240-mg dose every 2 weeks), the UCC tumor type was removed, and the entry criteria were updated. Decreased the duration of nivolumab infusion. Cohort decisions about timing of enrollment, dose level, and dose frequency would be based on evolving clinical data from an ongoing NKTR-214 monotherapy and nivolumab combination therapy studies conducted by the Sponsor and the development partner, respectively. Dose-limiting toxicitywindows were defined and the end of treatment visit was extended.

Added new immunotherapy naïve cohorts for urothelial carcinoma and triple-negative breast cancer as well as patient populations that were either relapsed or refractory to checkpoint inhibition for the treatment of melanoma, renal cell carcinoma, and non-small cell lung cancer resulting in 8 expansion cohorts across 5 tumor types. Added 3 dose escalation cohorts to evaluate nivolumab at a 360 mg every 3 week dosing schedule. Revised the entry criteria based on feedback from Investigators, Safety Review Committee, and EU requirements; revised the dose-limiting toxicity criteria; added intravenous hydration to Cycle 1 Days 1 and 2 and recommended ≥ 2 L per day of oral hydration on Days 3 to 5 of Cycle 1 and Days 1-5 of Cycle 2 and beyond. Clarified timing of tumor biopsy.

Removed 2 dosing cohorts from Part 1 per FDA guidance: • NKTR-214 0.003 mg/kg every 3 weeks + nivolumab 360 mg every 3 weeks • NKTR-214 0.003 mg/kg every 2 weeks + nivolumab 240 mg every 2 weeks

Added the rationale for the Safety Review Committee-approved recommended Phase 2 dose for Part 2, clarified the entry criteria, and updated the IV hydration guidelines with minimum volume requirements (≥ 1 L) and intravenous hydration on Day 1 of all cycles.

Changed Part 2 cohorts to create more homogenous patient populations and added a new cohort for urothelial carcinoma. Added Part 3 (schedule finding) and Part 4 (dose expansion) to assess the safety, tolerability, and efficacy of the triplet combination (NKTR-214 + nivolumab + ipilimumab) in renal cell carcinoma first-line and non-small cell lung cancer first-line. Thus, the objectives, endpoints, entry criteria, schedule of events, statistical methods (including analysis sets) were updated. Extended the duration of NKTR-214 infusion to reduce the incidence of infusion reactions and increase tolerability, capped the continuation of treatment in patients with confirmed complete response at 2 years, modified the dose-limiting toxicity criteria, updated the reasons for end of treatment, allowed prophylaxis for flu-like symptoms and/or rash/pruritus, and decreased the duration of stable disease for clinical benefit rate to ≥ 7 weeks.

Added 11 cohorts across new and existing tumor types in Part 2, added 5 cohorts (3 non-small cell lung cancer, 2 triple-negative breast cancer) in which the doublet was administered with the chemotherapy, added 5 cohorts to allow for administrative reclassification of previously enrolled patients by the Sponsor, and patient eligibility criteria were adjusted. Added tumor types, associated entry criteria, and dosing schedules for the triplet regimen in Parts 3 and 4. Clarified the exploratory objectives. Added that investigator could administer intravenous fluid on Day 2 of Cycle 2 and beyond if deemed necessary. The following cohorts were closed to enrollment: • Part 2 (n = 7) – Cohorts 1a and 2a (enrolled a sufficient number of patients); Cohorts 1e, 2c, 3i, 4c, and 5d (represent the 5 aforementioned cohorts that were added for administrative reclassification of previously enrolled patients) • Part 4 (n = 1) – Cohort 10a.1

The study was closed to further patient screening and enrollment. All active patients continued treatment and follow-up per protocol. Previously closed cohorts (including some that never enrolled patients, see Section 9.1.2.2) included all cohorts in Part 1; Cohorts 1a, 1b, 2a, 3b, 3f, 3g, 4a, 5a, 7, and 9 in Part 2; schedule 1 renal cell carcinoma (10a.1) in Parts 3 and 4. Several cohorts in Part 2 were previously closed via administrative letter (29 March 2019) because registration would not be pursued (1c, 1d, 6a, 6b, 8a, 8b), enrollment was met (2b, 3c, 4b), or the cohort never opened (9 [clinical study results of nivolumab in SCLC showed no advantage in overall survival]). Part 4 Cohort 12a.3 (melanoma), and Cohorts 5b and 5c were also closed. The protocol was updated with the results of a comprehensive review of cerebrovascular accident-related safety information across the NKTR-214 clinical development program after 3 patients receiving the triplet therapy had serious adverse events (SAEs) of cerebrovascular accident (1 fatal) in the current study. Added safety measures to mitigate the risk of cerebrovascular accident: cerebrovascular accident elevated to adverse event (AE) of special interest; cerebrovascular accident AE management algorithm to evaluate cardiac and neurologic events and provide a standard set of tests for evaluation and follow-up of cerebrovascular accident events; and implemented preventative measures (eg, increased monitoring of renal function; delay treatment if renal parameters not met; and contact patients after Cycles 1 and 2 to reinforce hydration guidelines and assess for symptomatology and compliance). Redefined required reporting period for AEs and SAEs as the time of first study drug(s) administration until 100 days after the last dose of all study drug(s).