Stephanie Anne Kronenberg

BACKGROUND: In patients with melanoma, ipilimumab (an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) prolongs overall survival, and nivolumab (an antibody against the programmed death 1 [PD-1] receptor) produced durable tumor regression in a phase 1 trial. On the basis of their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in patients with advanced melanoma. METHODS: We administered intravenous doses of nivolumab and ipilimumab in patients every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). The combined treatment was subsequently administered every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses. RESULTS: A total of 53 patients received concurrent therapy with nivolumab and ipilimumab, and 33 received sequenced treatment. The objective-response rate (according to modified World Health Organization criteria) for all patients in the concurrent-regimen group was 40%. Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was observed in 65% of patients. At the maximum doses that were associated with an acceptable level of adverse events (nivolumab at a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram), 53% of patients had an objective response, all with tumor reduction of 80% or more. Grade 3 or 4 adverse events related to therapy occurred in 53% of patients in the concurrent-regimen group but were qualitatively similar to previous experience with monotherapy and were generally reversible. Among patients in the sequenced-regimen group, 18% had grade 3 or 4 adverse events related to therapy and the objective-response rate was 20%. CONCLUSIONS: Concurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; ClinicalTrials.gov number, NCT01024231.).

LBA9003^ Background: We report updated survival and clinical activity in initially enrolled cohorts and activity by BRAF MT status in a phase I trial of concurrent and sequenced NIVO + IPI. Methods: MEL pts (n=53, enrolled 2009-2012, data analysis Dec 2013) with ≤3 prior therapies received IV concurrent NIVO + IPI, Q3Wk × 4 doses, followed by NIVO Q3Wk × 4. At wk 24, NIVO + IPI continued Q12Wk × 8 in pts with disease control and no DLT. Tumor responses were evaluated by WHO and immune-related criteria. Results: Pt characteristics included stage M1c: 55% and prior systemic therapy: 40%. Across doses, 1- and 2-y OS rates were 82% and 75%. Clinical activity was similar to previous reports except CRs rose to 9/53 (17%). Pts with/without tumor BRAF MT (n=36) had similar activity (Table). By wk 36, 42% demonstrated ≥80% tumor reduction. Median duration of response (DOR) was not reached (NR). Of 22 pts with objective response, 14 (64%) had DOR ≥24 wk (range: 25+, 106+). Treatment-related adverse events were as reported previously: grade 3-4, 53% of pts; most common: ↑ lipase and AST (13% ea). Data for sequenced cohorts are shown (Table). Conclusions: Concurrent NIVO + IPI therapy showed encouraging survival and a manageable safety profile in advanced MEL pts. Responses were observed regardless of BRAF MT status and were durable in the majority of pts. Forty additional pts were enrolled (last pt: Nov 2013) on a cohort of NIVO 1 mg/kg + IPI 3 mg/kg Q3Wk × 4 doses, followed by NIVO 3mg/kg Q2Wk (the selected regimen for phase II/III trials). Clinical trial information: NCT01024231. NIVO (mg/kg) + IPI (mg/kg) [n] 1-Y OS rate, % [pts at risk] Median OS, mo ACAR, % ACAR by BRAF MT status,* % [n] Pos Neg Unk 0.3 + 3 [14] 56 [7] 14.8 57 50 [4] 67 [3] 57 [7] 1 + 3 [17] 94 [13] NR 65 50 [2] 50 [6] 78 [9] 3 + 1 [16] 89 [3] NR 81 67 [3] 85 [13] – [0] 3 + 3 [6] 100 [5] NR 83 100 [1] 75 [4] 100 [1] Concurrent [53] 82 [28] 39.7 70 60 [10] 73 [26] 71 [17] Sequenced† [32] Insufficient followup 13.0 44 44 [9] 47 [15] 38 [8] n: no. response-evaluable pts. ACAR: aggregate clinical activity rate = CR+PR+uCR+uPR+irCR+irPR+SD ≥24 wk+ irSD ≥24 wk. *Retrospective analysis. †Pts began NIVO Q2Wk × 48 doses within 4-12 wk after last IPI dose.

LBA9003^ Background: We report updated survival and clinical activity in initially enrolled cohorts and activity by BRAF MT status in a phase I trial of concurrent and sequenced NIVO + IPI. Methods: MEL pts (n=53, enrolled 2009-2012, data analysis Dec 2013) with ≤3 prior therapies received IV concurrent NIVO + IPI, Q3Wk × 4 doses, followed by NIVO Q3Wk × 4. At wk 24, NIVO + IPI continued Q12Wk × 8 in pts with disease control and no DLT. Tumor responses were evaluated by WHO and immune-related criteria. Results: Pt characteristics included stage M1c: 55% and prior systemic therapy: 40%. Across doses, 1- and 2-y OS rates were 82% and 75%. Clinical activity was similar to previous reports except CRs rose to 9/53 (17%). Pts with/without tumor BRAF MT (n=36) had similar activity (Table). By wk 36, 42% demonstrated ≥80% tumor reduction. Median duration of response (DOR) was not reached (NR). Of 22 pts with objective response, 14 (64%) had DOR ≥24 wk (range: 25+, 106+). Treatment-related adverse events were as reported previously: grade 3-4, 53% of pts; most common: ↑ lipase and AST (13% ea). Data for sequenced cohorts are shown (Table). Conclusions: Concurrent NIVO + IPI therapy showed encouraging survival and a manageable safety profile in advanced MEL pts. Responses were observed regardless of BRAF MT status and were durable in the majority of pts. Forty additional pts were enrolled (last pt: Nov 2013) on a cohort of NIVO 1 mg/kg + IPI 3 mg/kg Q3Wk × 4 doses, followed by NIVO 3mg/kg Q2Wk (the selected regimen for phase II/III trials). Clinical trial information: NCT01024231. [Table: see text]

3007 Background: 4-1BB agonists markedly enhance cytotoxic T-cell responses, resulting in anti-tumor activity in several models. PF-05082566 is a fully humanized IgG2 agonist monoclonal antibody targeting 4-1BB.This portion of the first-in-human phase I study assessed the safety, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of PF-0508256 monotherapy in patients with advanced cancer. Methods: An open-label, dose escalation study was conducted in patients with advanced malignancies for which no curative therapy was available. Cohorts of 3-6 patients were enrolled initially using a 3+3 design (0.006 to 0.3 mg/kg), then a Time-To-Event CRM design for higher doses (0.6 to 5 mg/kg). Patients received PF-05082566 via intravenous infusion every 4 weeks (one cycle) with an 8 week period for assessment of dose-limiting toxicity (DLT). Radiographic assessments were conducted every 8 weeks, using RECIST 1.1. Results: 27 patients have been treated with PF-05082566 up to the 0.3 mg/kg dose level, including colorectal cancer (n=11), Merkel cell carcinoma (n=6), pancreatic adenocarcinoma (n=2), and one each of nasopharyngeal cancer, ampullary cancer, squamous cell lung cancer, carcinoma of unknown primary, melanoma, sarcoma, follicular lymphoma, and lymphocytic lymphoma (SLL). 25 patients completed the DLT assessment period and 7 patients remain on therapy. All discontinuations from treatment were due to disease progression. Median number of cycles ranged from 2 (at 0.006 mg/kg) to 7 (at 0.24 mg/kg). There was no apparent relationship between increasing doses and the frequency or severity of treatment emergent adverse events, which were mostly Grade 1. One patient treated at 0.06 mg/kg had Grade 3 elevation in alkaline phosphatase. No additional significant elevations in liver enzymes and no DLTs have occurred to date. Preliminary PK data suggests a linear increase in drug exposure with increasing dose, and a half life of ~10 days. A best overall response of stable disease was observed in 22% (6/27) patients. Conclusions: PF-05082566 was well tolerated, with evidence of disease stabilization in multiple patients. Enrollment continues at higher dose levels to obtain additional safety, PK, PD, and efficacy data. Clinical trial information: NCT01307267.

9012^ Background: CTLA-4 and PD-1 are critical immune checkpoint receptors. In MEL pts, ipilimumab (anti-CTLA-4) prolonged survival in two phase III trials, and nivolumab (anti-PD-1) produced an objective response rate (ORR) of 31% (n=106) in a phase I trial. PD-1 is induced by CTLA-4 blockade, and combined blockade of CTLA-4/PD-1 showed enhanced antitumor activity in murine models. Thus, we initiated the first phase 1 study to evaluate nivolumab/ipilimumab combination therapy. Methods: MEL pts with ≤3 prior therapies received IV nivolumab and ipilimumab concurrently, q3 wk × 4 doses, followed by nivolumab alone q3 wk × 4 (Table). At wk 24, combined treatment was continued q12 wk × 8 in pts with disease control and no DLT. In two sequenced-regimen cohorts, pts with prior standard ipilimumab therapy were treated with nivolumab (q2 wk × 48). Results: As of Dec. 6, 2012, 69 pts were treated. We report efficacy data on 37 pts with concurrent therapy in completed cohorts 1-3 (Table); ORR was 38% (95% CI: 23-55). In cohort 2 (MTD), ORR was 47% and 41% of pts had ≥80% tumor reduction at 12 wk (Table) with some pts showing rapid responses, prompt symptom resolution, and durable CRs. Related adverse events (rAEs) for concurrent therapy were similar in nature with some higher in frequency than those typically seen for the monotherapies and were generally manageable using immunosuppressants. Cohort 3 exceeded the MTD (DLT: gr 3-4 ↑ lipase). At the MTD, gr 3-4 rAEs occurred in 59% of pts and included uveitis/choroiditis, colitis, and reversible lab abnormalities. Conclusions: Nivolumab and ipilimumab can be combined with a manageable safety profile. Clinical activity for concurrent therapy appears to exceed that of published monotherapy data, with rapid and deep tumor responses (≥80% tumor reduction at 12 wk) in 30% (11/37) of pts. A phase III trial is planned to compare concurrent combination dosing with each monotherapy. Clinical trial information: NCT01024231. [Table: see text]