Raid Aljumaily

Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial

BACKGROUNDnThe approval of anti-programmed death ligand 1 (PD-L1) and anti-programmed death 1 agents has expanded treatment options for patients with locally advanced or metastatic urothelial carcinoma. Avelumab, a human monoclonal anti-PD-L1 antibody, has shown promising antitumour activity and safety in this disease. We aimed to assess the safety profile in patients (both post-platinum therapy and cisplatin-naive) treated with avelumab and to assess antitumour activity of this drug in post-platinum patients.nnnMETHODSnIn this pooled analysis of two cohorts from the phase 1 dose-expansion JAVELIN Solid Tumor study, patients aged 18 years and older with histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma that had progressed after at least one previous platinum-based chemotherapy were enrolled from 80 cancer treatment centres or hospitals in the USA, Europe, and Asia. Eligible patients had adequate end-organ function, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and at least one measurable lesion. Cisplatin-ineligible patients who might have been previously treated in the perioperative setting, including platinum-naive patients, were also eligible. Patients unselected for PD-L1 expression received avelumab (10 mg/kg, 1 h intravenous infusion) every 2 weeks until confirmed disease progression, unacceptable toxicity, or other criterion for withdrawal. The primary endpoint for this efficacy expansion cohort was confirmed best overall response (according to RECIST version 1.1), adjudicated by independent review. Safety analysis was done in all patients who received at least one dose of avelumab. Antitumour activity was assessed in post-platinum patients who received at least one dose of avelumab. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort of patients with metastatic urothelial carcinoma is closed and the trial is ongoing.nnnFINDINGSnBetween Sept 3, 2014, and March 15, 2016, 329 patients with advanced metastatic urothelial carcinoma were screened for enrolment into this study; 249 patients were eligible and received treatment with avelumab for a median of 12 weeks (IQR 6·0-19·7) and followed up for a median of 9·9 months (4·3-12·1). Safety and antitumour activity were evaluated at data cutoff on June 9, 2016. In 161 post-platinum patients with at least 6 months of follow-up, a best overall response of complete or partial response was recorded in 27 patients (17%; 95% CI 11-24), including nine (6%) complete responses and 18 (11%) partial responses. The most frequent treatment-related adverse events (any grade in ≥10% patients) were infusion-related reaction (73 [29%]; all grade 1-2) and fatigue (40 [16%]). Grade 3 or worse treatment-related adverse events occurred in 21 (8%) of 249 patients, the most common of which were fatigue (four [2%]), and asthenia, elevated lipase, hypophosphataemia, and pneumonitis in two (1%) patients each. 19 (8%) of 249 patients had a serious adverse event related to treatment with avelumab, and one treatment-related death occurred (pneumonitis).nnnINTERPRETATIONnAvelumab showed antitumour activity in the treatment of patients with platinum-refractory metastatic urothelial carcinoma; a manageable safety profile was reported in all avelumab-treated patients. These data provide the rationale for therapeutic use of avelumab in metastatic urothelial carcinoma and it has received accelerated US FDA approval in this setting on this basis.nnnFUNDINGnMerck KGaA, and Pfizer Inc.

Abstract CT074: Non-comparative, open-label, multiple cohort, phase 1/2 study to evaluate nivolumab (NIVO) in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in Merkel cell carcinoma (MCC)

Background: NIVO (anti-PD-1) is approved for the treatment of several cancers including advanced melanoma, but its efficacy in other types of skin cancer has not yet been evaluated. MCC is a rare and aggressive form of skin cancer, with most tumors being associated with the Merkel cell polyomavirus. MCCs frequently express PD-L1, and MCC-reactive T cells express PD-1. Methods: In CheckMate 358 (NCT02488759), patients (pts) with 5 types of advanced virus-associated cancers who had received ≤2 prior therapies, with an ECOG PS of 0-1, were eligible to receive NIVO 240 mg Q2W until progression or unacceptable toxicity. Key exclusion criteria were active brain metastases, autoimmune disease, hepatitis, and HIV infection. Primary endpoints included objective response rate (ORR by RECIST v1.1) and safety; secondary endpoints were duration of response, progression-free survival (PFS), and overall survival (OS). Twenty-five pts with MCC were treated with a median follow-up of 26 wks (range: 5-35). Results: Among 25 treated pts, median age was 66 yrs, 68% were male, and 60% were treatment-naive; 12 of 18 (67%) tested tumors were virus-positive. In 22 response-evaluable pts, ORR was 68% (table) with ongoing responses in 13 of 15 (87%) pts. Responses occurred in treatment-naive pts (71%), in pts with 1-2 prior systemic therapies (63%), and in both virus-positive and virus-negative tumors; 67% of responses occurred at ~8 weeks. At 3 months, PFS and OS rates were 82% and 92%, respectively. Treatment-related adverse events of any grade and grade 3/4 occurred in 68% and 20% of pts; 12% of pts had treatment-related AEs that led to NIVO discontinuation. Conclusions: NIVO induces rapid and durable tumor regressions in the majority of treatment-naive and treatment-experienced pts with advanced MCC, with a manageable safety profile. Updated clinical response and biomarker data will be presented. Citation Format: Suzanne L. Topalian, Shailender Bhatia, Antoine Hollebecque, Ahmad Awada, Jan Paul De Boer, Ragini R. Kudchadkar, Anthony Goncalves, Jean-Pierre Delord, Uwe M. Martens, Jose Maria Lopez Picazo, Ana Oaknin, William C. Spanos, Raid Aljumaily, William H. Sharfman, Shangbang Rao, Ibrahima Soumaoro, Alexander Cao, Paul Nghiem, Dirk Schadendorf. Non-comparative, open-label, multiple cohort, phase 1/2 study to evaluate nivolumab (NIVO) in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in Merkel cell carcinoma (MCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT074. doi:10.1158/1538-7445.AM2017-CT074

A first-in-human phase 1a study of the bispecific anti-DLL4/anti-VEGF antibody navicixizumab (OMP-305B83) in patients with previously treated solid tumors

SummaryPurpose Navicixizumab (OMP-305B83) is a bispecific antibody that inhibits delta-like ligand 4 and vascular endothelial growth factor. This Phase 1a trial assessed escalating doses of navicixizumab in refractory solid tumors patients. Design A 3u2009+u20093 dose escalation design was used followed by the treatment of additional patients in an expansion cohort. Study objectives were determination of the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics, immunogenicity and efficacy. Results Sixty-six patients were treated once every 3xa0weeks in 8 dose-escalation cohorts (0.5, 1, 2.5, 3.5, 5, 7.5, 10, and 12.5xa0mg/kg) and an expansion cohort (7.5xa0mg/kg). The median age was 60xa0years and 68% of the patients were female. The most commonly enrolled tumor types were ovarian (12), colorectal (11) and breast, pancreatic, uterine and endometrial (4 each) cancers. As only 1 dose limiting toxicity occurred, the maximum tolerated dose was not reached, but 7.5xa0mg/kg was chosen as the dose for the expansion cohort. The treatment related adverse events (≥15% of patients) were hypertension (57.6%), headache (28.8%), fatigue (25.8%), and pulmonary hypertension (18.2%). Pulmonary hypertension was mostly asymptomatic at doses ≤5xa0mg/kg (6 Gr1, 1 Gr2), but was more severe at higher doses (4 Gr2, 1 Gr3). Navicixizumab’s half-life was 11.4xa0days and there was a moderate (29%) incidence of anti-drug antibody formation. Four patients (3 ovarian cancer, 1 uterine carcinosarcoma) had a partial response and 17 patients had stable disease. Nineteen patients had a reduction in the size of their target lesions including 7/11 patients with ovarian cancer. Four patients remained on study for >300xa0days and 2 of these patients were on study for >500xa0days. Conclusions Navicixizumab can be safely administered with manageable toxicities and these data showed preliminary signs of antitumor activity in multiple tumor types, but was most promising in ovarian cancer. As a result these data justify its continued development in combination Phase 1b clinical trials.

Abstract CT046: A phase I basket study of the PI3K inhibitor taselisib (GDC-0032) in PIK3CA-mutated locally advanced or metastatic solid tumors

Background:PIK3CA, a gene that encodes the α-isoform of the catalytic subunit of Class I PI3K (PI3Kα), is frequently mutated or amplified in solid tumors. Taselisib is an oral, potent, selective inhibitor of Class I PI3Kα, γ, and δ isoforms with enhanced activity against PIK3CA-mutated cancer models. Preclinical and clinical data demonstrated that single-agent taselisib has activity in multiple PIK3CA-mutated tumor types. Methods: This open-label phase I study (Cohort X of PMT4979g; NCT01296555) enrolled patients (pts) with PIK3CA-mutated tumors who had progressed after, or failed to respond to, at least one prior treatment regimen and were not candidates for regimens known to provide clinical benefit. Pts received single-agent taselisib (4 or 6 mg tablet, daily). Eleven subcohorts comprised various solid tumor types: endometrial, bladder, head and neck squamous cell carcinoma (HNSCC), cervical, gastric/gastroesophageal junction, small cell lung, triple-negative breast, colorectal (excluding KRAS-mutated tumors), squamous (excluding histologies in the other subcohorts), ovarian, and pts with PIK3CA mutant tumors not otherwise specified (excluding breast, colorectal, and non-small-cell lung cancers). Tumor tissue (archival or fresh) was assessed centrally for PIK3CA mutation or amplification. The primary endpoint was tolerability and safety of taselisib. Other endpoints included assessment of antitumor activity per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. Results: At data cutoff (May 1, 2017), 146 pts have been enrolled. Overall, the most common adverse events (AEs; ≥30% of pts) were diarrhea (58.2%), nausea (39.0%), hyperglycemia (31.5%), and fatigue (30.8%). Ninety-four pts (64.4%) experienced ≥1 grade ≥3 AE and 53 pts (36.3%) had grade ≥3 AEs related to taselisib. Sixty-eight pts (46.6%) had serious AEs (SAEs) and the most common SAEs (>2 pts) related to taselisib treatment were colitis (5.5%), diarrhea (4.1%), and hyperglycemia (3.4%). Nine pts (6.2%) had grade 5 events; one AE with a fatal outcome (0.7%) was assessed by the investigator as related to taselisib (septic shock). AEs that led to dose reduction, interruption, or withdrawal were reported in 34 pts (23.3%), 59 pts (40.4%), and 14 pts (9.6%), respectively. Overall, confirmed response rates were 8.9% (n=13) and clinical benefit rates (confirmed response or without disease progression for ≥6 months) were 12.3% (n=18). Confirmed responses were observed in pts with endometrial cancer (2/10 [20.0%]), HNSCC (4/21 [19.0%]), and cervical cancer (2/19 [10.5%]), as well as other tumor types. Conclusions: Single-agent taselisib had an acceptable safety profile (with AEs that were generally reversible and manageable; no new safety signals were identified) and preliminary clinical activity in pts with PIK3CA-mutated locally advanced or metastatic solid tumors. Citation Format: Komal Jhaveri, Dejan Juric, Cristina Saura, Andres Cervantes, Anton Melnyk, Manish R. Patel, Mafalda Oliveira, Valentina Gambardella, Vincent Ribrag, Cynthia X. Ma, Raid Aljumaily, Philippe L. Bedard, Jasgit C. Sachdev, John Bond, Surai Jones, Timothy R. Wilson, Michael C. Wei, Jose Baselga. A phase I basket study of the PI3K inhibitor taselisib (GDC-0032) in PIK3CA-mutated locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT046.

1316PEfficacy and immune activation with PEGylated human IL-10 (AM0010) in combination with an anti-PD1 in advanced NSCLC: Update

At therapeutic concentrations, AM0010 stimulates the cytotoxicity, survival and proliferation of intratumoral antigen activated CD8+ T cells in pre-clinical cancer models and in patients. AM0010 activates antigen stimulated CD8 T cells while PD-1 inhibits them. This provides the rationale for combining AM0010 and an anti-PD1. AM0010 monotherapy induced durable objective responses in ocular melanoma and renal cell cancer. AM0010 alone or in combination with chemotherapy and anti-PD1 has been well tolerated in this Phase 1 basket trial. Efficacy and Immune Activation with PEGylated human IL-10 (AM0010) in Combination with an anti-PD1 in Advanced NSCLC Update