Kent C. Shih

Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial

BACKGROUND Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy. METHODS In this multicentre, international, prospective, single-group, open-label, phase 2 trial, patients with stage IV chemotherapy-refractory, histologically confirmed Merkel cell carcinoma (aged ≥18 years) were enrolled from 35 cancer treatment centres and academic hospitals in North America, Europe, Australia, and Asia. Key eligibility criteria were an ECOG performance status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate haematological, hepatic, and renal function, and immune-competent status (patients with HIV, immunosuppression, haematological malignancies, and previous organ transplantation were excluded). Patient selection was not based on PD-L1 expression or Merkel cell polyomavirus status. Collection of biopsy material or use of archival tissue for these assessments was mandatory. Avelumab was given intravenously at a dose of 10 mg/kg every 2 weeks. The primary endpoint was confirmed objective response (complete response or partial response) assessed according to RECIST version 1.1 by an independent review committee. Safety and clinical activity were assessed in all patients who received at least one dose of study drug (the modified intention-to-treat population). This trial is registered with ClinicalTrials.gov as NCT02155647. FINDINGS Between July 25, 2014, and Sept 3, 2015, 88 patients were enrolled and received at least one dose of avelumab. Patients were followed up for a median of 10·4 months (IQR 8·6-13·1). The proportion of patients who achieved an objective response was 28 (31·8% [95·9% CI 21·9-43·1]) of 88 patients, including eight complete responses and 20 partial responses. Responses were ongoing in 23 (82%) of 28 patients at the time of analysis. Five grade 3 treatment-related adverse events occurred in four (5%) patients: lymphopenia in two patients, blood creatine phosphokinase increase in one patient, aminotransferase increase in one patient, and blood cholesterol increase in one patient; there were no treatment-related grade 4 adverse events or treatment-related deaths. Serious treatment-related adverse events were reported in five patients (6%): enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis (n=1 each). INTERPRETATION Avelumab was associated with durable responses, most of which are still ongoing, and was well tolerated; hence, avelumab represents a new therapeutic option for advanced Merkel cell carcinoma. FUNDING Merck KGaA, Darmstadt, Germany.

Clinical impact of checkpoint inhibitors as novel cancer therapies.

Immune responses are tightly regulated via signaling through numerous co-stimulatory and co-inhibitory molecules. Exploitation of these immune checkpoint pathways is one of the mechanisms by which tumors evade and/or escape the immune system. A growing understanding of the biology of immune checkpoints and tumor immunology has led to the development of monoclonal antibodies designed to target co-stimulatory and co-inhibitory molecules in order to re-engage the immune system and restore antitumor immune responses. Anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies were among the first to be tested in the clinic, and ipilimumab was the first immune checkpoint inhibitor approved for an anticancer indication. Agents targeting the programmed death 1 (PD-1) pathway, either PD-1 or one of its ligands, programmed death ligand 1, are in active clinical development for numerous cancers, including advanced melanoma and lung cancer. Understanding the different mechanisms of action, safety profiles, and response patterns associated with inhibition of the CTLA-4 and PD-1 pathways may improve patient management as these therapies are moved in to the clinical practice setting and may also provide a rationale for combination therapy with different inhibitors. Additional immune checkpoint molecules with therapeutic potential, including lymphocyte activation gene-3 and glucocorticoid-induced tumor necrosis factor receptor-related gene, also have inhibitors in early stages of clinical development. Clinical responses and safety data reported to date on immune checkpoint inhibitors suggest these agents may have the potential to markedly improve outcomes for patients with cancer.

A phase I dose-escalation study to assess safety, tolerability, pharmacokinetics, and preliminary efficacy of the dual mTORC1/mTORC2 kinase inhibitor CC-223 in patients with advanced solid tumors or multiple myeloma

The mammalian target of rapamycin (mTOR) pathway is essential for tumor development, yet mTOR inhibitors have yielded modest results. This phase 1 study investigated the mTORC1/mTORC2 inhibitor CC‐223 in patients with advanced cancer.

Abstract CT079: Durable responses to avelumab (anti-PD-L1) in patients with Merkel cell carcinoma progressed after chemotherapy: 1-year efficacy update

Background: Merkel cell carcinoma (MCC), a rare, aggressive skin cancer, is a chemosensitive disease, but responses are seldom durable. Avelumab is a fully human anti-PD-L1 monoclonal antibody. In a phase 2 trial of avelumab in patients with previously treated metastatic MCC (mMCC), the objective response rate (ORR) after ≥6 months of follow-up was 31.8%, including complete response (CR) in 9.1%, the estimated proportion with duration of response (DOR) ≥6 months was 92%, and the 6-month progression-free survival (PFS) rate was 40% (95% CI 29-50) (Kaufman et al., Lancet Oncol 2016). Here we present updated efficacy data with ≥1 year of follow-up in all patients. Methods: Patients with distant mMCC and prior progression on chemotherapy received avelumab 10 mg/kg IV Q2W until confirmed progression, unacceptable toxicity, or withdrawal. Tumors were assessed every 6 weeks (RECIST v1.1 by independent review). ORR, DOR, PFS, and overall survival (OS) were evaluated. Time-to-event endpoints were analyzed using Kaplan-Meier methodology. Safety data were not analyzed for this update. Results: Patients with mMCC (N=88) were treated with avelumab. Median age was 72.5 years (range 33-88), and 53% had visceral disease. As of Sep 3, 2016, median follow-up was 16.4 months (range 12.0-25.3), and treatment was ongoing in 22% (n=19); main reasons for discontinuations were disease progression (n=44; 50%), death (n=7; 8%), adverse event (n=7; 8%), or withdrawal (n=4; 5%). ORR was 33.0% (95% CI 23.3-43.8) with 10 (11.4%) CRs and 19 (21.6%) partial responses, including 1 new CR and 1 patient improving from PR to CR since the 6-month analysis. The 6-month durable response rate was 30.6% (95% CI 20.9-40.3). Median DOR has not been reached (range 2.8-23.3+ months; 95% CI 18.0-not estimable), and responses were ongoing in 21/29 patients (72.4%) at the time of analysis. The estimated proportion of responders with ≥1-year duration of response was 74% (95% CI 53-87). Estimated 1-year PFS rate was 30% (95% CI 21-41) and 1-year OS rate was 52% (95% CI 41-62). Median OS was 12.9 months (95% CI 7.5-not estimable). Conclusion: In longer-term follow-up from this study of avelumab in patients with distant metastatic MCC progressed after chemotherapy, the majority of responses were durable beyond 1 year and 2 new CRs were reported. Maturing PFS and OS data suggest long-term benefit in a proportion of patients. Clinical trial information: NCT02155647. Citation Format: Howard L. Kaufman, Jeffery S. Russell, Omid Hamid, Shailender Bhatia, Patrick Terheyden, Sandra P. D’Angelo, Kent C. Shih, Celeste Lebbe, Michele Milella, Isaac Brownell, Karl D. Lewis, Jochen H. Lorch, Anja von Heydebreck, Lisa Mahnke, Paul Nghiem. Durable responses to avelumab (anti-PD-L1) in patients with Merkel cell carcinoma progressed after chemotherapy: 1-year efficacy update [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 CT079. doi:10.1158/1538-7445.AM2017-CT079

A Phase II Study of the Combination of Bevacizumab, Pertuzumab, and Octreotide LAR for Patients with Advanced Neuroendocrine Cancers

ABSTRACT Purpose: To evaluate efficacy and safety of bevacizumab, pertuzumab, and octreotide depot for advanced neuroendocrine tumors. Methods: Patients received bevacizumab 15 mg/kg and pertuzumab 420 mg IV q21 days with octreotide depot 30 mg IM q28 days. Results: Toxicities in 43 patients included diarrhea (63%), fatigue (63%), hypertension (44%), and nausea (44%). Reversible G3 hypertension (26%) and LVEF decline (9%) occurred. 7/43 patients achieved objective response (typical carcinoid, 5; pancreatic NET, 2). Median PFS and OS were 6.5 and 26.4 months, respectively. Discussion: Bevacizumab, pertuzumab, and octreotide depot was well-tolerated with a 16% ORR. Results in the well-differentiated carcinoid tumors are thought provoking.

Phase II trial of preoperative pemetrexed plus carboplatin in patients with stage IB-III nonsquamous non-small cell lung cancer (NSCLC)

OBJECTIVES The combination of pemetrexed and carboplatin is a standard first-line treatment for patients with advanced NSCLC. In this pilot phase II trial, we evaluated the feasibility of using pemetrexed and carboplatin as neoadjuvant therapy, prior to definitive surgical resection, for patients with localized NSCLC. PATIENTS AND METHODS Patients with potentially resectable, previously untreated, clinical stage IB-III, nonsquamous NSCLC were eligible for this trial. All patients received 4 cycles of pemetrexed (500 mg/m2) and carboplatin (AUC 6.0) administered at 21 day intervals. Three to 6 weeks after completion of chemotherapy, definitive surgical resection was attempted. The primary endpoint of this trial was the 3-year survival rate. RESULTS Forty-six patients began protocol treatment, and 40 completed 4 courses of pemetrexed/carboplatin. Surgical resection was performed in 27 patients (59%); all had pathologic partial responses. The estimated 3-year survival rate for the entire group was 46%. Toxicity of neoadjuvant therapy was consistent with toxicity previously reported with pemetrexed/carboplatin. CONCLUSIONS Administration of 4 courses of pemetrexed/carboplatin was feasible. The efficacy was similar to neoadjuvant regimens previously investigated. A significant number of patients 19 of 46 (41%) in this trial did not have surgical resection after neoadjuvant therapy. Further investigation of the role of neoadjuvant pemetrexed/carboplatin requires a larger, randomized clinical trial.

Erlotinib plus either pazopanib or placebo in patients with previously treated advanced non-small cell lung cancer: A randomized, placebo-controlled phase 2 trial with correlated serum proteomic signatures: Erlotinib/Pazopanib for Advanced NSCLC

This study compared the efficacy and safety of treatment with erlotinib plus pazopanib versus erlotinib plus placebo in patients with previously treated advanced non–small cell lung cancer (NSCLC).

Sorafenib and continued erlotinib or sorafenib alone in patients with advanced non-small cell lung cancer progressing on erlotinib: A randomized phase II study of the Sarah Cannon Research Institute (SCRI)

PURPOSE To evaluate the efficacy of erlotinib, continued after tumor progression, plus sorafenib versus sorafenib alone in patients with refractory metastatic non-small cell lung cancer (NSCLC) who previously benefitted from single-agent erlotinib. PATIENTS AND METHODS Patients with progressive refractory NSCLC who had previously benefitted from erlotinib (objective response or stable disease >8weeks) were randomized to receive treatment with either erlotinib and sorafenib (400mg orally twice daily) or sorafenib alone. Patients were evaluated for response every 8 weeks, and continued treatment until disease progression or intolerable toxicity. RESULTS Fifty-three patients were randomized (erlotinib/sorafenib, 25; sorafenib, 28) and 52 patients received study treatment. Patients in both groups received a median of 8weeks of treatment. The median PFS was 3.1months for erlotinib/sorafenib versus 1.7months for sorafenib alone; response rates were 8% and 4%, respectively. Both regimens were tolerable, but toxicity was more frequent with erlotinib/sorafenib. CONCLUSIONS These results do not suggest any benefit in continuing erlotinib after tumor progression in patients with refractory metastatic NSCLC. Both regimens tested had limited efficacy, consistent with results from other studies. ClinicalTrials.gov ID:NCT00609804.

Abstract CT074: Phase I/II study of VAL-083 in patients with recurrent glioblastoma

Glioblastoma (GBM) is the most common brain cancer. Front-line systemic therapy with temozolomide (TMZ) is often ineffective due to O6-methylguanine-DNA-methyltransferase (MGMT)-mediated resistance and patients with recurrent glioma have limited treatment options and very poor prognosis. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent that readily crosses the blood-brain barrier and has demonstrated activity against GBM in prior NCI-sponsored clinical trials. VAL-083 induces cross-links at N7 of guanine causing double-strand DNA breaks and apoptosis independent of MGMT expression against multiple GBM cell lines and cancer stem cells in vitro. VAL-083 cytotoxic activity also appears to be less dependent on wild type p53 compared to other alkylating agents. The main goal of this clinical trial was to determine an appropriate dose for VAL-083 for advancement to Phase II/III trials as a potential new treatment for refractory GBM. METHOD: Open-label, single-arm Phase I dose-escalation study (3+3 design) of IV treatment with VAL-083 on days 1, 2, 3 of a 21-day cycle, until MTD was reached. In Phase II, additional patients with GBM are treated at the MTD to gather further safety and outcomes data. Patients must have histologically confirmed GBM, previously treated with surgery and radiation and must have failed both TMZ and bevacizumab, unless contraindicated. RESULTS: Phase I has been completed and 40 mg/m2/d confirmed as the MTD. 29 GBM patients were enrolled in Phase I across 9 dose cohorts (1.5 - 50 mg/m2/d). Myelosuppression was mild; no drug-related serious adverse events were reported at doses ?40 mg/m2/d. Dose limiting toxicities (DLT), consisting of thrombocytopenia, were observed at 50 mg/m2/d and at an interim 45 mg/m2/d cohort. Platelet nadir occurred around day 20 and resolved rapidly and spontaneously. Pharmacokinetic analyses show dose-dependent linear systemic exposure with a short 1-2h plasma terminal half-life; average Cmax 781 ng/mL (5.3μM) at 40 mg/m2/d resulting in estimated CNS concentrations within the IC50 range observed for GBM cell-lines in vitro. A 14 patient Phase II expansion cohort was enrolled at 40 mg/m2/d. Safety observations in the Phase II expansion cohort to date are consistent with Phase I: Observed myelosuppression is mild, with the exception of 1 patient previously treated with CCNU who developed grade 4 thrombocytopenia. To date, 20 GBM patients (6 patients in Phase I and 14 patients in Phase II) have been treated with VAL-083 at therapeutic doses of 30 or 40 mg/m2/d. CONCLUSIONS: VAL-083 at 40 mg/m2/d on days 1, 2, 3 of a 21-day cycle exhibits a favorable safety profile and the Phase I part of the study showed a trend toward clinically meaningful improved survival in refractory GBM patients. Updated safety and outcomes data from the Phase II expansion cohort will be presented. ClinicalTrials.gov Identifier NCT01478178. Citation Format: Kent C. Shih, Manish R. Patel, Nicholas Butowski, Gerald S. Falchook, Sani H. Kizilbash, Jeffrey A. Bacha, Dennis M. Brown, Anne Steino, Richard Schwartz, Sarath Kanekal, Lorena M. Lopez, Howard A. Burris. Phase I/II study of VAL-083 in patients with recurrent glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT074.

Abstract CT404: Phase I/II study of VAL-083 in patients with recurrent glioblastoma multiforme

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Median survival for patients with recurrent glioblastoma multiforme (GBM) is less than 6 months. Front-line systemic therapy is temozolomide, but chemo-resistance due to O6-methylguanine-DNA-methyltransferase (MGMT) activity has been implicated in poor outcomes. VAL-083 is a structurally unique bi-functional DNA alkylating small molecule drug that crosses the blood-brain barrier and accumulates in brain tumor tissue. Previous human clinical studies by several investigators have suggested that VAL-083 has anti-tumor activity against a broad range of tumor types including GBM. In preclinical in vitro studies, VAL-083 demonstrated activity in a wide range of cancer cell lines, including pediatric and adult GBM cell lines and GBM cancer stem cells. Notably, due to crosslink formation on N7 of guanine, VAL-083 overcomes chemo-resistance to MGMT in vitro. In light of extensive safety data from several clinical trials and promising efficacy signals in CNS tumors, DelMar initiated a new clinical study to determine the safety, tolerability, pharmacokinetics, anti-tumor activity in patients with recurrent GBM. This is an open-label, single-arm Phase I/II dose-escalation study in patients with histologically-confirmed initial diagnosis of malignant GBM. The study utilizes a 3+3 dose-escalation design. Patients receive VAL-083 i.v. on days 1, 2, and 3 of a 21 day cycle. GBM patients have previously been treated with surgery and/or radiation, if appropriate, and must have failed both bevacizumab and temozolomide, unless contraindicated. In the ongoing trial, cohorts 1 through 4 (10 mg/m2) have completed the trial successfully with no drug-related serious adverse events (SAEs), and maximum tolerated dose (MTD) was not yet reached. Enrollment for Cohort 5 (20 mg/m2) has been initiated. Pharmacokinetic analyses show dose-dependent increase in exposure with a short 1-2 hour plasma half-life and a Cmax of 20 hours) with preferential accumulation to brain tumor tissue. MGMT status of patients and drug concentration in the CSF are being evaluated when possible. ClinicalTrials.gov Identifier: [NCT01478178][1] Citation Format: Kent C. Shih, Manish R. Patel, Jeffrey Bacha, Dennis M. Brown, William J. Garner, Anne Steino, Richard S. Schwartz, Sarath Kanekal, Mike Li, Lorena M. Lopez, Howard A. Burris. Phase I/II study of VAL-083 in patients with recurrent glioblastoma multiforme. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT404. doi:10.1158/1538-7445.AM2014-CT404 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01478178&atom=%2Fcanres%2F74%2F19_Supplement%2FCT404.atom