Maria Catherine Pietanza

Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer

Purpose Patients with extensive-stage disease small-cell lung cancer (SCLC) have poor survival outcomes despite first-line chemotherapy with etoposide and platinum. This randomized, double-blind phase III study evaluated the efficacy and safety of ipilimumab or placebo plus etoposide and platinum in patients with newly diagnosed extensive-stage disease SCLC. Patients and Methods Patients were randomly assigned at a ratio of one to one to receive chemotherapy with etoposide and platinum (cisplatin or carboplatin) plus ipilimumab 10 mg/kg or placebo every 3 weeks for a total of four doses each in a phased induction schedule (chemotherapy in cycles one to four; ipilimumab or placebo beginning in cycle three up to cycle six), followed by ipilimumab or placebo maintenance every 12 weeks. Primary end point was overall survival (OS) among patients receiving at least one dose of blinded study therapy. Results Of 1,132 patients randomly assigned, 954 received at least one dose of study therapy (chemotherapy plus ipilimumab, n = 478; chemotherapy plus placebo, n = 476). Median OS was 11.0 months for chemotherapy plus ipilimumab versus 10.9 months for chemotherapy plus placebo (hazard ratio, 0.94; 95% CI, 0.81 to 1.09; P = .3775). Median progression-free survival was 4.6 months for chemotherapy plus ipilimumab versus 4.4 months for chemotherapy plus placebo (hazard ratio, 0.85; 95% CI, 0.75 to 0.97). Rates and severity of treatment-related adverse events were similar between arms, except for diarrhea, rash, and colitis, which were more frequent with chemotherapy plus ipilimumab. Rate of treatment-related discontinuation was higher with chemotherapy plus ipilimumab (18% v 2% with chemotherapy plus placebo). Five treatment-related deaths occurred with chemotherapy plus ipilimumab and two with chemotherapy plus placebo. Conclusion Addition of ipilimumab to chemotherapy did not prolong OS versus chemotherapy alone in patients with newly diagnosed extensive-stage disease SCLC. No new or unexpected adverse events were observed with chemotherapy plus ipilimumab. Several ongoing studies are evaluating ipilimumab in combination with programmed death-1 inhibitors in SCLC.

Phase II Trial of Gefitinib and Everolimus in Advanced Non-small Cell Lung Cancer

Introduction: Concurrent signal transduction inhibition with the epidermal growth factor receptor (EGFR) inhibitor gefitinib and the mammalian target-of-rapamycin inhibitor everolimus has been hypothesized to result in enhanced antitumor activity in patients with non-small cell lung cancer (NSCLC). This phase II trial assessed the efficacy of the combination of gefitinib and everolimus in patients with advanced NSCLC. Methods: Two cohorts of 31 patients with measurable stage IIIB/IV NSCLC were enrolled: (1) no prior chemotherapy and (2) previously treated with cisplatin or carboplatin and docetaxel or pemetrexed. All patients received daily everolimus 5 mg and gefitinib 250 mg. Response was assessed after 1 month and then every 2 months. Pretreatment tumor specimens were collected for mutation testing. Results: Sixty-two patients were enrolled (median age: 66 years, 50% women, 98% stage IV, all current/former smokers, and 85% adenocarcinoma). Partial responses were seen in 8 of 62 patients (response rate: 13%; 95% confidence interval: 5–21%); five responders had received no prior chemotherapy. Three partial responders had an EGFR mutation. Both patients with a KRAS (G12F) mutation responded. The median time to progression was 4 months. Median overall survival was 12 months, 27 months for no prior chemotherapy patients, and 11 months for patients previously treated with chemotherapy. Conclusions: The 13% partial response rate observed did not meet the prespecified response threshold to pursue further study of the combination of gefitinib and everolimus. The response rate in patients with non-EGFR mutant tumors was 8%, likely reflecting activity of everolimus. Further investigation of mammalian target-of-rapamycin inhibitors in patients with NSCLC with KRAS G12F-mutated tumors is warranted.

Phase II trial of temozolomide in patients with relapsed sensitive or refractory small cell lung cancer, with assessment of methylguanine-DNA methyltransferase as a potential biomarker.

Purpose: This phase II study was conducted to assess the efficacy of temozolomide in patients with relapsed small cell lung cancer (SCLC). Experimental Design: Patients with disease progression after one or two prior chemotherapy regimens received temozolomide at 75 mg/m2/d for 21 days of a 28-day cycle. The primary endpoint was the overall response rate [ORR; complete response (CR) plus partial response (PR)], which was evaluated separately in sensitive and refractory cohorts. In the available tissue, we assessed O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status by PCR and MGMT expression by immunohistochemistry. Results: Sixty-four patients were accrued: 48 patients in the sensitive cohort and 16 in the refractory group. One CR and 10 PRs were noted in sensitive patients [ORR, 23%; 95% confidence interval (CI), 12%–37%]. Two PRs were seen in the refractory cohort (ORR, 13%; 95% CI, 2%–38%). As second- and third-line treatment, the ORR was 22% (95% CI, 9%–40%) and 19% (95% CI, 7%–36%), respectively. Among patients with target brain lesions, 38% had a CR or PR (95% CI, 14%–68%). Grade ≥3 thrombocytopenia and neutropenia were observed in nine patients (14%). A greater number of cases with methylated MGMT had a response compared to those with unmethylated MGMT (38% vs. 7%; P = 0.08). Conclusion: Temozolomide has activity in relapsed SCLC, particularly for brain metastases. Response to temozolomide may correlate with MGMT methylation in SCLC. Clin Cancer Res; 18(4); 1138–45. ©2012 AACR.

Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma–like and Non–Small Cell Carcinoma–like Subsets

Purpose: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive neoplasm, whose biologic relationship to small cell lung carcinoma (SCLC) versus non-SCLC (NSCLC) remains unclear, contributing to uncertainty regarding optimal clinical management. To clarify these relationships, we analyzed genomic alterations in LCNEC compared with other major lung carcinoma types. Experimental Design: LCNEC (n = 45) tumor/normal pairs underwent targeted next-generation sequencing of 241 cancer genes by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) platform and comprehensive histologic, immunohistochemical, and clinical analysis. Genomic data were compared with MSK-IMPACT analysis of other lung carcinoma histologies (n = 242). Results: Commonly altered genes in LCNEC included TP53 (78%), RB1 (38%), STK11 (33%), KEAP1 (31%), and KRAS (22%). Genomic profiles segregated LCNEC into 2 major and 1 minor subsets: SCLC-like (n = 18), characterized by TP53+RB1 co-mutation/loss and other SCLC-type alterations, including MYCL amplification; NSCLC-like (n = 25), characterized by the lack of coaltered TP53+RB1 and nearly universal occurrence of NSCLC-type mutations (STK11, KRAS, and KEAP1); and carcinoid-like (n = 2), characterized by MEN1 mutations and low mutation burden. SCLC-like and NSCLC-like subsets revealed several clinicopathologic differences, including higher proliferative activity in SCLC-like tumors (P < 0.0001) and exclusive adenocarcinoma-type differentiation marker expression in NSCLC-like tumors (P = 0.005). While exhibiting predominant similarity with lung adenocarcinoma, NSCLC-like LCNEC harbored several distinctive genomic alterations, including more frequent mutations in NOTCH family genes (28%), implicated as key regulators of neuroendocrine differentiation. Conclusions: LCNEC is a biologically heterogeneous group of tumors, comprising distinct subsets with genomic signatures of SCLC, NSCLC (predominantly adenocarcinoma), and rarely, highly proliferative carcinoids. Recognition of these subsets may inform the classification and management of LCNEC patients. Clin Cancer Res; 22(14); 3618–29. ©2016 AACR.

A phase II study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in relapsed small cell lung cancer

INTRODUCTION We previously reported data on the safety, tolerability, and recommended phase II dose of obatoclax mesylate in conjunction with topotecan in patients with advanced solid tumor malignancies. Preliminary efficacy data suggested activity in patients with recurrent small cell lung cancer (SCLC). Based on these data, we performed a phase II study of obatoclax mesylate plus topotecan in patients with relapsed SCLC to assess efficacy. METHODS This was an open-label, single-arm, phase II extension of obatoclax mesylate plus topotecan in patients with relapsed SCLC. Obatoclax mesylate was given intravenously (IV) at a dose of 14mg/m(2) on days 1 and 3 with IV topotecan at 1.25mg/m(2) on days 1-5 of an every 3-week cycle. The primary end-point of this study was overall response rate. RESULTS Nine patients with recurrent SCLC were enrolled into the first stage of the study. Patients received a median of 2 cycles of treatment. All patients were evaluable for the primary end-point of overall response. There were no partial or complete responses. Five patients (56%) had stable disease. The remaining four patients (44%) developed progressive disease. The most common grade 3 or 4 adverse events included thrombocytopenia (22%), anemia (11%), neutropenia (11%), and ataxia (11%). CONCLUSION Obatoclax mesylate added to topotecan does not exceed the historic response rate seen with topotecan alone in patients with relapsed SCLC following the first-line platinum-based therapy.

Neoadjuvant and Adjuvant Chemotherapy in Resected Pulmonary Large Cell Neuroendocrine Carcinomas: A Single Institution Experience

BACKGROUND Pulmonary large cell neuroendocrine carcinomas (LCNEC) are aggressive neoplasms with poor prognosis. The role of neoadjuvant and adjuvant therapies in these tumors remains uncertain. METHODS We performed a retrospective review of a prospective database. Kaplan-Meier estimates of overall survival (OS) were determined and compared across prognostic factors using log-rank analysis and the Cox proportional hazards model. RESULTS One hundred patients with resected LCNEC were identified from 1992 to 2008. Of these, 54% were male and 98% current or former smokers (mean 60.3 pack-years). Twenty-two patients received neoadjuvant platinum chemotherapy with a response rate of 68% (15 of 22). Eighty percent (80 of 100) underwent lobectomy and 11% (11 of 100) pneumonectomy with a 90% (90 of 100) complete resection (R0) rate. Seventy-one percent (71 of 100) were stage I-II, and 20 of 71 received platinum adjuvant chemotherapy. Mean OS was 40 months. Univariate factors associated with decreased OS included male gender (p = 0.007), increasing tumor (T) stage (p = 0.004), and stage III-IV disease (p = 0.04). Stage IB patients fared significantly worse than IA (p = 0.006). Multivariate analyses identified male gender (hazard ratio [HR] 2.3, p = 0.007), comorbid pulmonary disease (HR 2.3, p = 0.012), and pathologic stage (HR = 2.2, p = 0.011) as associated with risk of death. Univariate analysis in stage IB-IIIA completely resected (R0) patients receiving combination platinum-based induction and (or) adjuvant chemotherapy showed a trend toward improved OS (median survival 7.4 vs 2 years, p = 0.052). CONCLUSIONS The LCNEC has a high response rate to platinum-based neoadjuvant chemotherapy. Resected advanced-stage patients receiving combination neoadjuvant and (or) adjuvant chemotherapy may have a survival advantage. These therapies should be considered in resectable patients with LCNEC.

Targeting the differential addiction to anti-apoptotic BCL-2 family for cancer therapy

BCL-2 family proteins are central regulators of mitochondrial apoptosis and validated anti-cancer targets. Using small cell lung cancer (SCLC) as a model, we demonstrated the presence of differential addiction of cancer cells to anti-apoptotic BCL-2, BCL-XL or MCL-1, which correlated with the respective protein expression ratio. ABT-263 (navitoclax), a BCL-2/BCL-XL inhibitor, prevented BCL-XL from sequestering activator BH3-only molecules (BH3s) and BAX but not BAK. Consequently, ABT-263 failed to kill BCL-XL-addicted cells with low activator BH3s and BCL-XL overabundance conferred resistance to ABT-263. High-throughput screening identified anthracyclines including doxorubicin and CDK9 inhibitors including dinaciclib that synergized with ABT-263 through downregulation of MCL-1. As doxorubicin and dinaciclib also reduced BCL-XL, the combinations of BCL-2 inhibitor ABT-199 (venetoclax) with doxorubicin or dinaciclib provided effective therapeutic strategies for SCLC. Altogether, our study highlights the need for mechanism-guided targeting of anti-apoptotic BCL-2 proteins to effectively activate the mitochondrial cell death programme to kill cancer cells.

ORAL02.01: Safety and Efficacy of Single-Agent Rovalpituzumab Tesirine, a DLL3-Targeted ADC, in Recurrent or Refractory SCLC: Topic: Medical Oncology

All Treated Patients (TC2/3 or IC2/3) Cohort 1 (1L) 139 24% (17-32) 7.3 (5.6-9.1) 20.1 (20.1-NE) Cohort 2 (2L) 268 19% (15-24) 2.8 (2.6-4.1) 15.5 (12.3-NE) Cohort 3 (3L+) 252 19% (15-25) 3.0 (2.8-4.1) 13.2 (10.3-17.5) PD-L1 TC3 or IC3 Subgroup Cohort 1 (1L) 65 32% (21-45) 7.3 (4.9-12.0) NE (12.0-NE) Cohort 2 (2L) 122 25% (18-34) 4.1 (2.6-6.5) 15.1 (12.0-NE) Cohort 3 (3L+) 115 30% (22-39) 4.2 (3.0-6.2) 17.5 (11.1-NE)

Novel therapeutic approaches for small cell lung cancer: the future has arrived.

Thirty thousand patients are diagnosed with small cell lung cancer (SCLC) in the United States each year [1]. Tobacco exposure is strongly associated with the development of this disease. SCLC has a unique natural history with a much shorter doubling time, higher growth fraction and earlier development of widespread metastases than any of the non-small cell histologies. Although SCLC is characterized by a superior initial response rate to chemotherapy and radiation, even responsive disease is typically associated with relapse within months after treatment, with the rapid development of chemo-resistance, leading to a dismal five year survival rate of 5% [2]. Few improvements have been made in the fundamentals of SCLC treatment. Notably, the standard chemotherapy regimen used for initial disease has not changed over the last three decades. First-line treatment for SCLC involves combination chemotherapy with cisplatin or carboplatin plus etoposide (with the addition of radiation therapy in limited stage), which results in a 60-80% overall response rate. However, all patients with extensive stage SCLC, and the majority of patients with limited SCLC, suffer relapse within months of completing initial therapy. Topotecan (Hycamtin; GlaxoSmithKline) is the only approved agent for recurrent or progressive SCLC, based on the results of three phase III trials [3-5]. There are no accepted regimens for patients whose disease has progressed after first- and second-line treatments for SCLC. As the prognosis for patients with recurrent SCLC is poor, there is a clear need for the development of new therapeutic strategies. Focusing on common tumor-specific molecular and cellular abnormalities may identify novel therapeutic targets in this challenging disease.

1473PPHASE 1B TRIAL OF ANTI-NOTCH 2/3 ANTIBODY OMP-59R5 IN COMBINATION WITH ETOPOSIDE AND CISPLATIN (EP) IN PATIENTS (PTS) WITH UNTREATED EXTENSIVE-STAGE SMALL-CELL LUNG CANCER (ED-SCLC): THE PINNACLE STUDY

ABSTRACT Aim: The Notch pathway plays a central role in embryonic development, the regulation of stem and progenitor cells, and is implicated centrally in many human cancers, including SCLC. OMP-59R5, a fully human IgG2 antibody, inhibits signaling of Notch2 and 3 receptors. Anti-tumor activity was noted in 7 of 9 pt-derived SCLC xenografts expressing Notch 2 and 3 with OMP-59R5 treatment. The maximum tolerated dose (MTD) of single agent OMP-59R5 was 7.5mg/kg IV every 3 weeks (Smith, EORTC 2012); the main dose-limiting toxicity (DLT) was Grade 3 diarrhea. This study is to determine the MTD, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of OMP-59R5 in combination with EP in ED-SCLC. Methods: Cohorts of 3 to 6 pts were treated at each dose level of OMP-59R5. OMP-59R5 was given IV on Day 1 of each 21 day cycle along with etoposide 100 mg/m2 on Days 1, 2, and 3 and cisplatin 80 mg/m2 on Day 1. After 6 cycles, pts continued OMP-59R5 alone every 21 days in the absence of disease progression or unacceptable toxicities. Results: By April 4, 2014, 11 pts were treated. One DLT of Grade 3 nausea was reported from a subject in the 10 mg/kg dose cohort that lasted more than 48 hours despite daily IV fluids and antiemetics. Frequently reported (≥30%) adverse events (all grades) regardless of relationship were: fatigue (81.8%), nausea (72.7%), anemia (63.6%), diarrhea (63.6%), decreased appetite (54.5%), weight loss (54.4%), hypomagnesemia (45.5%), peripheral edema (45.5%), dehydration (36.4%), neutropenia (36.4%), thrombocytopenia (36.4%), vomiting (36.4%) and elevated creatinine (36.4%). Of these, fatigue (54.5%), anemia (36.4%), diarrhea (36.4%) and nausea (36.4%) were considered related to OMP-59R5. The events were mostly Grade 1 or 2, and managed with supportive care. Additional data are below: OMP-59R5 Dose (mg/kg) 5 (n=3) 7.5 (n=3) 10 (n=5) Etoposide (mg/m2) 100 Cisplatin (mg/m2) 80 DLT evaluable 3 3 5 incidence - - 1 RECIST 1.1 evaluable 3 3 4 Best Response/ Partial Response 3 2 4 Stable Disease - 1 - Progressive Disease - - - pts still on treatment - 2 4 Conclusions: OMP-59R5 with EP is well tolerated. The MTD has not been reached. Encouraging anti-tumor activity is observed. Updated safety, PK/PD, and efficacy data will be presented. The Phase 2 part of PINNACLE will start in 2014. Disclosure: A. Kapoun: Employed by OncoMed Pharmaceuticals (Sponsor), receive salary and stocks; L. Xu: Employed by OncoMed Pharmaceuticals (Sponsor), receive salary and stocks; D. Hill: Employed by OncoMed Pharmaceuticals (Sponsor), receive salary and stocks; L. Zhou: Paid consultant for OncoMed Pharmaceuticals (sponsor); J. Dupont: Employed by OncoMed Pharmaceuticals (Sponsor), receive salary and stocks. All other authors have declared no conflicts of interest.