Drew W. Rasco

The Clinical Effect of the Dual-Targeting Strategy Involving PI3K/AKT/mTOR and RAS/MEK/ERK Pathways in Patients with Advanced Cancer

Purpose: This study evaluated the clinical relevance of the dual-targeting strategy involving PI3K/AKT/mTOR and RAF/MEK/ERK pathways. Experimental Design: We investigated safety, efficacy, and correlations between tumor genetic alterations and clinical benefit in 236 patients with advanced cancers treated with phase I study drugs targeting phosphoinositide 3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways in our Phase I Clinical Trials Program. Results: Seventy-six (32.2%) patients received a PI3K pathway inhibitor in combination with a MAPK pathway inhibitor (D), whereas 124 (52.5%) and 36 (15.3%), respectively, received an inhibitor of either the PI3K or MAPK pathways (S). The rates of drug-related grade >III adverse events were 18.1% for (S) and 53.9% for (D; P < 0.001); the rates of dose-limiting toxicities were 9.4% for (S) and 18.4% for (D; P = 0.06). The most frequent grade >III adverse events were transaminase elevations, skin rash, and mucositis. In our comprehensive tumor genomic analysis, of 9 patients who harbored coactivation of both pathways (colorectal cancer, n = 7; melanoma, n = 2), all 5 patients treated with (D) had tumor regression ranging from 2% to 64%. Conclusions: These results suggest that dual inhibition of both pathways may potentially exhibit favorable efficacy compared with inhibition of either pathway, at the expense of greater toxicity. Furthermore, this parallel pathway targeting strategy may be especially important in patients with coexisting PI3K pathway genetic alterations and KRAS or BRAF mutations and suggests that molecular profiling and matching patients with combinations of these targeted drugs will need to be investigated in depth. Clin Cancer Res; 18(8); 2316–25. ©2012 AACR.

Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Other Solid Tumors.

UNLABELLED We evaluated the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of abemaciclib, an orally bioavailable inhibitor of cyclin-dependent kinases (CDK) 4 and 6, in a multicenter study including phase I dose escalation followed by tumor-specific cohorts for breast cancer, non-small cell lung cancer (NSCLC), glioblastoma, melanoma, and colorectal cancer. A total of 225 patients were enrolled: 33 in dose escalation and 192 in tumor-specific cohorts. Dose-limiting toxicity was grade 3 fatigue. The maximum tolerated dose was 200 mg every 12 hours. The most common possibly related treatment-emergent adverse events involved fatigue and the gastrointestinal, renal, or hematopoietic systems. Plasma concentrations increased with dose, and pharmacodynamic effects were observed in proliferating keratinocytes and tumors. Radiographic responses were achieved in previously treated patients with breast cancer, NSCLC, and melanoma. For hormone receptor-positive breast cancer, the overall response rate was 31%; moreover, 61% of patients achieved either response or stable disease lasting ≥6 months. SIGNIFICANCE Abemaciclib represents the first selective inhibitor of CDK4 and CDK6 with a safety profile allowing continuous dosing to achieve sustained target inhibition. This first-in-human experience demonstrates single-agent activity for patients with advanced breast cancer, NSCLC, and other solid tumors. Cancer Discov; 6(7); 740-53. ©2016 AACR.See related commentary by Lim et al., p. 697This article is highlighted in the In This Issue feature, p. 681.

A phase 1b study of trametinib, an oral Mitogen-activated protein kinase kinase (MEK) inhibitor, in combination with gemcitabine in advanced solid tumours

PURPOSE This phase 1b study determined the safety, tolerability, and recommended phase 2 dose (RP2D) and schedule of trametinib in combination with gemcitabine. Secondary objectives included assessment of clinical activity and steady-state pharmacokinetics. METHODS Adults with advanced solid tumours, adequate organ function and Eastern Co-operative Oncology Group performance status (ECOG PS) ⩽ 1 were eligible. Once-daily oral trametinib (1mg, 2mg, 2.5mg) was escalated in a 3+3 design with standard gemcitabine dosing (1000 mg/m(2) IV Days 1, 8, and 15 of 28-day cycles). During expansion, trametinib 2mg was combined with gemcitabine. Pharmacokinetics samples were collected on Day 15 pre-dose and 1, 2, 4 and 6h post-dose; tumour assessments were repeated every two cycles. RESULTS Between 8/2009 and 11/2010, 31 patients (pancreas = 11, breast = 6, non-small cell lung cancer (NSCLC) = 4, other = 10) were treated. Dose-limiting toxicities (DLTs) occurred in each cohort, and included febrile neutropenia, transaminase elevation and uveitis. The RP2D was declared as trametinib 2mg daily with standard gemcitabine dosing. Common grade 3/4 toxicities at the RP2D included: neutropenia (38%), thrombocytopenia (19%) and transaminase elevation (14%). Of 10 patients with measurable pancreatic cancer, three partial responses (30%) were documented; two additional patients achieved objective responses (breast, complete response (CR); salivary glands, partial response (PR)). Pharmacokinetics suggested no change in exposures of either drug in combination. CONCLUSION Administration of trametinib at its full monotherapy dose of 2mg daily in combination with standard gemcitabine dosing (1000 mg/m(2) IV Days 1, 8, and 15 every 28 days) was feasible. Though most toxicities were manageable, the addition of trametinib may increase gemcitabine-associated myelosuppression. Future studies of this combination will require monitoring to maintain dose and schedule.

Looking beyond surveillance, epidemiology, and end results: patterns of chemotherapy administration for advanced non-small cell lung cancer in a contemporary, diverse population.

Introduction: Chemotherapy prolongs survival without substantially impairing quality of life for medically fit patients with advanced non-small cell lung cancer (NSCLC), but population-based studies have shown that only 20 to 30% of these patients receive chemotherapy. These earlier studies have relied on Medicare-linked Surveillance, Epidemiology, and End Results (SEER) data, thus excluding the 30 to 35% of lung cancer patients younger than 65 years. Therefore, we determined the use of chemotherapy in a contemporary, diverse NSCLC population encompassing all patient ages. Methods: We performed a retrospective analysis of patients diagnosed with stage IV NSCLC from 2000 to 2007 at the University of Texas Southwestern Medical Center. Demographic, treatment, and outcome data were obtained from hospital tumor registries. The association between these variables was assessed using univariate analysis and multivariate logistic regression. Results: In all, 718 patients met criteria for analysis. Mean age was 60 years, 58% were men, and 45% were white. Three hundred fifty-three patients (49%) received chemotherapy. In univariate analysis, receipt of chemotherapy was associated with age (53% of patients younger than 65 years versus 41% of patients aged 65 years and older; p = 0.003) and insurance type (p < 0.001). In a multivariate model, age and insurance type remained associated with receipt of chemotherapy. For individuals receiving chemotherapy, median survival was 9.2 months, compared with 2.3 months for untreated patients (p < 0.001). Conclusions: In a contemporary population representing the full age range of patients with advanced NSCLC, chemotherapy was administered to approximately half of all patients—more than twice the rate reported in some earlier studies. Patient age and insurance type are associated with receipt of chemotherapy.

Predictors and impact of second-line chemotherapy for advanced non-small cell lung cancer in the United States: real-world considerations for maintenance therapy.

Introduction: Recent clinical trials incorporating maintenance chemotherapy into the initial treatment of advanced non-small cell lung cancer (NSCLC) have highlighted the benefits of exposing patients to second-line therapies. We, therefore, determined the predictors and impact of second-line chemotherapy administration in a contemporary, diverse NSCLC population. Methods: We performed a retrospective analysis of consecutive patients diagnosed with stage IV NSCLC from 2000 to 2007 at clinical facilities associated with the University of Texas Southwestern Medical Center. Demographic, disease, treatment, and outcome data were obtained from hospital tumor registries. The association between these variables was assessed using univariate analysis and multivariate logistic regression. Results: A total of 406 patients in this cohort received first-line chemotherapy and were included in the analysis. Mean age was 59 years, 28% were women, and 59% were white. Among these patients, 197 (49%) received second-line chemotherapy. Among those patients who had not progressed after four to six cycles of first-line chemotherapy, 67% received second-line chemotherapy. Receipt of second-line chemotherapy was significantly associated with patient insurance type (p = 0.007), number of cycles of first-line chemotherapy (p < 0.001), and receipt of prechemotherapy palliative radiation therapy (p = 0.005) but was not associated with patient age, gender, race, histology, or year of diagnosis. In a multivariate model, second-line chemotherapy administration remained associated with insurance type (p = 0.003), number of cycles of first-line chemotherapy (p < 0.001), and receipt of prechemotherapy palliative radiation therapy (p = 0.008). The number of cycles of first-line chemotherapy and administration of second-line chemotherapy were associated with overall survival in both univariate and multivariate analyses. Conclusions: In this unselected, contemporary, and diverse cohort of patients with advanced NSCLC, 67% of individuals whose disease had not progressed after four to six cycles of first-line chemotherapy eventually received second-line chemotherapy. Markers of socioeconomic status, symptom burden, and response to and tolerance of first-line chemotherapy were associated with receipt of second-line chemotherapy. These factors may assist in the selection of patients most likely to benefit from maintenance chemotherapy.

Abstract CT232: Clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with metastatic breast cancer

LY2835219 is a novel cell cycle inhibitor selective for the cyclin-dependent kinases CDK4 and CDK6 (CDK4/6), which act in a protein complex with D-type cyclins to enable G1 to S cell cycle progression. Preclinical models indicate this complex plays a critical role in breast cancer. We conducted a phase I study with expansion cohorts to evaluate the safety, pharmacokinetics, and antitumor activity of LY2835219 in 5 different tumor types: glioblastoma; melanoma; and cancers of the lung, colon/rectum and breast. In the expansion cohorts, LY2835219 was administered continuously at 150-200mg orally every 12 hours on Days 1-28 of a 28-day cycle. RECIST v1.1 was used to assess tumor response. The most common possibly related treatment-emergent adverse events across the expansion cohorts (n=132) included diarrhea (5% G3/4), nausea (3% G3/4), fatigue (2% G3/4), vomiting (2% G3/4) and neutropenia (11% G3/4). In the metastatic breast cancer (MBC) cohort, 47 patients with a median of 7 prior systemic regimens received therapy with LY2835219. Across all MBC patients, 9 achieved a best overall response of confirmed partial response (PR), 24 achieved stable disease (SD), 11 had progressive disease (PD), and 3 were not evaluable for response. Among the 36 HR+ patients, there were 9 confirmed partial responses for an ORR of 25%. In addition, 20 of these 36 HR+ patients (56%) had SD: 7 patients had SD Citation Format: Amita Patnaik, Lee S. Rosen, Sara M. Tolaney, Anthony W. Tolcher, Jonathan W. Goldman, Leena Gandhi, Kyriakos P. Papadopoulos, Muralidhar Beeram, Drew W. Rasco, Scott P. Myrand, Palaniappan Kulanthaivel, Lily Li, Martin Frenzel, Damien M. Cronier, Edward M. Chan, Keith T. Flaherty, Patrick Y. Wen, Geoffrey I. Shapiro. Clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with metastatic breast cancer. [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 CT232. doi:10.1158/1538-7445.AM2014-CT232

First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin's lymphomas

This phase I study evaluated the safety, tolerability, and pharmacokinetics of copanlisib, an intravenously administered pan-phosphatidylinositol 3-kinase inhibitor in patients with advanced solid tumors or non-Hodgkins lymphoma. Copanlisib was well tolerated with a manageable safety profile, with anti-tumor activity in both advanced solid tumors and hematological malignancies.

Phase I First-in-Human Study of CUDC-101, a Multitargeted Inhibitor of HDACs, EGFR, and HER2 in Patients with Advanced Solid Tumors

Purpose: This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose (RD) for CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 as a 1-hour intravenous (i.v.) infusion for 5 consecutive days every 2 weeks. Experimental Design: Twenty-five patients with advanced solid tumors received escalating doses of CUDC-101 (range, 75–300 mg/m2/day) following a standard 3 + 3 dose escalation design. Results: The MTD was determined to be 275 mg/m2. Common grade 1/2 adverse events included nausea, fatigue, vomiting, dyspnea, pyrexia, and dry skin. DLTs occurred in 1 patient in the 275-mg/m2 dose cohort (grade 2 serum creatinine elevation, n = 1) and 3 patients in the 300-mg/m2 dose cohort (grade 2 serum creatinine elevation, n = 2; pericarditis, n = 1), all of which were transient and reversible. CUDC-101 exposure increased linearly with the mean maximum concentration (Cmax), clearance (CL), volume of distribution at steady-state (Vdss), area under curve (AUC), and terminal elimination half-life (t1/2) at the MTD dose of 9.3 mg/L, 51.2 L/h, 39.6 L, 9.95 h·ng/mL and 4.4 hours, respectively. Acetylated histone H3 induction was observed in posttreatment skin samples from 3 patients in the 275-mg/m2 dose cohort, suggesting adequate systemic exposure and target inhibition. One patient with gastric cancer had a partial response and 6 patients had stable disease. Conclusion: CUDC-101 administered by 1-hour i.v. infusion for 5 consecutive days every 2 weeks was generally well tolerated with preliminary evidence of antitumor activity. A dose of 275 mg/m2 is recommended for further clinical testing. Clin Cancer Res; 20(19); 5032–40. ©2014 AACR.

Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors

Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination with the humanized, PD-1–blocking IgG4 mAb pembrolizumab in patients with advanced solid tumors. Experimental Design: Utomilumab (0.45–5.0 mg/kg) and pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab dose escalation was conducted using the time-to-event continual reassessment method. Results: Twenty-three patients received combination treatment with no dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1 to 2, without any treatment-related discontinuations. Six patients (26.1%) had confirmed complete or partial responses. Pharmacokinetics and immunogenicity of utomilumab and pembrolizumab were similar when administered alone or in combination. A trend toward higher levels of activated memory/effector peripheral blood CD8+ T cells was observed in responders versus nonresponders. Conclusions: The safety, tolerability, and clinical activity demonstrated by utomilumab in combination with pembrolizumab support further investigation in patients with advanced solid tumors. Clin Cancer Res; 23(18); 5349–57. ©2017 AACR. See related commentary by Pérez-Ruiz et al., p. 5326

Safety, Pharmacokinetics and Pharmacodynamics of a Humanized anti-Semaphorin 4D Antibody, in a First-In-Human Study of Patients with Advanced Solid Tumors

Purpose: Study objectives included evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of VX15/2503 in advanced solid tumor patients. Experimental Design: Weekly i.v. doses were administered on a 28-day cycle. Safety, immunogenicity, PK, efficacy, T-cell membrane–associated SEMA4D (cSEMA4D) expression and saturation, soluble SEMA4D (sSEMA4D) serum levels, and serum biomarker levels were evaluated. Results: Forty-two patients were enrolled into seven sequential cohorts and an expansion cohort (20 mg/kg). VX15/2503 was well tolerated. Treatment-related adverse events were primarily grade 1 or 2 and included nausea (14.3%) and fatigue (11.9%); arthralgia, decreased appetite, infusion-related reaction, and pyrexia were each 7.3%. One pancreatic cancer patient (15 mg/kg) experienced a Grade 3 dose-limiting toxicity; elevated γ-glutamyl transferase. Complete cSEMA4D saturation was generally observed at serum antibody concentrations ≥0.3 μg/mL, resulting in decreased cSEMA4D expression. Soluble SEMA4D levels increased with dose and infusion number. Neutralizing anti-VX15/2503 antibodies led to treatment discontinuation for 1 patient. VX15/2503 Cmax and AUC generally increased with dose and dose number. One patient (20 mg/kg) experienced a partial response, 19 patients (45.2%) exhibited SD for ≥8 weeks, and 8 (19%) had SD for ≥16 weeks. Subjects with elevated B/T lymphocytes exhibited longer progression-free survival. Conclusions: VX15/2503 was well tolerated and produced expected PD effects. The correlation between immune cell levels at baseline and progression-free survival is consistent with an immune-mediated mechanism of action. Future investigations will be in combination with immunomodulatory agents. Clin Cancer Res; 22(4); 827–36. ©2015 AACR.