Ashish Sangal

Maintaining clarity: Review of maintenance therapy in non-small cell lung cancer

The purpose of this article is to review the role of maintenance therapy in the treatment of advanced non-small cell lung cancer (NSCLC). A brief overview about induction chemotherapy and its primary function in NSCLC is provided to address the basis of maintenance therapies foundation. The development of how maintenance therapy is utilized in this population is discussed and current guidelines for maintenance therapy are reviewed. Benefits and potential pitfalls of maintenance therapy are addressed, allowing a comprehensive review of the achieved clinical benefit that maintenance therapy may or may not have on NSCLC patient population. A review of current literature was conducted and a table is provided comparing the results of various maintenance therapy clinical trials. The table includes geographical location of each study, the number of patients enrolled, progression free survival and overall survival statistics, post-treatment regimens and if molecular testing was conducted. The role of molecular testing in relation to therapeutic treatment options for advanced NSCLC patients is discussed. A treatment algorithm clearly depicts first line and second line treatment for management of NSCLC and includes molecular testing, maintenance therapy and the role clinical trials have in treatment of NSCLC. This treatment algorithm has been specifically tailored and developed to assist clinicians in the management of advanced NSCLC.

Evaluation and comparison of two commercially available targeted next-generation sequencing platforms to assist oncology decision making

Background It is widely acknowledged that there is value in examining cancers for genomic aberrations via next-generation sequencing (NGS). How commercially available NGS platforms compare with each other, and the clinical utility of the reported actionable results, are not well known. During the course of the current study, the Foundation One (F1) test generated data on a combination of somatic mutations, insertion and deletion polymorphisms, chromosomal abnormalities, and deoxyribonucleic acid (DNA) copy number changes at ~250× coverage, while the Paradigm Cancer Diagnostic (PCDx) test generated the same type of data at >5,000× coverage, plus provided messenger RNA (mRNA) expression levels. We sought to compare and evaluate paired formalin-fixed paraffin-embedded tumor tissue using these two platforms. Methods Samples from patients with advanced solid tumors were submitted to both the F1 and PCDx vendors for NGS analysis. Turnaround time (TAT) was calculated. Biomarkers were considered clinically actionable if they had a published association with treatment response in humans and were assigned to the following categories: commercially available drug (CA), clinical trial drug (CT), or neither option (hereafter referred to as “None”). Results The demographics of the 21 unique patient tumor samples included ten men and eleven women, with a median age of 56 years. Due to insufficient archival tissue from the same collection period, in one case, we used samples from different collections. PCDx reported first results faster than F1 in 20 cases. When received at both vendors on the same day, PCDx reported first results for 14 of 15 cases, with a median TAT of 9 days earlier than F1 (P<0.0001). Categorization of CA compared to CT and none significantly favored PCDx (P=0.012). Conclusion In the current analysis, commercially available NGS platforms provided clinically relevant actionable targets (CA or CT) in 47%–67% of diverse cancer types. In the samples analyzed, PCDx significantly outperformed F1 in TAT, and had statistically significant higher clinically relevant actionable targets categorized as CA.

Tumor Cell-Free DNA Copy Number Instability Predicts Therapeutic Response to Immunotherapy

Purpose: Chromosomal instability is a fundamental property of cancer, which can be quantified by next-generation sequencing (NGS) from plasma/serum–derived cell-free DNA (cfDNA). We hypothesized that cfDNA could be used as a real-time surrogate for imaging analysis of disease status as a function of response to immunotherapy and as a more reliable tool than tumor biomarkers. Experimental Design: Plasma cfDNA sequences from 56 patients with diverse advanced cancers were prospectively collected and analyzed in a single-blind study for copy number variations, expressed as a quantitative chromosomal number instability (CNI) score versus 126 noncancer controls in a training set of 23 and a blinded validation set of 33. Tumor biomarker concentrations and a surrogate marker for T regulatory cells (Tregs) were comparatively analyzed. Results: Elevated CNI scores were observed in 51 of 56 patients prior to therapy. The blinded validation cohort provided an overall prediction accuracy of 83% (25/30) and a positive predictive value of CNI score for progression of 92% (11/12). The combination of CNI score before cycle (Cy) 2 and 3 yielded a correct prediction for progression in all 13 patients. The CNI score also correctly identified cases of pseudo-tumor progression from hyperprogression. Before Cy2 and Cy3, there was no significant correlation for protein tumor markers, total cfDNA, or surrogate Tregs. Conclusions: Chromosomal instability quantification in plasma cfDNA can serve as an early indicator of response to immunotherapy. The method has the potential to reduce health care costs and disease burden for cancer patients following further validation. Clin Cancer Res; 23(17); 5074–81. ©2017 AACR.

A phase Ib study of pembrolizumab plus chemotherapy in patients with advanced cancer (PembroPlus)

Background:Pembrolizumab (P) is an anti-PD-1 antibody that blocks the interaction between programmed cell death protein 1 (PD-1) on T-cells and PD-L1 and PD-L2 on tumour cells. A phase Ib trial of P plus chemotherapy was undertaken to evaluate the safety and efficacy.Methods:Patients with advanced, metastatic solid tumours were enrolled onto one of six treatment arms. Pembrolizumab was given: with gemcitabine (G), G+docetaxel (D), G+nab-paclitaxel (NP), G+vinorelbine (V) or irinotecan (I) until progression or toxicity, or with liposomal doxorubicin (LD) for up to 15 cycles, progression or toxicity. Safety monitoring and response assessments were conducted.Results:Forty-nine patients were enrolled and treated. The most common adverse events were transaminitis, cytopenias, rash, diarrhoea, fatigue, nausea and vomiting. Arm 2 was closed due to poor accrual. The recommended phase II dose (RP2D) was determined for Arms 1, 3a, 4, 5 and 6. There were eight partial responses across multiple tumour types.Conclusions:Standard dose P can be safely combined with G, G+NP, G+V, I and LD. Efficacy was observed in multiple tumour types and evaluation to determine if response and duration of response are more robust than what would be expected for chemotherapy or immunotherapy alone requires further validation.

Abstract 3138: Changes in tumor cell-free DNA copy number instability (CNI) predict therapeutic response in metastatic cancers

Background: Tumor cell-free DNA (cfDNA) has the potential to provide minimally invasive patient specific biomarkers to monitor tumor burden. Gains and losses of chromosomal regions - as a hallmark of cancer - have been detected in plasma as copy number aberrations (CNAs), and for several cancers a relation to tumor size has been reported. Longitudinal observations during anti-cancer therapy have been mostly anecdotal. We measured CNAs changes during treatment by computing a genomic copy number instability index (CNI) of cfDNA to evaluate its potential to predict cytotoxic chemotherapy (chemo) response. Methods: 24 patients (pts) with advanced esophageal cancer (EC; n = 2), colorectal cancer (CRC; n = 3), non-Hodgkin lymphoma (NHL; n = 3), pancreatic ductal adenocarcinomas (PDAC; n = 4), and non-small cell lung cancer (NSCLC; n = 12) were included and assessable for response. DNA was extracted from pre-treatment plasma samples at baseline and sequentially for up to six cycles of chemotherapy. Copy-numbers were called from shotgun sequencing (Illumina) after mapping and quality filtering reads were counted in 5.5MBp windows (sliding) yielding a read coverage of 24,000-fold per bin. The read counts were transformed into log2 ratios and converted into a score based on Gaussian transformations. Concentration of total cfDNA was determined by digital PCR. Treatment response by imaging was recorded by RECIST 1.1 or EORTC PET/CT criteria. For pts with baseline CNI>40 (representing the 99.99% level for non-cancer healthy controls), CNI change was considered predictive of response or stable disease when there was a reduction of CNI ≥50% relative to baseline. Disease progression was demonstrated when: 1) CNI was ≥50% over nadir and Citation Format: Glen J. Weiss, Julia Beck, Donald P. Braun, Kirsten Bornemann-Kolatzki, Heather Barilla, Rhiannon Cubello, Ashish Sangal, Robert P. Whitehead, Madappa Kundranda, Vivek Khemka, Howard B. Urnovitz, Ekkehard Schutz. Changes in tumor cell-free DNA copy number instability (CNI) predict therapeutic response in metastatic cancers. [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 3138.

A prospective pilot study of genome-wide exome and transcriptome profiling in patients with small cell lung cancer progressing after first-line therapy

Background Small cell lung cancer (SCLC) that has progressed after first-line therapy is an aggressive disease with few effective therapeutic strategies. In this prospective study, we employed next-generation sequencing (NGS) to identify therapeutically actionable alterations to guide treatment for advanced SCLC patients. Methods Twelve patients with SCLC were enrolled after failing platinum-based chemotherapy. Following informed consent, genome-wide exome and RNA-sequencing was performed in a CLIA-certified, CAP-accredited environment. Actionable targets were identified and therapeutic recommendations made from a pharmacopeia of FDA-approved drugs. Clinical response to genomically-guided treatment was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Results The study completed its accrual goal of 12 evaluable patients. The minimum tumor content for successful NGS was 20%, with a median turnaround time from sample collection to genomics-based treatment recommendation of 27 days. At least two clinically actionable targets were identified in each patient, and six patients (50%) received treatment identified by NGS. Two had partial responses by RECIST 1.1 on a clinical trial involving a PD-1 inhibitor + irinotecan (indicated by MLH1 alteration). The remaining patients had clinical deterioration before NGS recommended therapy could be initiated. Conclusions Comprehensive genomic profiling using NGS identified clinically-actionable alterations in SCLC patients who progressed on initial therapy. Recommended PD-1 therapy generated partial responses in two patients. Earlier access to NGS guided therapy, along with improved understanding of those SCLC patients likely to respond to immune-based therapies, should help to extend survival in these cases with poor outcomes.

Abstract CT134: Phase I/II trial of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma

Background: Pembrolizumab (P) is a checkpoint inhibitor that blocks the interaction between programmed cell death protein 1 on T-cells and PD-L1 and PD-L2 on tumor cells. We conducted a single center phase Ib/II study of gemcitabine, nab-paclitaxel, and P (GNP) to evaluate the safety and efficacy in metastatic pancreatic adenocarcinoma (PDAC) (NCT02331251). Methods: PDAC patients (pts) with measurable disease, biopsy proven metastasis, adequate laboratory tests, and KPS ≥ 70% were eligible and received gemcitabine and nab-paclitaxel on days 1 and 8 and P 2 mg/kg on day 1 every 21 days until progression or toxicity. Safety monitoring, RECIST 1.1, and irRECIST assessments were conducted. Response imaging was performed prior to cycle 4, then every 3 months. Results: 17 pts with a median age of 56 were treated. 11 were women and all had a KPS of at least 80%. Any grade drug-related treatment adverse events (AEs) occurred in 100% of patients; the most common (>20% pts) were anemia, thrombocytopenia, hypoalbuminemia, ALT and ALK elevation, fatigue, rash, nausea, vomiting, diarrhea, fever, insomnia, and edema in limbs. Grade 3 events (>10% pts) were hyponatremia, thrombocytopenia, and neutropenia (2 case each, 11.8%). Dose-limiting toxicities occurred only in previously treated PDAC (grade 3 thrombocytopenia; grade 3 fatigue and thrombocytopenia) and the cohort was subsequently divided into chemo naive and previously treated pts. The recommended phase II dose (RP2D) for chemo naive PDAC was gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2. Of the 8 evaluable chemo naive PDAC, the disease control rate (partial response [PR] + stable disease[SD]) was 100%. There were 2 PR on treatment for ~11 and 15 months and there are 3 pts still too early to assess. The primary endpoint of >15% complete response was not met. The best response for previously treated pts was SD. For chemo naive and previously treated PDAC, the 6-month survival rate is 89% (with 3 pts still on study less than 3 months) and 40%, respectively. The median PFS and OS is 5 and 10.3 months and 2.1 and 4.1 months for chemo naive and previously treated pts, respectively. Conclusions: GNP can be safely given to chemo naive PDAC pts. Efficacy appears to be similar to slightly improved over previously reported results for standard weekly x 3 every 28 day gemcitabine and nab-paclitaxel dosing. Citation Format: Glen J. Weiss, Jordan Waypa, Jessica Coats, Lisa Blaydorn, Kayla McGahey, Ashish Sangal, Robert P. Whitehead, Vivek Khemka. Phase I/II trial of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma [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 CT134. doi:10.1158/1538-7445.AM2017-CT134

Abstract A50: Phase Ib/II study of pembrolizumab plus chemotherapy: Initial results of metastatic cancer patients

Background: A selective anti-PD-1 antibody, pembrolizumab (P), blocks the interaction between programmed death-1 (PD-1) on T-cells and PD-L1 and PD-L2 on tumor cells. We report safety and clinical activity of P combined with chemotherapy in patients with metastatic cancer (NCT02331251). Methods: Patients (pts) with confirmed metastatic solid tumors were treated with P 2 mg/kg on day 1 every 21 day cycle on 1 of 6 different arms: gemcitabine (G) on days 1 and 8, G on days 1 and 8 + docetaxel (D) on day 8, G + nab-paclitaxel (NP) on days 1 and 8, G + vinorelbine (V) on days 1 and 8, irinotecan (I) on day 1, or liposomal doxorubicin (LD) on day 1 until progression or toxicity. Eligibility included ≥1 measurable tumor lesion, Karnofsky Performance Status (KPS) of ≥70%, and adequate organ function. Tumors were assessed every 3 cycles using RECIST 1.1 and immune-related response criteria and best overall response (BOR) was evaluated. Results: 37 pts have been enrolled at the time of submission (Table I). Median age was 55 (range 33-74) and median KPS was 80%. 3 patients (2 sarcoma, 1 ER+ breast cancer) had history of gemcitabine exposure before dosing on the G+V arm, and 2 patients with NSCLC had prior exposure to nivolumab for ≥ 2 months. The maximum tolerated dose (MTD) was exceeded for arms 3, 4, and 5 (Table I), and arm 3 dosing was subsequently divided into chemo naive (arm 3a) and previously treated (arm 3b) PDAC pts. Any grade drug-related treatment adverse events (AEs) occurred in 95% of patients; the most common (>10% pts) were skin rash, fatigue, diarrhea, anorexia, neutropenia, anemia, thrombocytopenia, and extremity edema. 1 infusion-related reaction was observed, related to LD. 24 patients are currently evaluable for BOR, 10 are still too early to evaluate. One PDAC pt is on G+NP for 8+ months with PR. Two SCLC pts continue on I for 7+ months with PR. 1 sarcoma pts continue on LD for 3+ and 6+ months with SD. Conclusions: In pts with metastatic cancer, P plus chemotherapy appears to be safe. P plus G phase 2 has begun enrolling TNBC pts. We anticipate confirmation of the recommended phase 2 dose for ∼3 of the 6 arms by the time of the conference. Citation Format: Glen J. Weiss, Marci Pierog, Lisa Blaydorn, Ashish Sangal, Jiaxin Niu, John H. Farley, Vivek Khemka. Phase Ib/II study of pembrolizumab plus chemotherapy: Initial results of metastatic cancer patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A50.

Abstract 624: Evaluation and comparison of two commercially available targeted NGS platforms to assist oncology decision making

Background: It is widely acknowledged that there is value in examining cancers for genomic aberrations via Next-Generation Sequencing (NGS) on formalin-fixed paraffin-embedded (FFPE) tumor tissue. How commercially available NGS platforms compare with each other and the clinical utility of the reported actionable results is not well known. During the course of the study, the Foundation One (F1) test generated data on a combination of somatic mutations, indels, chromosomal abnormalities, and DNA copy number changes at ∼250X coverage, while the PCDx test generated the same type of data at >5,000X coverage plus provided mRNA expression levels. We sought to compare and evaluate paired FFPE tumor using these two platforms. Methods: Paired FFPE blocks from patients were submitted to both vendors for NGS analysis. Samples were from patients with advanced solid tumors. Patients either had a cancer type for which no standard of care exists or had progression on >1 line of systemic therapy. Turnaround time (TAT) was calculated (calendar days between the date sample received at the vendor to time of first NGS report). A biomarker was considered actionable if it has a published association with treatment response in humans. The assay report was assigned the highest of the following categories based on the list of actionable biomarker(s): commercially available drug (CA) (highest), clinical trial drug (CT), or neither option (NO) (lowest). Results: There were 10M:11F; median age was 56 (range 35-65). The most common cancer types were 7 thoracic, 4 GI, and 3 GU. Paired F1 and PCDx results for 21 unique patient tumors submitted between 3/2014 and 9/2014 were available. Due to insufficient archival tissue from the same collection period, 1 case used samples from different collections. PCDx reported first results faster than F1 in 20 cases. When received at both vendors on the same day, PCDX reported first results for 14 of 15 cases, with a median TAT of 9 days earlier than F1 (range -7 to 14 days). PCDx and F1 reported a CA 6 and 5 times, CT 4 and 4 times, and NO 11 and 12 times; respectively. PCDx provided higher ranking actionable targets for 5 cases vs. 3 cases for F1; the rest had equivalent ranking. Conclusions: In this analysis, commercially available NGS platforms provided clinically relevant actionable targets (CA or CT) in ∼45% of diverse cancer types. PCDx outperformed F1 in TAT and clinically relevant higher ranking of actionable targets. Citation Format: Glen J. Weiss, Brandi R. Hoff, Robert P. Whitehead, Ashish Sangal, Susan A. Gingrich, Vivek Khemka. Evaluation and comparison of two commercially available targeted NGS platforms to assist oncology decision making. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 624. doi:10.1158/1538-7445.AM2015-624