Juliana Eng

Impact of Concurrent PIK3CA Mutations on Response to EGFR Tyrosine Kinase Inhibition in EGFR-Mutant Lung Cancers and on Prognosis in Oncogene-Driven Lung Adenocarcinomas.

Introduction: In patients with epidermal growth factor receptor (EGFR)-mutant or KRAS-mutant lung adenocarcinomas, the prognostic impact of a concurrent PIK3CA mutation remains unclear. Although preclinical data suggest that sensitivity to EGFR tyrosine kinase inhibition (TKI) is decreased in EGFR-mutant lung cancers also harboring a PIK3CA mutation, this interaction has not been explored clinically. Methods: Patients with lung adenocarcinomas harboring a PIK3CA mutation concurrent with a separate driver mutation were identified through mutational hotspot testing, multiplex sizing assays, and fluorescence in situ hybridization. Overall survival and outcomes with EGFR TKI monotherapy (EGFR-mutant) were estimated using Kaplan–Meier methods and compared between double-mutant (EGFR-mutant or KRAS-mutant, concurrent PIK3CA-mutant) and single-mutant patients (EGFR-mutant or KRAS-mutant, PIK3CA wild-type) using log-rank tests. Results: In EGFR-mutant and KRAS-mutant lung cancers, a concurrent PIK3CA mutation was associated with a decrease in median overall survival: 18 versus 33 months (EGFR double mutant, n = 10 versus single mutant, n = 43, p = 0.006), and 9 versus 16 months (KRAS double mutant, n = 16 versus single mutant, n = 47, p = 0.020). In EGFR-mutant lung cancers, a concurrent PIK3CA mutation did not impact benefit from EGFR TKI monotherapy. Single versus double mutant: objective response rate, 83% (n = 29) versus 62% (n = 6, p = 0.80); median time to progression, 11 (n = 29) versus 8 months (n = 6, p = 0.84); and median duration of TKI therapy, 15 (n = 32) versus 15 months (n = 10, p = 0.65). Conclusion: A concurrent PIK3CA mutation is a poor prognostic factor in patients with advanced EGFR-mutant or KRAS-mutant lung adenocarcinomas. There was no evidence that clinical benefit from EGFR TKI monotherapy is affected by a concurrent PIK3CA mutation in EGFR-mutant lung cancers.

Outcomes of chemotherapies and HER2 directed therapies in advanced HER2-mutant lung cancers

Human epidermal growth factor receptor 2 (HER2, ERBB2) mutations occur in 3% of lung adenocarcinomas. While case reports and series have shown activity of HER2 targeted agents in these patients, little is known about outcomes of chemotherapies. Patients with stage IV HER2-mutant lung cancers at Memorial Sloan Kettering were reviewed. Patient demographics, types of HER2 mutations, duration of systemic treatments and survival were analyzed. We identified 38 patients with HER2-mutant lung cancers: median age 62; majority were women (n=24), never smokers (n=22), and all had adenocarcinomas. A 12 base pair in-frame insertion YVMA in exon 20 (p.A775_G776insYVMA) was present in 24 (63%, 95% CI 46-78%) patients. In addition, there were four 9 base pair insertions, one 6 base pair insertion, and five 3 base pair insertions in exon 20, and four single bp substitutions (exon 20 L755F, V777L, D769H, exon 8 S310F). The median overall survival from date of diagnosis of stage IV disease was 2.3 years (95% CI 1.2-2.6). The median duration of chemotherapy was 4.3 months (68 treatments, range 0-21 months): 6.2 months for pemetrexed ±platinum/bevacizumab, 4 months for taxane ±platinum/bevacizumab, 2.6 months for gemcitabine, 3.5 months for vinorelbine. The median duration of HER2 tyrosine kinase inhibitors was 2.2 months (28 treatments, range 0.3-16.3 months). As we search for better targeted therapies for patients with HER2-mutant lung cancers, chemotherapy remains an important component of care.

Abstract CT225: Ado-trastuzumab emtansine for HER2 amplified or HER2 overexpressed cancers: A phase II “basket” trial

Background: The use of therapies targeting the human epidermal growth factor receptor 2 (HER2, ERBB2) has transformed care in breast and gastric cancers. HER2 amplification has emerged as a therapeutic target in 2-5% of lung cancers, 6% of bladder cancers, 5-12% of endometrial cancers, and 2-5% of ovarian and colorectal cancers. High level HER2 protein overexpression by immunohistochemistry correlates with HER2 amplification. Ado-trastuzumab emtansine is an antibody drug conjugate linking the HER2 targeted monoclonal antibody trastuzumab, with the cytotoxic anti-microtubule drug emtansine. This agent improves response and survival in patients with HER2 amplified or HER2 overexpressed breast cancers. We hypothesize that ado-trastuzumab emtansine will be effective in any tumor with HER2 amplification or overexpression, regardless of the primary site. Methods/Design: This phase II “basket” trial at Memorial Sloan Kettering (MSK) will evaluate ado-trastuzumab emtansine across 4 cohorts of patients with HER2 amplified or HER2 overexpressed advanced lung, bladder, endometrial, and other cancers. All patients will receive ado-trastuzumab emtansine at 3.6 mg/m 2 IV every 21 days until disease progression or unacceptable toxicity. The primary endpoint is objective response rate (ORR). Patients will be molecularly selected primarily through the MSK-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), where all patients with advanced cancers can have tumor next generation sequencing (NGS) performed with a capacity to sequence 15,000 tumors each year. MSK-IMPACT uses the Illumina HiSeq platform to screen for potentially actionable genetic alterations, including single base substitutions, indels, copy number alterations and selected fusions across 341 cancer-related genes, including HER2 amplification. HER2 amplification assessment by our NGS assay correlates well with amplification by in-situ hybridization, is less operator-dependent and is performed concurrently with the mutation profile. In the first 6 months since introducing MSK-IMPACT into routine patient care, we have already identified HER2 amplification in 7 of 227 (3%) lung cancers sequenced, 4 of 67 (6%) bladder cancers sequenced, and 2 of 50 (4%) endometrial cancers sequenced. Using a Simon optimal two-stage design, a one-sided Type I error rate α at 10% and power of 80%, a true ORR ≤ 10% will be considered unacceptable (null hypothesis) whereas a true ORR ≥ 30% will merit further study (alternative hypothesis). In each cohort, 7 patients will be accrued in the first stage; if there are no responses observed, the cohort will be closed. Otherwise, 11 additional patients will be accrued for second stage. A cohort will be deemed worthy of further investigation if ≥4 responses are observed in 18 patients. Exploratory analysis will examine the concordance among the HER2 biomarkers: gene amplification, protein overexpression and gene mutation. Citation Format: Bob T. Li, Marjorie Zauderer, Jamie Chaft, Alexander Drilon, Juliana Eng, Camelia Sima, Vicky Makker, Gopa Iyer, Yelena Janjigian, David Hyman, Maria Arcila, Jose Baselga, Mark G. Kris. Ado-trastuzumab emtansine for HER2 amplified or HER2 overexpressed cancers: A phase II “basket” trial. [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 CT225. doi:10.1158/1538-7445.AM2015-CT225

Clinical outcomes of patients with resected, early-stage ALK-positive lung cancer

OBJECTIVES Reports of the prognostic significance of ALK-rearrangement in resected non-small cell lung cancer (NSCLC) have been contradictory. We aimed to determine the prognosis of early-stage ALK-positive lung cancers relative to KRAS- and EGFR-mutant lung cancers. MATERIAL AND METHODS We reviewed medical records of patients with resected NSCLC harboring an ALK rearrangement (n = 29) or a driver mutation in EGFR (n = 255) or KRAS (n = 480). Recurrence-free survival (RFS) was estimated for each genotype with the differences reported as a hazard ratio (HR). RESULTS Among the 764 patients, 555 (73%), 101 (13%), and 108 (14%) had stage I, II, and III NSCLC, respectively. ALK-positive patients were distributed across all stages: 10 (34%) stage I, 6 (21%) stage II, and 13 (45%) stage III. Median RFS was not reached for EGFR-mutant patients, 24.3 months (95%CI 11.4-65.3) for ALK-positive patients, and 72.9 months (95%CI 59.7 to undefined) for KRAS-mutant patients. When adjusted for stage, ALK-positive NSCLC remained associated with worse RFS compared to EGFR-mutant (HR 1.8, 95%CI: 1.1-3.1), but not when compared to KRAS-mutant (HR 1.3, 95%CI: 0.8-2.1) NSCLC. CONCLUSIONS In this large series of resected NSCLC, ALK rearrangements were associated with a trend toward inferior disease outcomes compared to other clinically relevant genomic subsets. These data support the need for clinical trials evaluating use of ALK inhibitors among ALK-positive patients with localized or locally-advanced disease.

New Discoveries for the Treatment of Lung Cancer and the Role of Small Biopsy Material

While shifts in the treatment paradigms for cancer have been altogether infrequent, a common thread that links many of them is the pairing of an oncogenic driver event with a rationally targeted therapy. Thus, imatinib is used for the treatment of chronic myelogenous leukemia (bcr-abl translocations) and gastrointestinal stromal tumors (c-kit mutations), all-trans-retinoic acid for the treatment of acute promyelocytic leukemia (t(15;17)(q22;q21)), and vemurafenib for the treatment of melanoma (BRAF V600E mutations). 2004 marked the therapeutic paradigm shift for lung cancer, when sequencing efforts by multiple groups identified activating mutations in the epidermal growth factor receptor (EGFR) gene from rare lung adenocarcinoma patients who had substantial responses to EGFR tyrosine kinase inhibitors then under study in a number of clinical trials.