Daniel Haggstrom

AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.

BACKGROUND The EGFR T790M mutation is the most common mechanism of drug resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients who have lung cancer with an EGFR mutation (EGFR-mutated lung cancer). In preclinical models, the EGFR inhibitor AZD9291 has been shown to be effective against both EGFR tyrosine kinase inhibitor-sensitizing and T790M resistance mutations. METHODS We administered AZD9291 at doses of 20 to 240 mg once daily in patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors. The study included dose-escalation cohorts and dose-expansion cohorts. In the expansion cohorts, prestudy tumor biopsies were required for central determination of EGFR T790M status. Patients were assessed for safety, pharmacokinetics, and efficacy. RESULTS A total of 253 patients were treated. Among 31 patients enrolled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at the doses evaluated. An additional 222 patients were treated in five expansion cohorts. The most common all-cause adverse events were diarrhea, rash, nausea, and decreased appetite. The overall objective tumor response rate was 51% (95% confidence interval [CI], 45 to 58). Among 127 patients with centrally confirmed EGFR T790M who could be evaluated for response, the response rate was 61% (95% CI, 52 to 70). In contrast, among 61 patients without centrally detectable EGFR T790M who could be evaluated for response, the response rate was 21% (95% CI, 12 to 34). The median progression-free survival was 9.6 months (95% CI, 8.3 to not reached) in EGFR T790M-positive patients and 2.8 months (95% CI, 2.1 to 4.3) in EGFR T790M-negative patients. CONCLUSIONS AZD9291 was highly active in patients with lung cancer with the EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT01802632.).

Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer: AURA study phase II extension component

Purpose Osimertinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for both EGFR-TKI sensitizing ( EGFRm) and T790M resistance mutations. AURA (NCT01802632) is a phase I/II clinical trial to determine the dose, safety, and efficacy of osimertinib. This article reports the results from the phase II extension component. Patients and Methods Patients with EGFR-TKI-pretreated EGFRm- and T790M-positive advanced non-small-cell lung cancer (NSCLC) received once-daily osimertinib 80 mg. T790M status was confirmed by central testing from a tumor sample taken after the most recent disease progression. Patients with asymptomatic, stable CNS metastases that did not require corticosteroids were allowed to enroll. The primary end point was objective response rate (ORR) by independent radiology assessment. Secondary end points were disease control rate, duration of response, progression-free survival (PFS), and safety. Patient-reported outcomes comprised an exploratory objective. Results In total, 201 patients received treatment, with a median treatment duration of 13.2 months at the time of data cutoff (November 1, 2015). In evaluable patients (n = 198), ORR was 62% (95% CI, 54% to 68%), and the disease control rate was 90% (95% CI, 85 to 94). Median duration of response in 122 responding patients was 15.2 months (95% CI, 11.3 to not calculable). Median PFS was 12.3 months (95% CI, 9.5 to 13.8). The most common possibly causally related adverse events (investigator assessed) were diarrhea (43%; grade ≥ 3, < 1%) and rash (grouped terms; 40%; grade ≥ 3, < 1%). Interstitial lung disease (grouped terms) was reported in eight patients (4%; grade 1, n = 2; grade 3, n = 3; grade 5, n = 3). Conclusion In patients with EGFRm T790M advanced NSCLC who progress after EGFR-TKI treatment, osimertinib provides a high ORR, encouraging PFS, and durable response.

nab-Paclitaxel-Based Therapy in Underserved Patient Populations: The ABOUND.70+ Study in Elderly Patients With Advanced NSCLC

The phase 4 ABOUND.70+ trial assessed the safety and efficacy of nab-paclitaxel/carboplatin continuously or with a 1-week break between cycles in elderly patients with advanced non-small cell lung cancer (NSCLC). Patients ≥70 years with locally advanced/metastatic NSCLC were randomized 1:1 to first-line nab-paclitaxel days 1, 8, 15 plus carboplatin day 1 of a 21-day cycle (21d) or the same nab-paclitaxel/carboplatin regimen with a 1-week break between cycles (21d + break; 28d). The primary endpoint was the percentage of patients with grade ≥ 2 peripheral neuropathy (PN) or grade ≥ 3 myelosuppression. Other key endpoints included progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). A total of 143 patients were randomized (71 to 21d, 72 to 21d + break). The percentage of patients with grade ≥ 2 PN or grade ≥ 3 myelosuppression was similar between the 21d and 21d + break arms (76.5 and 77.1%; P = 0.9258). Treatment exposure was lower in the 21d arm compared with the 21d + break arm. Median OS was 15.2 and 16.2 months [hazard ratio (HR) 0.72, 95% CI 0.44–1.19; P = 0.1966], median PFS was 3.6 and 7.0 months (HR 0.48, 95% CI 0.30–0.76; P < 0.0019), and ORR was 23.9 and 40.3% (risk ratio 1.68, 95% CI 1.02–2.78; P = 0.0376) in the 21d and 21d + break arms, respectively. In summary, the 1-week break between treatment cycles significantly improved PFS and ORR but did not significantly reduce the percentage of grade ≥ 2 PN or grade ≥ 3 myelosuppression. Overall, the findings support the results of prior subset analyses on the safety and efficacy of first-line nab-paclitaxel/carboplatin in elderly patients with advanced NSCLC.

ATNT-27ASSESSING THE SAFETY OF COMBINATION THERAPY WITH BEVACIZUMAB AND OPTUNETM FOR HIGH GRADE GLIOMAS.

BACKGROUND: The prognosis for patients with high grade gliomas remains dismal. In addition to cytotoxic therapy, the FDA has approved bevacizumab and OptuneTM (Tumor Treating Fields) for recurrent glioblastoma. Given the prognosis and multiple treatment options, many clinicians have elected to offer combined therapy. We examined our patient population at two institutions where combination therapy has been used. METHODS: We retrospectively reviewed clinical courses of all patients receiving OptuneTM who have been concurrently managed with bevacizumab or experienced prior therapy with bevacizumab. Toxicity was described for those patients. Patients who received OptuneTM for at least 4 weeks with concurrent bevacizumab were analyzed for overall survival from time of initiation of concurrent therapy. RESULTS: We identified 37 patients, 26 males and 11 females. Of those, 33 patients received concurrent therapy, and all of those patients had prior bevacizumab exposure. OptuneTM was started as single therapy in 4 patients after bevacizumab exposure and failure. 6 patients experienced contact dermatitis which did not delay therapy. 1 patient had a small skin erosion which did not delay therapy. 2 patients had small skin erosions which delayed OptuneTM therapy. 1 patient had folliculitis and skin erosions and ulcers which necessitated cessation of therapy. 1 patient had a grade 2 intracranial bleed with no clinical sequelae aside from the need to hold bevacizumab. 29 patients received this therapy for at least 4 weeks. Median duration of concurrent therapy was 4 months. Median OS from initiation of concurrent therapy was 5.3 months. CONCLUSIONS: In our dataset, there was no toxicity appreciated aside from mild skin toxicity in the majority of patients. Combining bevacizumab and OptuneTM does not appear to significantly increase risk of bleeding or stroke. The incidence and severity of skin reactions were comparable to those described previously. Additional trials to investigate this combination are ongoing.

Abstract B105: Characterization of the activity of AZD9291 in patients (pts) with T790M ‘negative’ advanced non-small cell lung cancer (aNSCLC)

Objective AZD9291 is an oral, selective, irreversible EGFR-TKI, effective against EGFR-TKI-sensitizing (EGFRm) and resistance T790M mutations. Pre-study tumor samples from pts enrolled into expansion cohorts of a PhI study (AURA, NCT01802632) were tested centrally for T790M status. Pts with T790M positive tumor samples had higher objective response rate (ORR) than pts with no detectable T790M (T790M ‘negative’): 78/127 (61%) and 13/61 (21%), respectively (Janne et al 2015). Exploratory analyses to characterize AZD9291 activity in pts whose tumors were T790M negative by central test were performed. Methods Pts with EGFRm aNSCLC and acquired resistance to EGFR-TKIs were enrolled into expansion cohorts of the AURA study. The T790M status of pre-study tumor samples was determined locally (any method allowed) and/or centrally using the cobas TM EGFR mutation test (Roche Molecular Systems, Inc.). Presence of T790M in plasma derived ctDNA was determined by digital PCR (BEAMing). Pts with a centrally determined tumor based T790M negative status were then classified into one of nine groups according to local tumor status (T790M positive, negative, or unknown) and ctDNA status (T790M positive, negative, or unknown). Clinical outcome is reported for each group. Results 69 pts with T790M negative tumor status were determined centrally, and received AZD9291; 35 and 21 were also negative by local test and ctDNA, respectively and 7 were negative by all 3 tests; despite a negative central test, T790M positive tumor status was identified in 11 pts by prior local test and 26 by ctDNA. 17 pts with a central T790M negative status responded to AZD9291 treatment. ORR was 55% (6/11) in pts with a central T790M negative/local positive test result. No objective responses (0/7) were observed in pts with T790M negative tumor status by all three tests. Additional analysis of the sub-groups, by immediate prior TKI, EGFRm status, and duration of response will be available for presentation. Discussion In 69 pts with centrally identified T790M negative tumor status, 17 achieved a confirmed response. Of these, 12 were T790M positive by local test, ctDNA, or both. Different sensitivity and specificity of assays, tumor heterogeneity, and ctDNA shedding may explain positive results in this small group of pts classified as central T790M negative. The data support the hypothesis that T790M directed inhibitors are active against T790M driven resistance. Citation Format: Pasi A. Janne, Enriqueta Felip, Dong-Wan Kim, Thomas John, Daniel E. Haggstrom, Myung-Ju Ahn, Kenneth S. Thress, Suzanne C. Jenkins, Helen Mann, Mireille V. Cantarini, Simon P. Dearden, James Chih-Hsin Yang. Characterization of the activity of AZD9291 in patients (pts) with T790M ‘negative’ advanced non-small cell lung cancer (aNSCLC). [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 B105.

Abstract C80: Development of EGFR C797S mutation in serial liquid biopsy assessments in the clinical practice setting

Introduction: EGFR T790M has emerged as an important biomarker to predict response to 3rd-generation tyrosine kinase inhibitors (TKI). Therapies such as AZD 9291 and Rociletinib demonstrated impressive results in the clinical setting in patients with non-small cell lung cancer (NSCLC). However just as this resistance biomarker (T790M) has developed as a result of treatment with prior EGFR TKIs, EGFR C797S mutation is an acquired resistance mechanism to EGFR T790M inhibitors. This mutation was recently reported for the first time in clinical practice utilizing tissue-biopsy based next generation sequencing (NGS) and in the clinical trial setting in cell-free circulating DNA (cfDNA). Here we report the first case of a patient with NSCLC and emergence of C797S mutation utilizing a cfDNA biopsy-free NGS panel in serial assessments in the clinical setting. Methods: Patients with NSCLC were seen at Levine Cancer Institute and had serial blood draws to assess molecular aberrations in cfDNA over time for comparison with radiographic reviews. Blood samples were sent to Guardant360 for assessment by NGS with a targeted cfDNA NGS panel for 68 genes with complete exon sequencing for all 28 exons in EGFR, and other genes in the panel. Mutant allele fractions (MAF) are reported as% of mutant DNA molecules divided by total molecules (mostly leukocyte DNA-derived) overlapping the same mutated nucleotide base position. Results: A 50 year old African-American female never-smoker with lung adenocarcinoma developed a tissue-biopsy confirmed EGFR T790M mutation after 12 months on erlotinib for EGFR exon 19 deletion. She had significant clinical and radiographic responses to a 3rd generation TKI started May 2014. cfDNA NGS tests in March and April 2015 showed no genomic alterations detectable. In late May 2015, she developed clinical symptoms of cough, dyspnea and fatigue but no definitive radiographic evidence of progression on scans June 2015. She received steroids and antibiotics and continued treatment with the 3rd generation TKI. However, corresponding cfDNA NGS testing revealed emergence of multiple low level mutations and the original deletion in EGFR (EGFR L747_P753 DelInsS, T790M, C797S, and A755G variant of uncertain significance) and TP53 (all Discussion: Complete exon sequencing of cfDNA upon clinical progression uncovered the simultaneous re-emergence of the original driver EGFR exon 19 del and resistance driver mutation EGFR T790M as well as the emergence of the next resistance driver mutation EGFR C797S. The latter mutation interferes with covalent binding of a 3rd generation TKI and under treatment pressure, the tumor appears to have simultaneously evolved two different EGFR C797S clones at low MAFs. cfDNA can be a dynamic measure of tumor response, easily obtained from a patient on any visit with potential for detection before macroscopic/radiographic evidence of progression, as demonstrated in this case with tumor evolution of the EGFR T790M and C797S alterations. Citation Format: Kathryn F. Mileham, Qing Zhang, Carol J. Farhangfar, Daniel E. Haggstrom, Stephen Fairclough, Oliver A. Zill, Daniel R. Carrizosa, Richard B. Lanman, Edward S. Kim. Development of EGFR C797S mutation in serial liquid biopsy assessments in the clinical practice setting. [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 C80.