Sophie Sun

Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): a double-blind, randomised, phase 3 trial

BACKGROUND Dacomitinib is an irreversible pan-HER tyrosine-kinase inhibitor with preclinical and clinical evidence of activity in non-small-cell lung cancer. We designed BR.26 to assess whether dacomitinib improved overall survival in heavily pretreated patients with this disease. METHODS In this double-blind, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) with advanced or metastatic non-small-cell lung cancer from 75 centres in 12 countries. Eligible patients had received up to three previous lines of chemotherapy and either gefitinib or erlotinib, and had assessable disease (RECIST 1.1) and tumour tissue samples for translational studies. Patients were stratified according to centre, performance status, tobacco use, best response to previous EGFR tyrosine-kinase inhibitor, weight loss within the previous 3 months, and ethnicity, and were then randomly allocated 2:1 to oral dacomitinib 45 mg once-daily or matched placebo centrally via a web-based system. Treatment continued until disease progression or unacceptable toxicity. The primary outcome was overall survival in the intention-to-treat population; secondary outcomes included overall survival in predefined molecular subgroups, progression-free survival, the proportion of patients who achieved an objective response, safety, and quality of life. This study is completed, although follow-up is ongoing for patients on treatment. This study is registered with ClinicalTrials.gov, number NCT01000025. FINDINGS Between Dec 23, 2009, and June 11, 2013, we randomly assigned 480 patients to dacomitinib and 240 patients to placebo. At the final analysis (January, 2014), median follow-up was 23·4 months (IQR 15·6-29·6) for patients in the dacomitinib group and 24·4 months (11·5-38·9) for those in the placebo group. Dacomitinib did not improve overall survival compared with placebo (median 6·83 months [95% CI 6·08-7·49] for dacomitinib vs 6·31 months [5·32-7·52] for placebo; hazard ratio [HR] 1·00 [95% CI 0·83-1·21]; p=0·506). However, patients in the dacomitinib group had longer progression-free survival than those in the placebo group (median 2·66 months [1·91-3·32] vs 1·38 months [0·99-1·74], respectively; HR 0·66 [95% CI 0·55-0·79]; p<0·0001), and a significantly greater proportion of patients in the dacomitinb group achieved an objective response than in the placebo group (34 [7%] of 480 patients vs three [1%] of 240 patients, respectively; p=0·001). Compared with placebo, the effect of dacomitinib on overall survival seemed similar in patients with EGFR-mutation-positive tumours (HR 0·98, 95% CI 0·67-1·44) and EGFR wild-type tumours (0·93, 0·71-1·21; pinteraction=0·69). However, we noted qualitative differences in the effect of dacomitinib on overall survival for patients with KRAS-mutation-positive tumours (2·10, 1·05-4·22) and patients with KRAS wild-type tumours (0·79, 0·61-1·03; pinteraction=0·08). Compared with placebo, patients allocated dacomitinib had significantly longer time to deterioration of cough (p<0·0001), dyspnoea (p=0·049), and pain (p=0·041). 185 (39%) of 477 patients who received dacomitinib and 86 (36%) of 239 patients who received placebo had serious adverse events. The most common grade 3-4 adverse events were diarrhoea (59 [12%] patients on dacomitinib vs no controls), acneiform rash (48 [10%] vs one [<1%]), oral mucositis (16 [3%] vs none), and fatigue (13 [3%] vs four [2%]). INTERPRETATION Dacomitinib did not increase overall survival and cannot be recommended for treatment of patients with advanced non-small-cell lung cancer previously treated with chemotherapy and an EGFR tyrosine-kinase inhibitor. FUNDING Canadian Cancer Society Research Institute and Pfizer.

Lessons learned from the application of whole-genome analysis to the treatment of patients with advanced cancers

Given the success of targeted agents in specific populations it is expected that some degree of molecular biomarker testing will become standard of care for many, if not all, cancers. To facilitate this, cancer centers worldwide are experimenting with targeted “panel” sequencing of selected mutations. Recent advances in genomic technology enable the generation of genome-scale data sets for individual patients. Recognizing the risk, inherent in panel sequencing, of failing to detect meaningful somatic alterations, we sought to establish processes to integrate data from whole-genome analysis (WGA) into routine cancer care. Between June 2012 and August 2014, 100 adult patients with incurable cancers consented to participate in the Personalized OncoGenomics (POG) study. Fresh tumor and blood samples were obtained and used for whole-genome and RNA sequencing. Computational approaches were used to identify candidate driver mutations, genes, and pathways. Diagnostic and drug information were then sought based on these candidate “drivers.” Reports were generated and discussed weekly in a multidisciplinary team setting. Other multidisciplinary working groups were assembled to establish guidelines on the interpretation, communication, and integration of individual genomic findings into patient care. Of 78 patients for whom WGA was possible, results were considered actionable in 55 cases. In 23 of these 55 cases, the patients received treatments motivated by WGA. Our experience indicates that a multidisciplinary team of clinicians and scientists can implement a paradigm in which WGA is integrated into the care of late stage cancer patients to inform systemic therapy decisions.

Pan Canadian Rash Trial: A Randomized Phase III Trial Evaluating the Impact of a Prophylactic Skin Treatment Regimen on Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor–Induced Skin Toxicities in Patients With Metastatic Lung Cancer

PURPOSE Erlotinib is an epidermal growth factor receptor inhibitor approved for patients with advanced non-small-cell lung cancer (NSCLC) whose epidermal growth factor receptor expression status is positive or unknown. Although it is efficacious, erlotinib can cause skin toxicity. This prospective, randomized phase III trial examined the effect of prophylactic treatment of erlotinib-induced skin rash. PATIENTS AND METHODS Patients receiving erlotinib in the second- or third-line setting for advanced NSCLC were randomly assigned to prophylactic minocycline (100 mg twice per day for 4 weeks), reactive treatment (after rash developed, per grade of rash), or no treatment unless severe (grade 3). Rash incidence and severity, time to maximal rash, time to resolution, and overall survival (OS) were compared among treatment groups. RESULTS In all, 150 patients were randomly assigned, 50 to each of three treatment arms. The incidence of skin toxicity was 84% regardless of treatment arm. Prophylactic treatment with minocycline significantly lengthened the time to the most severe grade of rash. Grade 3 rash was significantly higher in the no-treatment arm. OS was not significantly different among treatment arms, but patients receiving prophylactic or reactive treatments had a longer OS (7.6 and 8 months, respectively) than those who received no rash treatment (6 months). Rash was not self-limiting. CONCLUSION The incidence of all grades of rash did not differ statistically among the three arms, so the trial was negative. The incidence of grade 3 skin toxicities was reduced in patients who were treated with prophylactic minocycline or reactive treatment. Efficacy was not compromised. Prophylactic minocycline and reactive treatment are both acceptable options for the necessary treatment of erlotinib-induced rash in the second- or third-line setting of metastatic NSCLC.

Personalized oncogenomics: clinical experience with malignant peritoneal mesothelioma using whole genome sequencing.

Peritoneal mesothelioma is a rare and sometimes lethal malignancy that presents a clinical challenge for both diagnosis and management. Recent studies have led to a better understanding of the molecular biology of peritoneal mesothelioma. Translation of the emerging data into better treatments and outcome is needed. From two patients with peritoneal mesothelioma, we derived whole genome sequences, RNA expression profiles, and targeted deep sequencing data. Molecular data were made available for translation into a clinical treatment plan. Treatment responses and outcomes were later examined in the context of molecular findings. Molecular studies presented here provide the first reported whole genome sequences of peritoneal mesothelioma. Mutations in known mesothelioma-related genes NF2, CDKN2A, LATS2, amongst others, were identified. Activation of MET-related signaling pathways was demonstrated in both cases. A hypermutated phenotype was observed in one case (434 vs. 18 single nucleotide variants) and was associated with a favourable outcome despite sarcomatoid histology and multifocal disease. This study represents the first report of whole genome analyses of peritoneal mesothelioma, a key step in the understanding and treatment of this disease.

Referral patterns in advanced non-small cell lung cancer: impact on delivery of treatment and survival in a contemporary population based cohort.

INTRODUCTION Chemotherapy improves overall survival (OS) in advanced non-small cell lung cancer (NSCLC), yet low rates of chemotherapy utilization have been observed. We sought to characterize the clinical effectiveness of chemotherapy in the general population by evaluating referral patterns, predictors of chemotherapy receipt and outcomes. METHODS All referred cases of stage IIIB/IV NSCLC in British Columbia from January 1 to December 31, 2009 were retrospectively reviewed. Patient demographics, tumor characteristics and treatments were extracted. OS was estimated using the Kaplan-Meier method. Cox Proportional Hazards modeling was used to control for confounding variables. Multiple logistic regression was used to assess factors that predicted for chemotherapy treatment. RESULTS 1373 patients were identified. Median age 70 years, 53% male, 37% ECOG ≥ 3. HISTOLOGY 34% non-squamous, 21% squamous and 46% NOS. 748 (54%) patients were assessed by medical oncology and 417 (30%) received chemotherapy. Predictors of chemotherapy treatment were younger age, ECOG 0-2, living in a rural area and not receiving radiotherapy. There was an improvement in OS in patients who received chemotherapy at 13.1 months versus best supportive care 5.4 months (p<0.0001). This remained statistically significant when controlling for ECOG, sex, age, histology (HR 0.68, CI 0.59-0.78). CONCLUSIONS In this population-based setting, 37% of patients had an ECOG ≥ 3 at the time of referral, 54% were assessed by a medical oncologist and only 30% received chemotherapy. This is despite the awareness that chemotherapy significantly improves survival. Strategies to optimize appropriate referral such that patients do not miss out on life-prolonging therapy should be evaluated.

Less Toxic Chemotherapy Improves Uptake of All Lines of Chemotherapy in Advanced Non–Small-Cell Lung Cancer: A 10-Year Retrospective Population-Based Review

Background: Over the past decade, well tolerated second-line therapies for advanced non–small-cell lung cancer have been approved including erlotinib and pemetrexed in addition to docetaxel. We hypothesize that the introduction of less toxic chemotherapy has increased treatment of advanced non–small-cell lung cancer resulting in improved survival. Methods: The BC Cancer Agency provides cancer care to 4.5 million. A retrospective review was conducted of all referred Stage IIIB/IV patients in four 1-year time cohorts; C1 baseline (1998) and 6 months after the provincial approval of C2 docetaxel (2001), C3 erlotinib (2006), and C4 pemetrexed (2007). Results: Two-thousand six-hundred and twenty-three patients were referred and 720 had systemic therapy. Characteristics: M/F 55%/45%, median age 67 (33–101), ECOG PS <=1/>=2/unknown 33%/56%/11%, squam/nonsquam/NOS 18%/41%/41%. More patients received first-line chemotherapy over time; 16%, 23%, 34%, and 33% C1–C4 respectively. In C1–C4 uptake of second line (21%, 27%, 37% and 55%) increased. Second-line docetaxel was frequently used in C2 (51%) but usage decreased in C4 to 7% versus erlotinib 50% and pemetrexed 26%. The median overall survival in the best supportive care group remained stable over time; however, increased use of systemic therapy was associated with improved survival C1 9.4 m versus C4 11.8 m (p = 0.023). Conclusions: This population-based data set represents the trend of treatments over time at community and tertiary care cancer treatment sites. Over a 10-year period an increased proportion of patients were treated with first-line chemotherapy and an even greater number with second-/third-line treatment with an associated improvement in overall survival.

Homologous Recombination Deficiency and Platinum-Based Therapy Outcomes in Advanced Breast Cancer

Purpose: Recent studies have identified mutation signatures of homologous recombination deficiency (HRD) in over 20% of breast cancers, as well as pancreatic, ovarian, and gastric cancers. There is an urgent need to understand the clinical implications of HRD signatures. Whereas BRCA1/2 mutations confer sensitivity to platinum-based chemotherapies, it is not yet clear whether mutation signatures can independently predict platinum response. Experimental Design: In this observational study, we sequenced tumor whole genomes (100× depth) and matched normals (60×) of 93 advanced-stage breast cancers (33 platinum-treated). We computed a published metric called HRDetect, independently trained to predict BRCA1/2 status, and assessed its capacity to predict outcomes on platinum-based chemotherapies. Clinical endpoints were overall survival (OS), total duration on platinum-based therapy (TDT), and radiographic evidence of clinical improvement (CI). Results: HRDetect predicted BRCA1/2 status with an area under the curve (AUC) of 0.94 and optimal threshold of 0.7. Elevated HRDetect was also significantly associated with CI on platinum-based therapy (AUC = 0.89; P = 0.006) with the same optimal threshold, even after adjusting for BRCA1/2 mutation status and treatment timing. HRDetect scores over 0.7 were associated with a 3-month extended median TDT (P = 0.0003) and 1.3-year extended median OS (P = 0.04). Conclusions: Our findings not only independently validate HRDetect, but also provide the first evidence of its association with platinum response in advanced breast cancer. We demonstrate that HRD mutation signatures may offer clinically relevant information independently of BRCA1/2 mutation status and hope this work will guide the development of clinical trials. Clin Cancer Res; 23(24); 7521–30. ©2017 AACR.

A population-based review of the feasibility of platinum-based combination chemotherapy after tyrosine kinase inhibition in EGFR mutation positive non-small cell lung cancer patients with advanced disease

INTRODUCTION The IPASS trial demonstrated superior progression free survival for Asian, light/never smoking, advanced, pulmonary adenocarcinoma patients treated with first-line gefitinib compared to carboplatin/paclitaxel, of which 59% of those tested were epidermal growth factor receptor (EGFR) mutation positive. In IPASS 39% of gefitinib treated patients went on to receive platin based polychemotherapy. We hypothesized that in a population-based setting fewer patients receive second-line platin based chemotherapy than those enrolled in a clinical trial. METHODS The Iressa Alliance program provided standardized EGFR mutation testing and appropriate access to gefitinib to all patients in British Columbia with advanced, non squamous non small cell lung cancer (NSCLC). We retrospectively analyzed clinical, pathologic data and outcomes for all patients tested in this program between March 2010 and June 2011. RESULTS A total of 548 patients were referred for testing and 22% of patients were mutation positive. Baseline characteristics of mutation negative and mutation positive; median age 67/65, male 41%/31%, Asian 15%/51%, never smoker 21%/58%, stage IV 80%/91%. Median overall survival was 12 months in mutation negative patients and not yet reached in mutation positive (p<0.0001). In mutation positive patients 5% of patients had a complete response, 46% partial response, 34% stable disease, 6% progressive disease. Twenty percent of patients continued on gefitinib after radiographic progression and clinical stability. Sixty-one gefitinib treated patients progressed at the time of analysis; 10% of patients received further gefitinib only, 38% platinum based doublet, 8% other chemotherapy and 44% no further treatment. Performance status most strongly predicted for delivery of second line chemotherapy. CONCLUSIONS This North American population based study shows similar efficacy of gefitinib in mutation positive patients compared to the IPASS trial. Contrary to our hypothesis, delivery of second line chemotherapy was feasible in a significant proportion of gefitinib treated patients.

Genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germline CHEK2:c.1100delC mutation and a concomitant diagnosis of metastatic invasive ductal breast carcinoma

We describe a woman with the known pathogenic germline variant CHEK2:c.1100delC and synchronous diagnoses of both pelvic genital type leiomyosarcoma (LMS) and metastatic invasive ductal breast carcinoma. CHEK2 (checkpoint kinase 2) is a tumor-suppressor gene encoding a serine/threonine-protein kinase (CHEK2) involved in double-strand DNA break repair and cell cycle arrest. The CHEK2:c.1100delC variant is a moderate penetrance allele resulting in an approximately twofold increase in breast cancer risk. Whole-genome and whole-transcriptome sequencing were performed on the leiomyosarcoma and matched blood-derived DNA. Despite the presence of several genomic hits within the double-strand DNA damage pathway (CHEK2 germline variant and multiple RAD51B somatic structural variants), tumor profiling did not show an obvious DNA repair deficiency signature. However, even though the LMS displayed clear malignant features, its genomic profiling revealed several characteristics classically associated with leiomyomas including a translocation, t(12;14), with one breakpoint disrupting RAD51B and the other breakpoint upstream of HMGA2 with very high expression of HMGA2 and PLAG1. This is the first report of LMS genomic profiling in a patient with the germline CHEK2:c.1100delC variant and an additional diagnosis of metastatic invasive ductal breast carcinoma. We also describe a possible mechanistic relationship between leiomyoma and LMS based on genomic and transcriptome data. Our findings suggest that RAD51B translocation and HMGA2 overexpression may play an important role in LMS oncogenesis.

Willingness of breast cancer patients to undergo biopsy and breast cancer clinicians’ practices around seeking biopsy at the time of breast cancer relapse

PurposeThe practice of seeking a biopsy to confirm a metastatic relapse of a prior breast cancer is individualized. Tumor samples have well-recognized importance in clinical and translational research, but also an increasing role in routine care. We sought to determine the attitudes of patients and breast cancer clinicians about biopsy at breast cancer relapses.MethodsConsenting breast cancer patients and clinicians completed questionnaires with scenarios of decreasing personal benefit and increasing discomfort or inconvenience associated with biopsy at relapse of a prior breast cancer. For each scenario, patients were asked whether they would, would not, or were unsure about agreeing to a biopsy. Clinicians provided information about their practice, research activities, and usual biopsy habits. They were asked to estimate how often patients would agree to a biopsy under each of the conditions presented to patient participants.ResultsThe majority of patients expressed a willingness to undergo a biopsy procedure of modest inconvenience and discomfort to establish an uncertain diagnosis, guide treatment, to participate in a trial, or for research purposes only. About 50% of patients indicated that they would undergo an invasive biopsy procedure requiring IV sedation or general anesthetic for purely altruistic reasons. In spite of being a largely academic group, clinician respondents underestimated patient willingness to have a biopsy in all scenarios, particularly when there was no attached personal benefit.ConclusionBreast cancer patients were very willing to undergo biopsy at breast cancer relapse for their routine care, clinical trials, or for research only. Clinicians act as the intermediary between patients and tumor tissue repositories, and clinician perceptions and practices should shift to match the altruistic attitudes of breast cancer patients.