JUNIPER Trial Branches Out in KRAS Mutation-Positive Advanced NSCLC

“In 2008 Linardou et al published results of a meta-analysis of studies in advanced non–small cell lung cancer (NSCLC) and metastatic colorectal cancer. They extracted data on 1008 patients; 165 from 17 manuscripts for the NSCLC portion of the meta-analysis had KRAS mutations. They sought to establish whether or not KRAS mutations could be candidate predictive biomarkers for antiepidermal growth factor (EGFR) treatments. The analysis yielded empirical evidence that KRAS mutations are highly specific negative predictors of response to EGFR tyrosine kinase inhibitors (TKIs) when given as single agents to patients with advanced NSCLC. Further implicating an association of KRAS mutations with poor outcomes, a retrospective analysis of data from 1036 patients with stage IV lung adenocarcinoma and KRAS mutation evaluated between 2002 and 2009, found the presence of KRAS mutations to be associated with shorter survival (HR, 1.21; P = .48).”

Anti-HER2 Agents Show Potential in NSCLC

“While targeting HER2 mutations is mainly associated with breast cancer, there could be therapeutic potential with anti-HER2 agents in non-small cell lung cancer (NSCLC). At this year’s International Lung Cancer Congress, Corey Langer, MD, discussed the potential for afatinib and neratinib—dual inhibitors of EGFR and HER2—in NSCLC, as well as the need for additional research, in order to truly comprehend HER2 targeted therapy in this particular setting.

“HER2 mutations occur in about 2% to 4% of patients with NSCLC, and for the most part, they are mutually exclusive with other molecular drivers (eg, EGFR, KRAS), according to Langer, director of Thoracic Oncology at the Abramson Cancer Center of the University of Pennsylvania. “Similar to EGFR and ALK, the HER2 mutations are more common in women, never-smokers, and adenocarcinoma histology,” Langer added.

“Regarding use of afatinib in these patients, Langer said, ‘There are limited but encouraging data in patients with HER2-mutant NSCLC treated with either afatinib or afatinib plus paclitaxel.’ “

Biodesix Launches GeneStrat Targeted Liquid Biopsy Mutation Test For Patients With Advanced Lung Cancer

“Biodesix, Inc. today announced the launch of GeneStrat™, a targeted liquid biopsy mutation test for genotyping tumors of patients with advanced non-small cell lung cancer (NSCLC). The blood test results are available within 72 hours, providing physicians actionable diagnostic information prior to making treatment decisions. GeneStrat is focused exclusively on the clinically actionable EGFR, KRAS, and BRAF mutations often used to guide targeted therapy treatment decisions. GeneStrat also captures the EGFR T790M mutation, which can be used for monitoring the emergence of the primary resistance mutation in the EGFR gene. It is anticipated that two drugs targeting the resistance mutation may be available later this year. GeneStrat uses the ddPCR platform to analyze cell-free tumor DNA and is highly concordant with tissue analysis, currently considered the gold standard.

“Roughly 30% of lung cancer patients either have insufficient biopsy tissue or are not candidates for a biopsy for tumor mutation profiling. Even in cases where tissue biopsy is available, the sense of urgency to treat is great, with one recent study showing that one out of four patients begin cancer treatment before receiving mutation test results. Requiring only a blood draw, GeneStrat offers a fast, minimally invasive alternative to a high-risk tissue biopsy or re-biopsy in patients with insufficient tissue.

“In addition to providing a minimally-invasive source of mutation status, liquid biopsy can be more cost-effective than traditional tissue biopsies. The mean cost of each tissue biopsy is $14,634 across all patients. The cost of a tissue biopsy can be up to four time higher in the 19.3% of patients who have complications associated with the biopsy. GeneStrat liquid biopsy can help avoid the cost and complications of repeat tissue biopsy.”

BIND-014 Being Tested as Treatment for Advanced/Metastatic NSCLC That's Squamous or KRAS+

The gist: The first patient has been enrolled in a clinical trial testing the drug BIND-014 in patients with advanced or metastatic non-small cell lung cancer (NSCLC) that is squamous or has a mutation in the KRAS gene. An earlier clinical trial found promising results for these patients. BIND-014 is a new form of the chemotherapy drug docetaxel. It is meant to home in on cancer cells to deliver chemotherapy directly.

“BIND Therapeutics, Inc. (BIND), a clinical-stage nanomedicine platform company developing targeted and programmable therapeutics called Accurins™, today announced its 2015 strategic overview and enrollment of the first patient expressing a KRAS mutation in a global, multicenter two-tiered phase 2 trial with BIND-014 in non-small cell lung cancer (NSCLC) patients with KRAS mutant tumors (mutated Kirsten ras oncogene homolog) or squamous histology. The trial was driven by positive results from the phase 2 trial in NSCLC presented at the EORTC-NCI-AACR Annual Symposium in Barcelona on November 19, 2014, with a confirmed objective response rate of 22 percent (n=9); one KRAS mutant NSCLC PR was also seen in the phase 1 trial with BIND-014, yielding a combined total response rate of 30 percent (n=10). Results from the phase 2 trial also suggested meaningful differentiation in NSCLC patients with squamous histology when compared to historical docetaxel results. BIND-014 results presented at EORTC-NCI-AACR also demonstrated a disease control rate of 66 percent and overall survival of 11.1 months (n=9) in NSCLC patients with squamous histology. BIND intends to begin accruing NSCLC patients with squamous cell histology in the two-tier phase 2 trial in 1Q 2015.”

Phase 2 Study Met Primary Objective of Showing Anti-Tumor Activity as Measured by Overall Response Rate at Q3W Dosing Schedule

The gist: A drug called BIND-014 has shown some promise for treating advanced or metastatic non-small cell lung cancer (NSCLC). In particular, it has shown promise for treating NSCLC tumors that have mutations in the KRAS gene. BIND-014 is a new form of the chemotherapy drug docetaxel. It is meant to home in on cancer cells to deliver chemotherapy directly. It is being compared to standard docetaxel in volunteer patients in a clinical trial. So far, the results are promising, but more research is needed.

“BIND Therapeutics, Inc. (NASDAQ: BIND), a clinical-stage nanomedicine platform company developing targeted and programmable therapeutics called AccurinsTM, today presented positive results from its ongoing Phase 2 study of BIND-014 in non-small cell lung cancer (NSCLC), demonstrating it has met the primary objective in the once every three weeks (Q3W) arm as measured by overall response rate (ORR). The data demonstrate that BIND-014 is well-tolerated with clinically meaningful anti-tumor activity at a lower dose than conventional docetaxel in patients with advanced or metastatic NSCLC. BIND-014 also demonstrates promising anti-tumor activity in patients with tumors expressing KRAS mutations (mutated Kirsten ras oncogene homolog). KRAS mutations in NSCLC are generally associated with poor response to currently available drug therapy regimens, including docetaxel. An additional signal was observed in patients with squamous cell carcinomas, a major NSCLC subtype poorly served by existing available therapies. These data were presented at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain.

“ ‘We believe the activity and tolerability of BIND-014 demonstrated in this study suggest meaningful differentiation from the historical docetaxel experience, in both the broader NSCLC patient population and in two important groups of patients with high unmet medical need,’ said Hagop Youssoufian, M.D., M.Sc., Chief Medical Officer, BIND Therapeutics. ‘Furthermore, as the first product candidate from our Medicinal Nanoengineering® platform to enter the clinic, we believe that the increased efficacy and reduced toxicity at a lower dose compared to historical docetaxel experience suggests that Accurins are successful in targeting the therapeutic payload to the tumor. Based on these positive results, we plan to conduct additional global, multicenter Phase 2 studies to confirm and expand the dataset on BIND-014 and to define an expeditious regulatory path for BIND-014.’ ”

No Progression-Free Survival Benefit of Dacomitinib vs Erlotinib Overall or in KRAS Wild-Type Disease in Pretreated Advanced NSCLC

The gist: Scientists recently tested whether the drug dacomitinib is better than erlotinib for treating people with advanced non-small cell lung cancer (NSCLC) who had already received a previous treatment. In terms of the amount of time that passed without a patient’s disease worsening, the scientists found that dacomitinib was no better than erlotinib. They also found that dacomitinib was no better than erlotinib for people with advanced NSCLC whose tumors did not have mutations in the KRAS gene (as detected by molecular testing). These findings came from a clinical trial in which the treatments were tested in volunteer patients.

“In a phase III ARCHER 1009 trial reported in The Lancet Oncology, Ramalingam et al found no progression-free survival benefit of the irreversible pan-HER tyrosine kinase inhibitor dacomitinib vs erlotinib among all patients with pretreated non–small cell lung cancer (NSCLC) or among those with KRAS wild-type tumors…

“In this double-blind trial, 878 patients from 134 centers in 23 countries with locally advanced or metastatic NSCLC and progression after one or two previous chemotherapy regimens were randomly assigned between June 2011 and March 2013 to receive oral dacomitinib at 45 mg/d (n = 439 [256 of which were KRAS wild-type tumors]) or erlotinib at 150 mg/d (n = 439 [263 of which were KRAS wild-type tumors]). Randomization was stratified by histology, ethnicity, Eastern Cooperative Oncology Group performance status, and smoking status. The coprimary endpoints were progression-free survival on independent review for all patients and for the subgroup with KRAS wild-type tumors.

“The dacomitinib and erlotinib groups were generally balanced for age (median, 64 and 62 years, 48% and 39% ≥ 65 years), sex (66% and 63% male), ethnicity (76% and 75% white, 21% and 20% Asian), histology (adenocarcinoma in 69% and 68%), disease stage (IV in 91% and 92%), never-smoker status (18% and 19%), KRAS status (wild-type in 58% and 60%, mutant in 16% and 15%, unknown in 26% and 25%), EGFR status (wild-type in 74% and 76%, mutant in 11% and 10%, unknown in 15% and 14%), and number of previous systemic therapies (1 in 58% and 64%, 2 in 40% and 33%)…

“The investigators concluded: ‘Irreversible EGFR inhibition with dacomitinib was not superior to erlotinib in an unselected patient population with advanced non-small-cell lung cancer or in patients with KRAS wild-type tumours. Further study of irreversible EGFR inhibitors should be restricted to patients with activating EGFR mutations.’ ”

Erbitux Edges Avastin for First-Line Colorectal Cancer Therapy

Editor’s note: This article discusses the results of a clinical trial—a research study with volunteer patients. The goal of the trial was to compare two drugs—bevacizumab and cetuximab—when they were added to the standard chemotherapy combo FOLFIRI. All patients who participated in the trial had metastatic colorectal cancer. The researchers found that patients treated with FOLFIRI plus cetuximab had longer overall survival times that patients treated with FOLFIRI plus bevacizumab. The results differ from those from another recent study, which found no significant difference between the two treatments.

“Adding cetuximab (Erbitux) to the standard first-line FOLFIRI chemotherapy regimen resulted in longer overall survival compared with FOLFIRI plus bevacizumab (Avastin) in patients with metastatic colorectal cancer, according to results of the phase III FIRE-3 trial published this month in the Lancet.

“This result was seen in patients with a wild-type exon 2 KRAS gene. The longer overall survival was observed despite there being no significant difference in objective response between the two study groups.

“The study analyzed data from 592 patients with KRAS exon 2 wild-type colorectal cancer treated with FOLFORI and either cetuximab (an epidermal growth factor receptor inhibitor) or bevacizumab (an angiogenesis inhibitor). Patients were recruited at 116 Austrian and German cancer centers.”

Cetuximab or Bevacizumab with Combi Chemo Equivalent in KRAS Wild-Type MCRC

“For patients with KRAS wild-type untreated colorectal cancer, adding cetuximab or bevacizumab to combination chemotherapy offers equivalent survival, researchers said at the ESMO 16th World Congress on Gastrointestinal Cancer in Barcelona.” ‘The CALGB/SWOG 80405 trial was designed and formulated in 2005, and the rationale was simple: we had new drugs —bevacizumab and cetuximab— and the study was designed to determine if one was better than the other in first-line for patients with colon cancer,’ said lead study author Alan P. Venook, distinguished Professor of Medical Oncology and Translational Research at the University of California, San Francisco, USA.

“The CALGB/SWOG 80405 trial studied patients whose tumours were KRAS wild-type at codons 12 and 13. Patients received mFOLFOX6 or FOLFIRI at the discretion of their doctor and were randomised to cetuximab (578 patients) or bevacizumab (559 patients).

” ‘There was no meaningful difference in outcome between treatment arms,’ said Venook. ‘In both arms patients lived close to 30 months. About 10% of patients lived more than 5 years. Overall patients did much better than anticipated and it was indifferent to the type of treatment.’ ”

Editor’s note: This story discusses the results of a clinical trial that tested a treatment for colorectal cancer in volunteer patients without mutations in the KRAS gene in their tumors (as detected by molecular testing). The goal of the trial was to compare two chemotherapy drugs—bevacizumab and cetuximab—to see whether one is better than the other as a first-line colorectal cancer for so-called “KRAS wild-type” colorectal cancer. The results showed that there was no significant difference between the two.

Combination Therapies for Lung Cancer

“CANCER NETWORK: Dr. Jänne, epidermal growth factor receptor (EGFR) inhibitors are a mainstay of therapy for those advanced-stage lung cancer patients with tumors that harbor specific EGFR mutations. What have we learned in the last few years about which patients respond to which oral agents and antibodies against EGFR? “

Editor’s note: While not strictly “news,” this interview provides a good overview of currently available treatments for lung cancer.