MET/EGFR Combo Effective for Advanced NSCLC


“The combination of osimertinib (Tagrisso) and the MET inhibitor savolitinib showed signs of efficacy for pretreated patients with MET-positive, EGFR-mutant non–small cell lung cancer (NSCLC), regardless of prior treatment with a T790M-directed therapy, according to findings from part B of the TATTON trial presented at the 2017 World Conference on Lung Cancer (WCLC).

“Across patients in the phase Ib study (N = 64), the objective response rate (ORR) was 47% with the combination of osimertinib and savolitinib. In those pretreated with a T790M-directed therapy (n = 30), the ORR was 33% and in those with T790M-negative disease (n = 23) the ORR was 61%. In patients with T790M-positive disease (n = 11), the ORR was 55% for the combination.”

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EGFR Inhibitor Rociletinib Active in EGFR T790M Mutation–Positive NSCLC Previously Treated With EGFR Inhibitors

“In a phase I/II study reported in The New England Journal of Medicine, Sequist et al found that rociletinib—an EGFR inhibitor active in the presence and absence of the EGFR T790M mutation known to mediate resistance to available EGFR inhibitors—produced a high response rate in patients with T790M-positive non–small cell lung cancer (NSCLC) who had progressed on prior EGFR inhibitor therapy. Responses were also observed in patients with T790M-negative disease.

“The study included 92 evaluable patients with EGFR-mutant NSCLC that had progressed on treatment with an EGFR inhibitor who were treated with a free-base form of rociletinib (first group of enrolled patients) at a dose of 900 mg twice daily (10 with centrally confirmed presence or absence of T790M mutation) or a hydrogen bromide salt form at doses of 500 mg twice daily to 1,000 mg twice daily (all remaining patients; 53 with centrally confirmed presence or absence of T790M mutation).

“A total of 83 patients were evaluable for response. Among 46 patients with centrally confirmed T790M-positive tumors, 59% (95% confidence interval [CI] = 45%–73%) had a partial response, and 35% had stable disease (disease control rate = 93%). Response rates were similar in patients with deletion 19 or L858R EGFR mutations. Estimated median progression-free survival at the time of analysis was 13.1 months (95% CI = 5.4–13.1 months), with data censored for 82% of patients. Among 17 patients with T790M-negative tumors on central testing, the response rate was 29% (95% CI = 8%–51%), and 29% had stable disease (disease control rate = 59%). Estimated median progression-free survival in these patients was 5.6 months (95% CI = 1.3 months to not reached). Among 20 patients whose tumors were not assessable for T790M mutation, the response rate was 15%.”

New Drugs Aim to Defeat Tumor Resistance to EGFR Inhibitors

In recent years, many people with non-small cell lung cancer (NSCLC) have been successfully treated with drugs called EGFR inhibitors. But over time, most patients develop resistance, and the drugs stop working. Researchers are hard at work developing new drugs to help patients who can no longer be treated with EGFR inhibitors.

EGFR inhibitors get their name from a gene called EGFR. Many lung cancer tumors have mutations in this gene. These mutations convert EGFR from a normal gene into a cancer gene that initiates and promotes cancer growth. Approximately 10% to 15% of white and 30% to 35% of Asian patients with NSCLC have EGFR mutations. Continue reading…

At ASCO, Next-Gen EGFR Inhibitors Show Early Promise in Lung Cancer Patients with T790M Mutations

“Next-generation EGFR inhibitors for treating metastatic non-small cell lung cancer patients who have acquired resistance to first-generation drugs in this class accurately hit mutant EGFR tumor cells and caused fewer serious side effects, early data presented at a major cancer conference showed.

“Researchers at the American Society of Clinical Oncology’s annual meeting here this week, presented preliminary data from human studies on three next-generation EGFR inhibitors: AstraZeneca’s AZD9291, Clovis Oncology’s CO-1686, and Hanmi Pharmaceutical’s HM61713. All three agents showed promising activity against patients who had EGFR mutations, had received prior treatment with a first-generation tyrosine kinase inhibitor – such as Roche’s Tarceva (erlotinib) and AstraZeneca’s Iressa (gefinitib) – and had T790M mutations.”

Editor’s note: For a more reader-friendly explanation of these new drugs, check out the “Drug resistance” section of our Chief Scientist’s latest blog post.

Researchers Report Double Dose of Promising Lung Cancer Findings

“Researchers with UCLA’s Jonsson Comprehensive Cancer Centerreport that two new experimental drugs have shown great promise in the treatment of patients with non–small-cell lung cancer, which accounts for about 85 percent of all lung cancers. Lung cancer is the leading cause of cancer death in the United States.

“The drugs—ramucirumab and CO-1868—were shown in separate clinical trials to increase survival times with fewer toxic side effects than standard treatments. The findings were presented this week at the American Society of Clinical Oncology annual meeting in Chicago.”

Editor’s note: For more on the ramucirumab findings, see our previous news post. To learn more about targeted therapies like CO-1686 and ramucirumab, visit our lung cancer Basics.

New EGFR Inhibitor AZD9291 Shows Promising Activity in Treatment-Resistant Non–Small Cell Lung Cancer

“Findings from a phase I study of a new mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, AZD9291, point to a promising new treatment option for patients with advanced, EGFR-mutant, non–small cell lung cancer (NSCLC) that is resistant to standard EGFR inhibitors. Roughly 50% of patients experienced tumor shrinkage, and the drug worked particularly well in patients with the T790M mutation (detected in 60% of patients), which causes the most common form of EGFR therapy resistance. The study was presented at a presscast in advance of the 2014 ASCO Annual Meeting (Abstract 8009^).”

Editor’s note: This story is about a new targeted therapy drug called AZD9291 that is designed to attack tumors with a mutation in the EGFR gene, as detected by molecular testing. In particular, it is designed for patients who are resistant to other so-called EGFR inhibitors as a result of developing a particular EGFR mutation known as T790M. In a clinical trial to test the drug in patients, it was found to show promising results for patients with advanced non-small cell lung cancer (NSCLC) with EGFR mutations, and even better results in patients with the T790M mutation.

Early Evidence Supports CO-1686 as a Treatment Option in Drug-Resistant EGFR-Mutant Lung Cancer

Drugs known as EGFR inhibitors—such as erlotinib (Tarceva), gefitinib (Iressa), and afatinib (Gilotrif)—are very effective in treating non-small cell lung cancer (NSCLC) with mutations in the EGFR gene. However, patients eventually develop drug resistance, usually caused by new EGFR mutations. T790M is the most common EGFR drug resistance mutation. CO-1686 is a novel drug that inhibits EGFR with the T790M mutation, as well as other mutant EGFR. A small study showed that eight of nine patients who had the T790M resistance mutation experienced more than 10% tumor shrinkage when treated with CO-1686. And, a new formulation of CO-1686 has been found to produce higher, more consistent, well-tolerated drug concentrations in patients.

New Drug May Offer Option for Lung Cancer Patients Resistant to Tarceva/Iressa

Drugs known as EGFR inhibitors—like erlotinib (Tarceva) and gefitinib (Iressa)—are used to treat non-small cell lung cancer (NSCLC) with so-called ‘activating mutations’ in the EGFR gene. Unfortunately, drug resistance develops relatively quickly in most patients. Resistance is often due to additional EGFR mutations, so-called ‘resistance mutations,’ such as EGFR T790M. Researcher have developed a new EGFR inhibitor, AZD9291, which targets both activating and resistance mutant forms of EGFR. AZD9291 inhibited the growth of EGFR-mutant NSCLC cell cultures and eradicated lung cancer tumors with either activating or resistance mutations in mice. Because AZD9291 is less active against normal, non-mutant EGFR, it may have fewer side effects than other EGFR inhibitors. Initial tests of AZD9291 in patients have been promising.

First T790M Inhibitor Shows Promise in Early Lung Cancer Trial

Researchers may finally have found a treatment for a type of non-small cell lung cancer (NSCLC) that resists currently available therapies, according results presented at the 2013 European Cancer Congress in Amsterdam, Netherlands. These resistant NSCLCs have an EGFR mutation called T790M, which is more common in Asian people; the experimental treatment is a T790M inhibitor called AZD9291. In an ongoing phase I clinical trial that included 12 people with lung cancers that had the T790M mutation, tumors shrank in more than half. This trial is currently enrolling new patients.