Diagnosis of adenocarcinoma of the lung, a major subtype of non-small lung cancer (NSCLC), nowadays triggers mandatory testing of tumor tissue for alterations in four genes: EGFR, ALK, ROS1, and more recently, BRAF. If present, these alterations predict sensitivity to specific targeted drugs approved by the U.S. Food and Drug Administration (FDA) that work better and often longer than standard chemotherapy, and are better tolerated.
However, there are many more targetable/actionable genomic alterations (also known as “drivers”) in NSCLC. This blog post will briefly discuss most of them, with the goal of promoting molecular testing for more than the four “usual suspects” mentioned above. Some patients with these alterations may benefit from FDA-approved drugs or from enrollment in clinical trials that are testing additional drugs and drug combinations. Continue reading…
“While several targeted therapies have emerged in recent years for treatment of non-small cell lung cancer (NSCLC) carrying the anaplastic lymphoma kinase (ALK) gene fusion, development of resistance to ALK inhibitors is an increasing problem. Furthermore, only one tyrosine kinase inhibitor (TKI), crizotinib, is currently approved for patients with ROS proto-oncogene 1 (ROS1) rearrangements. Lorlatinib, a novel, highly selective ALK and ROS1 targeting third-generation TKI has shown preclinical activity against known ALK resistance mutations and can penetrate the central nervous system (CNS), a common site of metastasis in ALK-positive or ROS1-positive NSCLC.”
“Pfizer Inc. (NYSE:PFE) today announced full results from the Phase 2 clinical trial of the investigational, next-generation tyrosine kinase inhibitor lorlatinib that exhibited clinically meaningful activity against lung tumors and brain metastases in a range of patients with ALK-positive and ROS1-positive advanced non-small cell lung cancer (NSCLC), including those who were heavily pretreated. Further, side effects were generally manageable and primarily mild to moderate in severity. The results [Abstract #OA 05.06] were presented by Professor Benjamin Solomon, lead investigator and medical oncologist at Peter MacCallum Cancer Centre, Melbourne, Australia, today during an oral session at the International Association for the Study of Lung Cancer (IASLC) 18th World Conference on Lung Cancer (WCLC) in Yokohama, Japan. Pfizer will also present data from several other lung cancer clinical programs.”
“Lorlatinib exhibits durable responses in pretreated patients with ALK-positive non–small-cell lung cancer (NSCLC) and promising intracranial activity and tumor responses in those patients who have brain metastases, regardless of prior therapy, according to findings from a phase I/II clinical study (abstract 9006) presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 2–6 in Chicago.
” ‘Lorlatinib demonstrated clinically meaningful and durable responses in ALK-positive patients receiving one or more prior ALK TKI [tyrosine kinase inhibitor], many of whom were heavily pretreated,’ said coauthor Sai-Hong Ignatius Ou, MD, of the University of California Irvine Chao Family Comprehensive Cancer Center in Orange, California.”
“The FDA has granted a breakthrough therapy designation to lorlatinib for use in patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) who have previously received 1 or more ALK inhibitors, according to Pfizer, the company developing the next-generation ALK/ROS1 tyrosine kinase inhibitor (TKI).
” ‘This regulatory designation recognizes the potential for lorlatinib to provide an important treatment option for patients with ALK-positive NSCLC whose cancers have progressed despite treatment,’ Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development, said in a release. ‘Pfizer’s rapid development of lorlatinib reflects a commitment to developing biomarker-driven therapies to meet the evolving needs of patients.’ ”
This year, the Annual Meeting of the American Society of Clinical Oncology (ASCO) did not produce any truly groundbreaking revelations about new treatments for lung cancer. However, researchers did report quite a few positive findings, and some disappointing ones. I have summarized some of the more prominent presentations below. Continue reading…
“Pfizer Inc. (NYSE:PFE) today announced encouraging new data from a Phase 1/2 study of lorlatinib, the proposed generic name for PF-06463922, Pfizer’s investigational, next-generation ALK/ROS1 tyrosine kinase inhibitor. The study showed clinical response in patients with ALK-positive or ROS1-positive advanced non-small cell lung cancer (NSCLC), including patients with brain metastases. These data were presented today in an oral presentation at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.
“The results presented are from the dose escalation component of an ongoing Phase 1 study of patients with ALK-positive or ROS1-positive NSCLC, with or without brain metastases, who were treatment-naïve or had disease progression after at least one prior tyrosine kinase inhibitor (TKI). Among patients with ALK-positive metastatic NSCLC, the overall response rate (ORR) with lorlatinib was 46 percent, with three patients achieving complete responses and 16 patients achieving a partial response (95% CI: 31-63). The median progression free survival (PFS) was 11.4 months (95% CI: 3.4 – 16.6). The majority of patients had received two or more prior ALK TKIs. Additionally, lorlatinib showed the ability to decrease the size of brain metastases in patients with ALK-positive or ROS1-positive metastatic NSCLC.”
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“The use of drugs that target genetic mutations driving the growth of tumors has revolutionized treatment for several serious forms of cancer, but in almost every case, tumors become resistant to the drugs’ therapeutic effects and resume growth, often through the emergence of new mutations, which has spurred the development of more powerful drugs that can overcome resistance mutations. In the Dec. 24 issue of New England Journal of Medicine, Massachusetts General Hospital (MGH) physicians report their study examining the evolution of drug resistance in a lung cancer patient treated with multiple different targeted therapies. When resistance developed to the third targeted therapy, the new mutation actually restored the cancer’s response to the very first targeted therapy drug used to treat the patient.”