Nuvalent Announces Submission of New Drug Application to FDA for Neladalkib in TKI Pre-treated Advanced ALK-Positive NSCLC

Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, announced the submission to the U.S. Food and Drug Administration (FDA) of the Company's NDA for neladalkib, an investigational ALK-selective inhibitor, in TKI pre-treated advanced ALK-positive NSCLC.

New Drug Application (NDA) based on data in TKI pre-treated patients from the global ALKOVE-1 Phase 1/2 clinical trial

"The advancement of neladalkib from first clinical trial initiation to NDA submission in less than four years represents a remarkable pace in oncology drug development, underscoring the vigor and urgency our team brought to this program and our deep commitment to the ALK-positive NSCLC community," said Darlene Noci, A.L.M., Chief Development Officer at Nuvalent. "We would like to extend our sincere gratitude to the patients, families and investigators who have made this progress possible, and are committed to working closely with the FDA throughout the NDA review process toward our goal of bringing neladalkib to patients as quickly as possible."

The application is based on data in TKI pre-treated patients with advanced ALK-positive NSCLC treated with neladalkib in the global, registration-directed ALKOVE-1 Phase 1/2 clinical trial. In this population, neladalkib demonstrated encouraging overall activity, including intracranial responses, the ability to address key drivers of disease progression, and a generally well-tolerated safety profile consistent with its ALK-selective, TRK-sparing design. The company plans to share detailed results at a future medical meeting.

Neladalkib has received breakthrough therapy designation from the FDA for the treatment of patients with locally advanced or metastatic ALK-positive NSCLC who have been previously treated with 2 or more ALK tyrosine kinase inhibitors and orphan drug designation for ALK-positive NSCLC.

About Neladalkib

Neladalkib is an investigational, brain-penetrant, ALK-selective inhibitor created with the aim to overcome limitations observed with currently available ALK inhibitors. Neladalkib is designed to remain active in tumors that have developed resistance to first-, second-, and third-generation ALK inhibitors, including tumors with single or compound treatment-emergent ALK mutations such as G1202R. In addition, neladalkib is designed for central nervous system (CNS) penetrance to improve treatment options for patients with brain metastases, and to avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family. Together, these characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ALK inhibitors and to drive deep, durable responses for patients across all lines of therapy. Neladalkib has received breakthrough therapy designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) who have been previously treated with 2 or more ALK tyrosine kinase inhibitors and orphan drug designation for ALK-positive NSCLC.

About the ALKOVE-1 Phase 1/2 Clinical Trial

The ALKOVE-1 trial (NCT05384626) is a first-in-human Phase 1/2 clinical trial for patients with advanced ALK-positive NSCLC and other solid tumors. The completed Phase 1 portion enrolled ALK-positive NSCLC patients who previously received at least one ALK TKI, or patients with other ALK-positive solid tumors who had been previously treated or for whom no satisfactory standard of care exists. The Phase 1 portion of the trial was designed to evaluate the overall safety and tolerability of neladalkib, with additional objectives including determination of the recommended Phase 2 dose (RP2D), characterization of the pharmacokinetic profile, and evaluation of preliminary anti-tumor activity. The global, single arm, open label Phase 2 portion is designed with registrational intent for TKI pre-treated patients with advanced ALK-positive NSCLC. Global enrollment in ALKOVE-1 remains ongoing for adult and adolescent patients with ALK-positive solid tumors outside of NSCLC, and adolescent patients with ALK-positive NSCLC.

Nuvalent Announces Submission of New Drug Application to FDA for Neladalkib in TKI Pre-treated Advanced ALK-Positive NSCLC

FDA Approves Krazati (adagrasib) for Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) with a KRASG12C Mutation

Mirati Therapeutics, Inc. (NASDAQ: MRTX), a targeted oncology company, announced the U.S. Food and Drug Administration (FDA)  approval of Krazati™ (adagrasib), a targeted treatment option for adult patients with KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.

This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s).

"The FDA approval of Krazati is a positive development for thousands of patients with KRASG12C mutations, including the approximately 14% of patients with NSCLC adenocarcinomas histology that harbor a KRASG12C mutation.1 Mirati is thrilled to make Krazati available in a tablet formulation to patients in the U.S. with advanced NSCLC who have progressed beyond a first-line treatment for the historically difficult-to-treat KRAS mutation," David Meek, chief executive officer, Mirati Therapeutics, Inc., continued, "We look forward to continuing to advance our Krazati development program including several monotherapy and combination studies in KRASG12C-mutated solid tumors."

Krazati has demonstrated a positive benefit-risk profile with accelerated approval based on the Phase 2 registration-enabling cohort of the KRYSTAL-1 study, evaluating Krazati 600 mg capsules administered orally twice daily in 116 patients with KRASG12C-mutated advanced NSCLC who previously received treatment with a platinum-based regimen and an immune checkpoint inhibitor. The primary efficacy endpoints were confirmed ORR and DOR as evaluated by blinded independent central review (BICR) according to response evaluation criteria in solid tumors (RECIST v1.1).

The trial demonstrated an ORR of 43% (95% CI: 34-53) with 80% (95% CI: 71-87) of patients achieving disease control. The median DOR was 8.5 months (95% CI: 6.2-13.8).

In a pooled efficacy analysis (n=132) including Phase 1/1b NSCLC and registrational Phase 2 NSCLC cohorts from the KRYSTAL-1 study evaluating adagrasib as a single agent at 600 mg capsules orally twice daily, adagrasib showed an ORR of 44% and a disease control rate of 81% based on BICR, a median DOR of 12.5 months (95% CI, 7.3-NE) and median overall survival of 14.1 months (94% CI, 9.2-19.2).

The safety profile of Krazati was evaluated in a pooled patient population with NSCLC and other solid tumors as a single agent at 600 mg orally twice daily in 366 patients enrolled in KRYSTAL-1 and KRYSTAL-12. The most common (≥ 25%) adverse reactions were nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, renal impairment, edema, dyspnea and decreased appetite. Permanent discontinuation of Krazati due to an adverse reaction occurred in 13% of patients.

Although KRASG12C is the most common KRAS mutation in NSCLC, patients have had limited options for the treatment of this debilitating and difficult-to-treat condition.2,3

"The approval of Krazati offers an effective therapy for patients with advanced NSCLC harboring the KRASG12C mutation. The positive ORR and DOR results, as observed in previously treated patients with NSCLC harboring the KRASG12C mutation, demonstrate the effectiveness of Krazati as an option for these difficult-to-treat patients," said Shirish M. Gadgeel, MD, chief of the Division of Hematology and Oncology, Department of Internal Medicine, Henry Ford Cancer Institute/Henry Ford Health System.

"KRASG12C in NSCLC is an area of high unmet need and new treatment options offer patients and our community new hope for survivorship," said Bonnie J. Addario, co-founder and board chair of the GO2 Foundation for Lung Cancer. "I'm pleased that patients have options, there's more awareness of this disease and we are all focused on improving the journeys of people living with KRASG12C-mutated NSCLC."

The Company partnered with Agilent and QIAGEN to develop blood- and tissue-based companion diagnostics (CDx), respectively, for Krazati that are now available. With tissue and blood modalities for companion diagnostics, patients have more flexibility, and clinicians have greater options for biomarker testing. These solutions help to personalize a patient's treatment path.

Mirati Therapeutics is launching Mirati & Me, a comprehensive program dedicated to supporting patients, caregivers and the oncology community including coverage and access, financial, educational and emotional support services. 

Ref : https://en.wikipedia.org/wiki/Adagrasib

FDA Expands Use of Xalkori (crizotinib) to Treat ROS-1 Positive Non-Small Cell Lung Cancer

In continuation of my update on Xalkori (crizotinib) 

The U.S. Food and Drug Administration today approved Xalkori (crizotinib) to treat people with advanced (metastatic) non-small cell lung cancer (NSCLC) whose tumors have an ROS-1 gene alteration. Xalkori is the first and only FDA approved treatment for patients with ROS-1 positive NSCLC.

Lung cancer is the leading cause of cancer-related deaths in the United States, with an estimated 221,200 new diagnoses and 158,040 deaths in 2015, according to the National Cancer Institute. ROS-1 gene alterations, thought to lead to abnormal cells, have been identified in various cancers, including NSCLC. ROS-1 gene alterations are present in approximately 1 percent of patients with NSCLC. The overall patient and disease characteristics of NSCLC with ROS-1 gene alterations appear similar to NSCLC with anaplastic lymphoma kinase (ALK) gene alterations, for which crizotinib use was previously approved. Xalkori was approved to treat certain patients with late-stage NSCLC that expresses an abnormal ALK gene in 2011.

“Lung cancer is difficult to treat, in part, because patients have different mutations, some of which are rare,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The expanded use of Xalkori will provide a valuable treatment option for patients with the rare and difficult to treat ROS-1 gene mutation by giving health care practitioners a more personalized way of targeting ROS-1 positive NSCLC.”

Xalkori is an oral medication that blocks the activity of the ROS-1 protein in tumors that have ROS-1 gene alterations. This effect on ROS-1 may prevent NSCLC from growing and spreading.

The safety and efficacy of Xalkori for the treatment of patients with ROS-1 positive tumors were evaluated in a multi-center, single-arm study of 50 patients with ROS-1 positive metastatic NSCLC. Patients received Xalkori twice daily to measure the drug’s effect on their lung cancer tumors. The studies were designed to measure overall response rate, the percentage of patients who experienced complete or partial shrinkage of their tumors. Results showed 66 percent of participants experienced a complete or partial shrinkage of their NSCLC tumors, an effect that lasted a median of 18.3 months.

FDA Expands Use of Xalkori (crizotinib) to Treat ROS-1 Positive Non-Small Cell Lung Cancer

Study: Alectinib 600 mg more effective than standard therapy in Asian ALK positive NSCLC patients

In continuation of my update on crizotinib and alectinib

 and  

A subanalysis of the phase III ALEX study has shown that alectinib 600 mg twice daily is more effective than standard of care crizotinib in Asian patients with anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC), researchers report at the ESMO Asia 2017 Congress.

The J-ALEX study demonstrated that alectinib 300 mg twice daily improved progression-free survival compared to crizotinib in Japanese patients with ALK positive NSCLC. (3) The ALEX study subsequently showed improvement in progression-free survival with alectinib 600 mg twice daily compared to crizotinib in a global population of ALK positive NSCLC patients. (4)

This subanalysis of the ALEX study investigated the efficacy and safety of alectinib 600 mg twice daily compared to crizotinib in Asian versus non-Asian patients with ALK positive NSCLC. As previously reported, the ALEX study included 303 patients who were randomised in a 1:1 ratio to receive alectinib or standard of care crizotinib. There were 69 Asian patients in each treatment group. The primary endpoint was progression-free survival.

A distinguishing feature of the study was that all patients underwent magnetic resonance imaging (MRI) of the brain every six months, regardless of whether or not they had brain metastases at the start of the study. The time to progression in the brain was measured and compared between the two treatment groups.

"Around 50% of NSCLC patients with ALK mutations will develop brain metastases so it is very important to demonstrate the efficacy of alectinib in the brain," said lead author Professor Tony S.K. Mok, Chairman, Department of Clinical Oncology, The Chinese University of Hong Kong.

The subanalysis showed similar efficacy and safety with alectinib in Asian and non-Asian patients. Progression-free survival was longer with alectinib compared to crizotinib in Asian and non-Asian populations, with hazard ratios (HRs) of 0.46 and 0.49, respectively. Alectinib reduced central nervous system (CNS) progression compared to crizotinib in the Asian and non-Asian groups, with cause-specific HRs of 0.21 and 0.16, respectively. Median overall survival was not reached in either subgroup.

Response rates to alectinib and crizotinib were 81.2% versus 76.8%, respectively, for the Asian subgroup and 84.3% versus 74.4%, respectively, for the non-Asian subgroup.

The rates of nausea, vomiting, and grade III toxicities overall were lower with alectinib compared to crizotinib, and similar between the Asian and non-Asian subgroups. Liver toxicity due to alectinib was slightly higher in the Asian compared to the non-Asian subgroup.

Mok said: "Alectinib 600 mg twice daily was similarly effective in Asian and non-Asian patients in the ALEX study in terms of progression-free survival, CNS progression, and response rate. The rates of toxicities were also comparable. The findings suggest that 600 mg should be the standard dose of alectinib across Asia."

Commenting on the research, Dr Pilar Garrido, Head of the Thoracic Tumour Section, Medical Oncology Department, Ramón y Cajal University Hospital, Madrid, Spain, said: "ALK rearrangements emerged as important therapeutic targets in NSCLC in 2007, defining a distinct molecular subset of tumours. Around 5% of NSCLC patients harbour ALK mutations and are highly sensitive to ALK tyrosine kinase inhibitors, which efficiently induce apoptosis. Patients wih advanced ALK positive NSCLC have a high lifetime risk of CNS metastases and a high frequency of brain metastases at diagnosis, with the CNS being the most common site of disease progression."

FDA Grants Accelerated Approval to Zegfrovy (sunvozertinib) for Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations

Dizal (SSE:688192), a biopharmaceutical company committed to developing novel medicines for the treatment of cancer and immunological diseases, announced  the U.S. Food and Drug Administration (FDA) approval of  Zegfrovy (sunvozertinib) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations (exon20ins), as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.

Zegfrovy, which has received Priority Review and Breakthrough Therapy Designation from the FDA, is the only approved targeted oral treatment for NSCLC with EGFR exon20ins. This indication is approved under Accelerated Approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

“We are proud to have developed Zegfrovy, a first-in-class oral therapy that offers a more effective treatment option with enhanced safety and ease of administration for NSCLC patients with EGFR exon20ins,” said Dr. Xiaolin Zhang, CEO of Dizal. “The accelerated approval of Zegfrovy marks a significant milestone that underscores our commitment to developing groundbreaking new medicines for patients with high unmet medical needs around the world.”

Zegfrovy is an oral, irreversible EGFR inhibitor with uniquely designed molecular structure targeting a wide spectrum of EGFR mutations with wild-type EGFR selectivity. In August 2023, Zegfrovy received accelerated approval in China. Today’s FDA approval follows Breakthrough Therapy Designation and Priority Review granted by both the U.S. FDA and the Center for Drug Evaluation (CDE)of China’s National Medical Products Administration (NMPA).

The FDA approval is supported by data from the multinational pivotal study WU-KONG1 Part B (WU-KONG1B), aiming to investigate the efficacy and safety of Zegfrovy in relapsed or refractory NSCLC with EGFR exon20ins. The study results were featured as an oral presentation at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting and were recently published in the Journal of Clinical Oncology.

“As the world's only approved targeted oral therapy for EGFR exon20ins NSCLC, Zegfrovy has expanded the treatment paradigm in this therapeutic area that has long lacked convenient and effective treatment options,” said Pasi A. Jänne, MD, PhD, Dana-Farber Cancer Institute of Harvard Medical School and lead principal investigator of WU-KONG1B. “Research findings from WU-KONG1B have demonstrated Zegfrovy’s significant therapeutic effects with consistent efficacy across both Asian and non-Asian patient populations. Its convenient once-daily oral dosing substantially improves administration convenience and patient adherence, which is an increasingly critical factor as lung cancer care shifts toward chronic disease management. The U.S. approval of Zegfrovy® marks a landmark in scientific advancement and represents a meaningful milestone in addressing the long-standing unmet medical needs of this underserved patient population."

“Zegfrovy has demonstrated breakthrough therapeutic value in the treatment of EGFR exon20ins NSCLC, as shown in a rigorous multinational clinical trial. Its potent antitumor activity, manageable safety profile, and convenient oral administration position it as an optimal treatment option in clinical practice,” said Prof. James Chih-Hsin Yang, MD, PhD, National Taiwan University Cancer Center Hospital and the Co-lead principal investigator of WU-KONG1B. “The approval of Zegfrovy in major global markets not only offers new hope for patients, but also reinforces our commitment to patient-centered research and the continued advancement of precision medicine in lung cancer."

“In NSCLC, EGFR exon20ins represent the third most common type of EGFR mutation. EGFR exon20ins are particularly challenging to treat due to their unique spatial conformation, diverse mutation subtypes, and high heterogeneity. As a result, patients face a poor prognosis and limited treatment options,” said Prof. Mengzhao Wang, MD, PhD, lead principal investigator of the China-based pivotal study WU-KONG6 of Zegfrovy and principal investigator of WU-KONG1B at Peking Union Medical College Hospital, “The results of the WU-KONG6 study demonstrated Zegfrovy’s clinical benefit superior to current options and lead to the drug’s approval in China. The U.S. approval of Zegfrovy will enable more patients around the world to benefit from this drug.”

The FDA simultaneously approved Thermo Fisher Scientific’s Oncomine™ Dx Express Test as a next-generation sequencing (NGS) companion diagnostic (CDx) for Zegfrovy to identify NSCLC patients with EGFR Exon20 insertions. NGS testing is recognized as a critical technology in cancer genomic profiling, facilitating the rapid and precise detection of DNA mutations in tumor cells. Combined with the Ion Torrent™ Genexus™ Dx System, the test delivers NGS results in as little as 24 hours to help inform more timely treatment decisions in patients with EGFR exon20ins NSCLC.

Additionally, Dizal has completed enrollment for its multinational phase III pivotal WU-KONG28 study, evaluating Zegfrovy versus platinum-based doublet chemotherapies in treatment naïve NSCLC patients with EGFR exon20ins across 16 countries and regions. At the 2023 European Society for Medical Oncology (ESMO) Annual Meeting, Dizal reported that Zegfrovy, as a single oral agent, achieved a confirmed objective response rate (ORR) of 78.6% and a median progression-free survival (mPFS) of 12.4 months in the first-line setting. With its potent antitumor activity and favorable safety profile, Zegfrovy demonstrated strong potential as an optimalfirst-line treatment for patients with EGFR exon20ins NSCLC.

Ref : https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=11672

FDA Grants Accelerated Approval to Zegfrovy (sunvozertinib) for Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations

Pfizer Presents Promising Data from Next Generation ALK/ROS1 Inhibitor in Advanced Non-Small Cell Lung Cancer

Pfizer Inc.    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.

lorlatinib

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.

“Many patients with ALK-positive or ROS1-positive metastatic NSCLC will progress beyond initial therapy and potentially develop brain metastases,” said Benjamin Solomon, MBBS, Associate Professor, Peter MacCallum Cancer Centre, Australia. “These early data suggest lorlatinib may be effective in a broad range of patients, including those who are heavily pre-treated or develop brain metastases. We are encouraged by these results and look forward to further investigating the full effects of lorlatinib in ALK-positive and ROS1-positive NSCLC.”

“We are excited by these data and the potential of lorlatinib to overcome resistance to ALK inhibitors, which remains a significant challenge for patients with ALK-positive NSCLC,” said Mace Rothenberg, MD, senior vice president, head of development, Pfizer Oncology. “Pfizer pioneered precision medicine in ALK-positive advanced NSCLC through the introduction of XALKORI® (crizotinib), which is widely recognized as a first-line standard of care for these patients, and we are committed to developing next-generation treatments that meet these patients’ evolving needs.”

In the phase 1 portion of the study, patients received lorlatinib on a continuous basis, once or twice daily. The primary objective was to identify the maximum tolerated dose and recommended Phase 2 dose. Patients were treated across 10 dose levels (10–200 mg). The recommended Phase 2 dose was 100 mg once daily. Other objectives included safety and efficacy by RECIST v1.1 including intracranial activity. Of 54 patients treated as of January 15, 2016, 41 were ALK-positive, 12 were ROS1-positive and one was unconfirmed. The majority of patients were previously treated with a TKI, including 20 with one prior TKI and 27 with more than one TKI. Additionally, 39 patients had brain metastases at baseline.

The most common treatment-related adverse events (AEs) were hypercholesterolemia (69%) and peripheral edema (37%). Hypercholesterolemia was the most common (11%) grade 3 or higher treatment-related AE and the most frequent reason for dose delay or reduction. No patients discontinued due to treatment-related AEs. At the recommended Phase 2 dose, 4 out of 17 patients (24%) experienced a treatment-related AE of any grade that led to a dose delay or hold.

The ongoing Phase 2 study is expected to enroll a total of 240 patients across six cohorts (five for ALK-positive and one for ROS1-positive patients with NSCLC), with enrollment defined by degree and type of prior treatment.

About Lorlatinib

Lorlatinib, the proposed generic name for PF-06463922, is an investigational next-generation ALK/ROS1 tyrosine kinase inhibitor that has been shown to be highly active in preclinical lung cancer models harboring chromosomal rearrangements of both ALK and ROS1. Lorlatinib was specifically designed to inhibit tumor mutations that drive resistance to other ALK inhibitors and to penetrate the blood brain barrier. A Phase 1/2 clinical trial of lorlatinib in patients with ALK-positive or ROS1-positive advanced NSCLC is currently ongoing. Lorlatinib has not yet been approved by any regulatory agency.

Pfizer Presents Promising Data from Next Generation ALK/ROS1 Inhibitor in Advanced Non-Small Cell Lung Cancer  

FDA Approves Tepmetko (tepotinib) as the First and Only Once-daily Oral MET Inhibitor for Patients with Metastatic NSCLC with METex14 Skipping Alterations

EMD Serono, the healthcare business sector of Merck KGaA, Darmstadt, Germany in the US and Canada,  announced that the US Food and Drug Administration (FDA) has approved Tepmetko (tepotinib) following Priority Review for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymal-epithelial transition (MET) exon 14 skipping alterations. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

The approval is based on results from the pivotal Phase II VISION study evaluating Tepmetko as monotherapy in patients with advanced NSCLC with METex14 skipping alterations.

"METex14 skipping occurs in approximately 3% to 4% of NSCLC cases, and patients with this aggressive lung cancer are often elderly and face a poor clinical prognosis," said Paul K. Paik, M.D., VISION primary investigator and Clinical Director, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center. "There is a pressing need for targeted treatments that have the potential to generate durable anti-tumor activity and improve the lives of patients with this challenging disease. Tepmetko offers an important and welcome new therapeutic option for patients with metastatic NSCLC harboring these genetic mutations."

"In recent years, the treatment of lung cancer has seen powerful progress in the understanding of the genetic mutations that lead to tumor growth, resistance and progression," said Andrea Ferris, President and CEO of LUNGevity. "The availability of a new precision medicine for NSCLC with METex14 skipping alterations advances patient access to targeted treatment and underscores the importance of routine comprehensive biomarker testing for patients with this challenging cancer."

Tepmetko is the first and only FDA approved MET inhibitor that offers once-daily oral dosing and is administered as two 225 mg tablets (450 mg). Patients with metastatic NSCLC should be selected for treatment with Tepmetko based on the presence of MET exon 14 skipping alterations.

"This approval of Tepmetko by the FDA is an important milestone on our mission to significantly improve the treatment of cancer where MET plays a driving role," said Danny Bar-Zohar, M.D., Global Head of Development for the Healthcare business of Merck KGaA, Darmstadt, Germany. "Our focus now is to ensure Tepmetko is accessible to patients in the United States and fully integrated into clinical practice given the important advance it represents for indicated patients as an oral once-a-day precision medicine."

EMD Serono, the healthcare business of Merck KGaA, Darmstadt, Germany in the US and Canada, is committed to providing patient access and reimbursement support for eligible Tepmetko patients through its Oncology Navigation Center™ (ONC) program in the US. ONC provides a spectrum of patient access and reimbursement support services intended to help US patients receive appropriate treatment access. ONC may be reached at 1-844-662-3631 (844-ONC-EMD1) between 8am-8pm Eastern Time, Monday through Friday, or by visiting OncNavigationCenter.com.

Tepmetko was the first oral MET inhibitor to receive a regulatory approval anywhere in the world for the treatment of advanced NSCLC harboring MET gene alterations, with its approval in Japan in March 2020. The FDA completed its review of Tepmetko under its Real-Time Oncology Review pilot program after previously granting the medicine Breakthrough Therapy Designation. The FDA also recently granted Tepmetko Orphan Drug Designation (ODD).

A Marketing Authorization Application for tepotinib for a similar indication was validated by the European Medicines Agency in November 2020. Applications have also been submitted in Australia, Switzerland, and Canada under the FDA's Project Orbis initiative, which provides a framework for concurrent submission and review of oncology medicines among international partners.1

VISION Study Pivotal Trial Results

VISION (NCT02864992) is an ongoing pivotal Phase II, multicenter, multi-cohort, single-arm, non-randomized, open-label study investigating tepotinib as monotherapy in 152 patients with a median age of 73 years with advanced or metastatic non-small cell lung cancer (NSCLC) with MET exon 14 (METex14) skipping alterations. Eligible patients were required to have advanced or metastatic NSCLC harboring METex14 skipping alterations, epidermal growth factor receptor (EGFR) wild-type and anaplastic lymphoma kinase (ALK) negative status, at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1. Patients received Tepmetko 450 mg once daily until disease progression or unacceptable toxicity. The major efficacy outcome measure is overall response rate (ORR) according to RECIST version 1.1 as assessed by a blinded independent review committee (BIRC). An additional efficacy outcome measure was duration of response (DOR) by BIRC. Patients with symptomatic CNS metastases, clinically significant uncontrolled cardiac disease, or who received treatment with any MET or hepatocyte growth factor (HGF) inhibitor were not eligible for the study. Data from the primary analysis of the VISION study were previously published online in The New England Journal of Medicine.2 

In the study, Tepmetko demonstrated an overall response rate of 43% (95% CI, 32–56) in treatment-naïve patients (n=69) and 43% (95% CI, 33-55) in previously treated patients (n=83). Median duration of response (DOR) was 10.8 months (95% CI, 6.9-NE) and 11.1 months (95% CI, 9.5-18.5) among treatment-naïve and previously treated patients, respectively. Duration of response of six months or more occurred among 67% of treatment-naïve patients and 75% of previously treated patients, and duration of response of nine months or more occurred among 30% of treatment-naïve patients and 50% of previously treated patients.3

The safety population included 255 patients with NSCLC positive for METex14 skipping alterations, who received Tepmetko in the VISION study. Fatal adverse reactions occurred in one patient (0.4%) due to pneumonitis, one patient (0.4%) due to hepatic failure, and one patient (0.4%) due to dyspnea from fluid overload. Serious adverse reactions occurred in 45% of patients who received Tepmetko. Serious adverse reactions occurring in >2% of patients included pleural effusion (7%), pneumonia (5%), edema (3.9%), dyspnea (3.9%), general health deterioration (3.5%), pulmonary embolism (2%), and musculoskeletal pain (2%). The most common adverse reactions (≥20%) in patients who received Tepmetko were edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea.

https://en.wikipedia.org/wiki/Tepotinib

FDA Grants Accelerated Approval to Hernexeos (zongertinib) for Previously Treated Patients with HER2-Mutant Advanced NSCLC

Boehringer Ingelheim’s Hernexeos (zongertinib tablets) has been approved by the U.S. Food and Drug Administration (FDA). The kinase inhibitor is indicated for the treatment of adult patients with unresectable or metastatic non-squamous non-small cell lung cancer (NSCLC) whose tumors have HER2 (ERBB2) tyrosine kinase domain activating mutations, as detected by an FDA-approved test, and who have received prior systemic therapy.1

This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.1

“With the approval of zongertinib, we have an effective, targeted, orally administered treatment option for patients with HER2 (ERBB2)-mutant non-small cell lung cancer in the U.S. that not only elicits a durable response but, importantly, has a manageable safety profile,” said Dr. John Heymach, MD, PhD, chair of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, and coordinating investigator for the Beamion-LUNG 1 trial. “In a patient population where there are currently limited treatment options, this approval represents a significant advancement in cancer care.”

Accelerated approval is based on data from the Phase Ib Beamion-LUNG 1 trial, demonstrating an objective response rate of 75% (N=71), 6% of patients had a complete response and 69% of patients had a partial response and a duration of response of ≥6 months in 58% of patients (n=53).1 Positive results from the Beamion-LUNG 1 trial were previously presented at the American Association for Cancer Research (AACR) Annual Meeting 2025 and simultaneously published in The New England Journal of Medicine.2

Zongertinib demonstrated a manageable safety profile with a 2.9% discontinuation rate. In the pooled safety population, the most common (> 20%) adverse reactions were diarrhea (53%), hepatotoxicity (27%), rash (27%), fatigue (22%), and nausea (21%).1

“We are grateful to be able to bring forward Hernexeos, which has the potential to reset the benchmark for those living with HER2-mutant advanced non-small cell lung cancer, a condition associated with a particularly poor prognosis,” said Shashank Deshpande, Chairman of the Board of Managing Directors and Head of Human Pharma at Boehringer Ingelheim. “Believing in the power of scientific innovation, we aim to provide meaningful improvements to this patient population. Recognizing its potential, we accelerated development to deliver this new treatment option to patients within four years of starting the first clinical trial."

Harnessing the power of precision medicine by targeting HER2 mutations in lung cancer

HER2 (ERBB2) mutations occur in approximately 2–4% of NSCLC cases and are associated with a poor prognosis and higher incidence of brain metastases.3,4,5Alterations in the HER2 (ERBB2) gene, including mutations, amplification and overexpression, trigger uncontrolled cell proliferation, inhibiting cell death, and promoting tumor growth and spread.3,5 Comprehensive biomarker testing using next generation sequencing determines a patient’s eligibility for treatment with zongertinib by identifying HER2 (ERBB2)-mutant advanced NSCLC.1,5

“The advocacy community is thrilled about the approval of zongertinib, as it is another testament to the importance of personalized options for lung cancer that allow for a much more targeted approach for a subgroup of patients who have been waiting many years for innovative treatments,” said Marcia Horn, President and CEO, International Cancer Advocacy Network and Executive Director of the Exon 20 Group/HER2 Warriors. “Understanding your cancer’s unique biomarkers, including HER2, through comprehensive testing is critical for all patients with NSCLC, as it can unlock targeted treatment options.”

About non-small cell lung cancer (NSCLC)

Lung cancer claims more lives than any other cancer type and the incidence is set to increase to over 3 million cases worldwide by 2040.5,6 NSCLC is the most common type of lung cancer.3 Due to a lack of symptoms and misdiagnoses,7 most patients with NSCLC present at stage III or IV, where the disease has metastasized locally or to other organs.8 The estimated 5-year survival rate historically has been less than 10% for metastatic disease.9,10,11 People living with advanced NSCLC can experience a detrimental physical, psychological, and emotional impact on their daily lives.12,13,14

About zongertinib

Zongertinib is a tyrosine kinase inhibitor (TKI) that selectively inhibits HER2 (ERBB2).1 This orally administered, targeted therapy was approved as Hernexeos® (zongertinib tablets) under the FDA’s Accelerated Approval Program, after securing Priority Review as well as Breakthrough Therapy and Fast Track Designations.1

The treatment is being evaluated in ongoing trials, across a range of advanced solid tumors with HER2 alterations.

https://en.wikipedia.org/wiki/Zongertinib#:~:text=Society%20and%20culture-,Legal%20status,under%20the%20brand%20name%20Hernexeos.

FDA Grants Accelerated Approval to Hernexeos (zongertinib) for Previously Treated Patients with HER2-Mutant Advanced NSCLC

Nuvalent Announces Submission of New Drug Application to FDA for Neladalkib in TKI Pre-treated Advanced ALK-Positive NSCLC

Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, today announced the submission to the U.S. Food and Drug Administration (FDA) of the Company's NDA for neladalkib, an investigational ALK-selective inhibitor, in TKI pre-treated advanced ALK-positive NSCLC.

New Drug Application (NDA) based on data in TKI pre-treated patients from the global ALKOVE-1 Phase 1/2 clinical trial

"The advancement of neladalkib from first clinical trial initiation to NDA submission in less than four years represents a remarkable pace in oncology drug development, underscoring the vigor and urgency our team brought to this program and our deep commitment to the ALK-positive NSCLC community," said Darlene Noci, A.L.M., Chief Development Officer at Nuvalent. "We would like to extend our sincere gratitude to the patients, families and investigators who have made this progress possible, and are committed to working closely with the FDA throughout the NDA review process toward our goal of bringing neladalkib to patients as quickly as possible."

The application is based on data in TKI pre-treated patients with advanced ALK-positive NSCLC treated with neladalkib in the global, registration-directed ALKOVE-1 Phase 1/2 clinical trial. In this population, neladalkib demonstrated encouraging overall activity, including intracranial responses, the ability to address key drivers of disease progression, and a generally well-tolerated safety profile consistent with its ALK-selective, TRK-sparing design. The company plans to share detailed results at a future medical meeting.

Neladalkib has received breakthrough therapy designation from the FDA for the treatment of patients with locally advanced or metastatic ALK-positive NSCLC who have been previously treated with 2 or more ALK tyrosine kinase inhibitors and orphan drug designation for ALK-positive NSCLC.

About Neladalkib

Neladalkib is an investigational, brain-penetrant, ALK-selective inhibitor created with the aim to overcome limitations observed with currently available ALK inhibitors. Neladalkib is designed to remain active in tumors that have developed resistance to first-, second-, and third-generation ALK inhibitors, including tumors with single or compound treatment-emergent ALK mutations such as G1202R. In addition, neladalkib is designed for central nervous system (CNS) penetrance to improve treatment options for patients with brain metastases, and to avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family. Together, these characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ALK inhibitors and to drive deep, durable responses for patients across all lines of therapy. Neladalkib has received breakthrough therapy designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) who have been previously treated with 2 or more ALK tyrosine kinase inhibitors and orphan drug designation for ALK-positive NSCLC.

https://go.drugbank.com/drugs/DB16688

FDA Approves Ibtrozi (taletrectinib) for Advanced ROS1-Positive Non-Small Cell Lung Cancer

Nuvation Bio Inc. announced the U.S. Food and Drug Administration (FDA)  approval of  Ibtrozi (taletrectinib) for the treatment of adult patients with locally advanced or metastatic ROS1-positive (ROS1+) non-small cell lung cancer (NSCLC). Ibtrozi is a highly selective, next-generation oral ROS1 tyrosine kinase inhibitor (TKI) designed to address some of the outstanding challenges of treating ROS1+ NSCLC. It has demonstrated high response rates with durable benefit and intracranial activity and is generally well tolerated, providing a new treatment option for patients with advanced ROS1+ NSCLC.

“The FDA approval of Ibtrozi marks a major milestone in the evolution of targeted therapy for advanced ROS1-positive NSCLC,” said David Hung, M.D., Founder, President and Chief Executive Officer of Nuvation Bio. “We believe one of the greatest threats to ROS1-positive lung cancer patients is disease progression, especially in the first-line setting. In pivotal trials, Ibtrozi delivered high response rates with sustained durability—truly meaningful benefits for patients. With its clinically proven efficacy and safety profile, we believe Ibtrozi has the potential to become a new standard for what targeted therapies can achieve in this type of lung cancer. With approvals for Ibtrozi now in the U.S. and China, and additional global filings underway, we remain committed to delivering innovative therapies that help patients stay ahead of their disease.”

ROS1+ NSCLC is a rare and aggressive form of lung cancer, accounting for approximately 2% of new NSCLC cases, or about 3,000 new diagnoses of advanced disease annually in the U.S. The median age at diagnosis for patients with this type of lung cancer is approximately 50 years old, and the disease is more likely to occur in people who have never smoked. Brain metastases are common and a leading cause of disease progression and mortality in this population.

“For people living with advanced ROS1-positive lung cancer, who tend to be diagnosed at a younger age, having another treatment option can make a real difference for them and their loved ones,” said Janet Freeman-Daily, Co-Founder and President of The ROS1ders. “The approval of this new targeted therapy is a meaningful step forward for the advanced ROS1+ lung cancer community and offers hope for patients facing the added challenge of cancer spreading to the brain.”

The FDA approval of Ibtrozi is supported by one of the largest global clinical trial programs in ROS1+ NSCLC to date, with over 300 patients enrolled in the pivotal TRUST-I and TRUST-II studies.

In TRUST-I, Ibtrozi achieved a confirmed overall response rate (cORR) of 90% in TKI-naïve patients. These findings were reinforced by the TRUST-II results, with a cORR of 85% in TKI-naïve patients. The median duration of response (DOR) was not yet reached for either trial, based on a cutoff date that is nearly five months later than that of the pooled TRUST-I and TRUST-II analysis published in April in the Journal of Clinical Oncology. For TRUST-I, with a median follow-up for responses of 40 months, the longest DOR was observed at 46.9 months and ongoing. For TRUST-II, with a median follow-up for responses of 19 months, the longest DOR was observed at 30.4 months and ongoing as of October 2024. Given the single-arm nature of the TRUST clinical studies, median progression-free survival (PFS) is not provided in the label.

Across the pivotal studies, consistent results were also observed among patients who were previously treated with a ROS1 TKI (TKI-pretreated). In TRUST-I, treatment with Ibtrozi achieved a cORR of 52% and median DOR of 13.2 months for TKI-pretreated patients, with median follow-up for responses of 33 months. In TRUST-II, treatment with Ibtrozi achieved a cORR of 62%, and as of October 2024 the median DOR was 19.4 months in these patients, with a median follow-up for responses of 19 months.

Brain metastases are among the most common and devastating complications in advanced ROS1+ NSCLC. Ibtrozi was designed to penetrate the central nervous system (CNS) and has demonstrated consistent intracranial responses in patients with measurable brain metastases at baseline. An intracranial response was achieved in 73% of TKI-naive patients (11/15) and 63% of TKI-pretreated patients (15/24).

“Patients living with advanced ROS1+ non-small cell lung cancer and their healthcare providers are in need of new treatment options,” added Nathan Pennell, M.D., Ph.D., TRUST study investigator and Professor of Medicine at the Cleveland Clinic. “Ibtrozi’s durability of response and ability to effectively penetrate the brain, coupled with a well-characterized and manageable safety profile, further addresses these critical needs for patients. I believe this now-approved therapy offers providers and patients a promising new option for the treatment of advanced ROS1+ non-small cell lung cancer.” Dr. Pennell is a compensated member of Nuvation Bio’s advisory committee.

Ibtrozi was generally well-tolerated, with most adverse events being low grade, transient and manageable. Patients infrequently (7%) discontinued treatment due to treatment-emergent adverse events (TEAEs). The most common adverse reactions (≥20%) included diarrhea (64%), nausea (47%), vomiting (43%), dizziness (22%), rash (22%), constipation (21%), and fatigue (20%). Overall, the majority of CNS events were mild to moderate (~90%) and resolved within days, and dose modifications due to these events were low (~5%). Approximately 90% of reported cases of dizziness were Grade 1 (mild) and transient. Liver enzyme elevations (AST 87%/ALT 85%) and QT prolongation (19%) were manageable with standard monitoring and dose modifications. Ibtrozi is approved as a 600 mg once-daily oral dose, supported by a half-life of approximately 66 hours and broad tissue distribution, including the brain, enabling sustained systemic and CNS exposure.

FDA Approves Ibtrozi (taletrectinib) for Advanced ROS1-Positive Non-Small Cell Lung Cancer

FDA Approves Exkivity (mobocertinib) for EGFR Exon20 Insertion+ Non-Small Cell Lung Cancer (NSCLC)

Takeda Pharmaceutical Company Limited  announced   the U.S. Food and Drug Administration (FDA)  approval of  Exkivity (mobocertinib) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. Exkivity, which was granted priority review and received Breakthrough Therapy Designation, Fast Track Designation and Orphan Drug Designation from the FDA, is the first and only approved oral therapy specifically designed to target EGFR Exon20 insertion mutations. This indication is approved under Accelerated Approval based on overall response rate (ORR) and DoR. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

“The approval of Exkivity introduces a new and effective treatment option for patients with EGFR Exon20 insertion+ NSCLC, fulfilling an urgent need for this difficult-to-treat cancer,” said Teresa Bitetti, president, Global Oncology Business Unit, Takeda. “Exkivity is the first and only oral therapy specifically designed to target EGFR Exon20 insertions, and we are particularly encouraged by the duration of the responses observed with a median of approximately 1.5 years. This approval milestone reinforces our commitment to meeting the needs of underserved patient populations within the oncology community.”

The FDA simultaneously approved Thermo Fisher Scientific’s Oncomine Dx Target Test as an NGS companion diagnostic for Exkivity to identify NSCLC patients with EGFR Exon20 insertions. NGS testing is critical for these patients, as it can enable more accurate diagnoses compared to polymerase chain reaction (PCR) testing, which detects less than 50% of EGFR Exon20 insertions.

“EGFR Exon20 insertion+ NSCLC is an underserved cancer that we have been unable to target effectively with traditional EGFR TKIs,” said Pasi A. Jänne, MD, PhD, Dana Farber Cancer Institute. “The approval of Exkivity (mobocertinib) marks another important step forward that provides physicians and their patients with a new targeted oral therapy specifically designed for this patient population that has shown clinically meaningful and sustained responses.”

“Patients with EGFR Exon20 insertion+ NSCLC have historically faced a unique set of challenges living with a very rare lung cancer that is not only underdiagnosed, but also lacking targeted treatment options that can improve response rates,” said Marcia Horn, executive director, Exon 20 Group at ICAN, International Cancer Advocacy Network. “As a patient advocate working with EGFR Exon20 insertion+ NSCLC patients and their families every day for nearly five years, I am thrilled to witness continued progress in the fight against this devastating disease and am grateful for the patients, families, healthcare professionals and scientists across the globe who contributed to the approval of this promising targeted therapy.”

The FDA approval is based on results from the platinum-pretreated population in the Phase 1/2 trial of Exkivity, which consisted of 114 patients with EGFR Exon20 insertion+ NSCLC who received prior platinum-based therapy and were treated at the 160 mg dose. Results were presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting from the Phase 1/2 trial and demonstrated a confirmed ORR of 28% per independent review committee (IRC) (35% per investigator) as well as a median DoR of 17.5 months per IRC, a median overall survival (OS) of 24 months and a median progression-free survival (PFS) of 7.3 months per IRC.

Spectrum Pharmaceuticals Submits New Drug Application for Poziotinib for metastatic NSCLC with HER2 exon 20 insertion mutations.

 

                  

Spectrum Pharmaceuticals, a biopharmaceutical company focused on novel and targeted oncology therapies,  announced that it has submitted its New Drug Application (NDA) for poziotinib to the U.S. Food and Drug Administration (FDA) for use in patients with previously treated locally advanced or metastatic non-small cell lung cancer (NSCLC) with HER2 exon 20 insertion mutations. The NDA submission is based on the positive results of Cohort 2 from the ZENITH20 clinical trial, which assessed the safety and efficacy of poziotinib. The product has received Fast Track designation and there is currently no treatment specifically approved by the FDA for this indication.

“The NDA submission for poziotinib marks an important step in achieving a first treatment for patients with HER2 exon 20 insertion mutations in lung cancer,” said Joe Turgeon, President and CEO of Spectrum Pharmaceuticals. “I want to thank the patients, investigators and our internal staff who have passionately worked to achieve this important milestone in an area of high unmet medical need.”

ZENITH20 Cohort 2 Clinical Results Summary

Results for Cohort 2 of the ZENITH20 clinical trial have been published in the Journal of Clinical Oncology (November 29, 2021), and can be accessed by clicking here.

Cohort 2 enrolled 90 patients who received an oral once daily dose of 16 mg of poziotinib. The intent-to-treat analysis demonstrated a confirmed objective response rate (ORR) of 27.8% (95% Confidence Interval (CI), 18.9%-38.2%). The observed lower bound of 18.9% exceeded the pre-specified lower bound of 17%. The median duration of response was 5.1 months and the median progression free survival was 5.5 months. In this cohort, 87% of patients had drug interruptions with 11 patients (12%) permanently discontinuing due to adverse events. 13 patients (14%) had treatment-related serious adverse events. As previously announced, the company had a successful pre-NDA meeting with the FDA which resulted in an agreement to submit an NDA for poziotinib. During the meeting, Spectrum confirmed with the FDA that Cohort 2 data could serve as the basis of an NDA submission. The company will continue to work with the FDA as appropriate, while the agency conducts its review.

About the ZENITH20 Clinical Trial

The ZENITH20 study consists of seven cohorts of NSCLC patients. Cohorts 1 (EGFR) and 2 (HER2) in previously treated NSCLC patients with exon 20 mutations and Cohort 3 (EGFR) in first-line patients have completed enrollment. Cohort 4 (HER2) in first-line NSCLC patients with exon 20 mutations is still enrolling patients. Cohorts 1- 4 are each independently powered for a pre-specified statistical hypothesis and the primary endpoint is objective response rate (ORR). Cohort 5 includes previously treated or treatment-naïve NSCLC patients with EGFR or HER2 exon 20 insertion mutations. Cohort 6 includes NSCLC patients with classical EGFR mutations who progressed while on treatment with first-line osimertinib and developed an additional EGFR mutation. Cohort 7 includes NSCLC patients with a variety of less common mutations in EGFR or HER2 exons 18-21 or the extracellular or transmembrane domains

 https://en.wikipedia.org/wiki/Poziotinib 

Combined drug treatment for lung cancer and secondary tumors

In continuation of my update on alectinib, erlotinib and  osimertinib

 

                                                                   alectinib

                                                    

                                                                     erlotinib

                                                  

                                                                             Osimertinib

Researchers at Kanazawa University report in the Journal of Thoracic Oncology a promising novel approach for a combined treatment of the most common type of lung cancer and associated secondary cancers in the central nervous system. The approach lies in combining two cancer drugs, with one compensating for a resistance side effect of the other.

In 20 to 40% of patients with cancer, metastasis (the development of secondary tumors) in the central nervous system (CNS) occurs. CNS metastasis impacts negatively on a patient's quality of life, and is associated with a poor health prognosis. In a form of cancer known as ALK-rearranged non-small-cell lung cancer (NSCLC), CNS metastasis is known to persist when drugs targeting primary tumors are used. Now, Seiji Yano from Kanazawa University and colleagues have investigated the origins for the resistence to such drugs, and tested a new therapeutic strategy on a mouse model.

The researchers looked at the drug alectinib. Although used in standard treatments for advanced ALK-rearranged NSCLC, approximately 20 to 30% of patients treated with alectinib develop CNS metastasis, which is attributed to acquired resistance to the drug.

By treating mice first injected with tumor cells with alectinib daily for 16 weeks, the scientists obtained a mouse model displaying alectinib resistance. By biochemical analyses of the mouse brains, Yano and colleagues were able to link the resistance to the activation of a protein known as epidermal growth factor receptor (EGFR). This activation is, in turn, a result of an increase in production of amphiregulin (AREG), a protein that binds to EGFR and in doing so 'activates' it.

Based on this insight, the researchers tested the effect of administering drugs used for inhibiting the action of EGFR in combination with alectinib treatment. The experiments showed that a combination treatment of alctinib with either erlotinib or osimertinib—two existing EGFR-inibiting drugs—prevented the progression of CNS metastasis, controlling the condition for over 30 days.

The scientists conclude that the combined use of alectinib and EGFR-inhibitors could overcome alectinib resistance in the mouse model of leptomeningeal carcinomatosis (LMC), a particular type of CNS metastasis. Quoting Yano and colleagues: "Our findings may provide rationale for clinical trials to investigate the effects of novel therapies dual-targeting ALK and EGFR in ALK-rearranged NSCLC with alectinib-resistant LMC."

Non-small-cell lung cancer

Non-small-cell lung carcinoma (NSCLC) and small-cell lung carcinoma (SCLC) are the two types of lung cancer. 85% of all lung cancers are of the NSCLC type. NSCLCs are less sensitive to chemotherapy than SCLCs, making drug treatment of the highest importance.

Alectinib is a drug used for treating NSCLC, with good efficiency. However, 20-30% of patients taking the drug develop secondary cancer in the central nervous system (CNS), which is associated with an acquired resistance to alectinib. Seiji Yano from Kanazawa University and colleagues have now made progress towards a novel therapy against this resistance: a combination of alectinib with other drugs.

Epidermal growth factor receptor inhibitors

The drugs that Yano and colleagues tested in combination with alectinib on a mouse model were of a type known as epidermal growth factor receptor (EGFR) inhibitors, including osimertinib and erlotinib. Both are being used as medication for treating NSCLC. The former was approved in 2017 as cancer treatment by the U.S. Food and Drug Administration and the European Commission. Yano and colleagues obtained results showing that EGFR inhibitors counteract resistance to alectinib and have therefore potential in novel therapies for NSCLC and secondary cancers in the CNS.

https://medicalxpress.com/news/2017-11-osimertinib-progression-free-survival-asian-egfr-mutated.html