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

Spectrum Pharmaceuticals Submits New Drug Application for Poziotinib

Spectrum Pharmaceuticals, a biopharmaceutical company focused on novel and targeted oncology therapies, announced the submission of  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.

More : https://investor.sppirx.com/news-releases/news-release-details/spectrum-pharmaceuticals-submits-new-drug-application-poziotinib

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

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 

New Drug Application of Plinabulin (Response Letter from the FDA) for Prevention of Chemotherapy-Induced Neutropenia (CIN)...

 BeyondSpring Pharmaceuticals  announced the receipt of  a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) for the New Drug Application (NDA) seeking approval of plinabulin in combination with granulocyte colony-stimulating factor (G-CSF) for the prevention of chemotherapy-induced neutropenia (CIN). The FDA issued the CRL to indicate that they have completed their review of the application and have determined that it cannot be approved in its present form.

 

The FDA’s CRL indicated that the results of the single registrational trial (106 Phase 3) was not sufficiently robust to demonstrate benefit and that a second well controlled trial would be required to satisfy the substantial evidence requirement to support the CIN indication.

“BeyondSpring strongly believes that plinabulin in combination with G-CSF has significant potential to raise the standard of care in CIN, a devastating side effect of chemotherapy,” said Dr. Lan Huang, BeyondSpring’s co-founder, chief executive officer and chairwoman. “The Company plans to request a meeting with the FDA and remains committed to its goal of bringing plinabulin to cancer patients in need globally.”

BeyondSpring remains confident in the efficacy and safety data for plinabulin in combination with G-CSF for the prevention of CIN. The Company expects to work closely with the FDA to consider the possible future clinical pathway for CIN, which may include a second study.

Plinabulin is the first drug candidate submitted for FDA approval that has the potential to work in the critical first week of chemotherapy treatment before G-CSF is effective, to prevent the onset and improve clinical outcomes of CIN.

Plinabulin, BeyondSpring’s lead asset, is a selective immunomodulating microtubule-binding agent (SIMBA), which is a potent antigen presenting cell (APC) inducer. It is a novel, intravenous infused, patent-protected, NDA-stage asset for CIN prevention and a Phase 3 anti-cancer candidate for non-small cell lung cancer (NSCLC) with recently released positive topline data. Plinabulin triggers the release of the immune defense protein, GEF-H1, which leads to two distinct effects: first is a durable anticancer benefit due to the maturation of dendritic cells resulting in the activation of tumor antigen-specific T-cells to target cancer cells, and the second is early-onset of action in CIN prevention after chemotherapy by boosting the number of hematopoietic stem/progenitor cells (HSPCs). Plinabulin received Breakthrough Therapy designation and priority review from both U.S. and China FDA for the CIN prevention indication. As a “pipeline in a drug,” plinabulin is being broadly studied in combination with various immuno-oncology agents that could boost the effects of the PD-1/PD-L1 antibodies and re-sensitize PD-1/PD-L1 antibody-resistant patients.

More

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

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.

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

Lorlatinib Superior to Crizotinib for ALK-Positive NSCLC

In continuation of my update on lorlatinib and  crizotinib

                                                                 lorlatinib

                                                               crizotinib

Among patients with previously untreated advanced ALK-positive non-small cell lung cancer (NSCLC), progression-free survival is significantly longer for those who receive first-line therapy with lorlatinib versus crizotinib, according to a study published in the Nov. 19 issue of the New England Journal of Medicine.

Alice T. Shaw, M.D., Ph.D., from the Massachusetts General Hospital Cancer Center in Boston, and colleagues conducted a global, randomized, phase 3 trial comparing lorlatinib with crizotinib in 296 patients with advanced ALK-positive NSCLC who were previously untreated for metastatic disease.

The researchers found that 78 and 39 percent of patients in the lorlatinib group and crizotinib group, respectively, were alive without disease progression at 12 months (hazard ratio for disease progression or death, 0.28). An objective response occurred in 76 and 58 percent of those in the lorlatinib and crizotinib groups, respectively. Among those with measurable brain metastases, an intracranial response occurred in 82 and 23 percent, respectively; an intracranial complete response occurred in 71 percent of those who received lorlatinib. Hyperlipidemia, edema, increased weight, peripheral neuropathy, and cognitive effects were the most common adverse events associated with lorlatinib. Compared with crizotinib, lorlatinib was associated with more grade 3 or 4 adverse events (mainly altered lipid levels; 72 versus 56 percent).

"Among patients with previously untreated, advanced ALK-positive NSCLC, those who received lorlatinib had significantly longer progression-free survival, a higher overall and intracranial response, and better quality of life than those who received crizotinib," the authors write.

Several authors disclosed financial ties to pharmaceutical companies, including Pfizer, which manufactures lorlatinib and funded the study.

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

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

FDA Approves Gavreto (pralsetinib) for the Treatment of Adults With Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY),  announced  the U.S. Food and Drug Administration (FDA) approval of Gavreto (pralsetinib) for the treatment of adults with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test. This indication was approved under the FDA’s accelerated approval program based on data from the Phase I/II ARROW study. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Gavreto is a once-daily, oral precision therapy designed to selectively target RET alterations, including fusions and mutations.

“The FDA approval of Gavreto for RET fusion-positive non-small cell lung cancer is an important step towards our goal of providing an effective treatment option for every person diagnosed with lung cancer, no matter how rare or hard-to-treat their type of disease,” said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. “We remain committed to finding personalized treatment options for people with cancer based on specific genomic or molecular alterations, and we look forward to partnering with Blueprint Medicines to further explore the potential of Gavreto across multiple RET-altered tumor types.”

RET-activating fusions and mutations are key disease drivers in many cancer types, including NSCLC and medullary thyroid cancer (MTC), and treatment options that selectively target these genetic alterations are limited. In NSCLC, RET fusions represent approximately 1-2% of patients. Biomarker testing for these fusions is the most effective way to identify people who are eligible for treatment with Gavreto.

The approval is based on the results from the Phase I/II ARROW study, in which Gavreto produced durable clinical responses in people with RET fusion-positive NSCLC with or without prior therapy, and regardless of RET fusion partner or central nervous system involvement. Gavreto demonstrated an overall response rate (ORR) of 57% (95% CI: 46%, 68%) and complete response (CR) rate of 5.7% in the 87 people with NSCLC previously treated with platinum-based chemotherapy, and the median duration of response (DoR) was not reached (95% CI: 15.2 months, not reached). In the 27 people with treatment-naïve NSCLC, the ORR was 70% (95% CI: 50%, 86%) with an 11% CR rate. The most common adverse reactions (≥25%) were fatigue, constipation, musculoskeletal pain and increased blood pressure (hypertension).

Gavreto is now the sixth FDA-approved medicine in Genentech’s portfolio of treatments for lung cancer. The FDA granted Breakthrough Therapy Designation to Gavreto for the treatment of RET fusion-positive NSCLC that has progressed following platinum-based chemotherapy and for RET mutation-positive MTC that requires systemic treatment and for which there are no acceptable alternative treatments.

The FDA has also granted Priority Review to Gavreto for the treatment of people with advanced or metastatic RET-mutant MTC and RET fusion-positive thyroid cancer, and is expected to make a decision on approval by February 28, 2021. This New Drug Application (NDA) was accepted for review under the FDA’s Real-Time Oncology Review (RTOR) pilot program, which aims to explore a more efficient review process to ensure safe and effective treatments are available to patients as early as possible.

For those who qualify, Blueprint Medicines will offer patient assistance programs for people prescribed Gavreto by their doctor through YourBlueprint™ . Please visit www.yourblueprint.com or contact 1-888-BLUPRNT for more information.

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

FDA Approves Gavreto (pralsetinib) for the Treatment of Adults With Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer

Early treatment with lorlatinib improves survival in some lung cancer patients: Lung cancer patients with a specific genetic alteration lived longer and were protected against metastasis to the brain when treated early with lorlatinib

In continuation of my update on Lorlatinib

Non-small-cell lung cancer (NSCLC) accounts for 87% of all cases of lung cancer. Some 5% of NSCLC cases are ALK-positive, which means they have a genetic abnormality in the anaplastic lymphoma kinase gene. ALK-positive NSCLC, which is not associated with smoking, is a particularly aggressive form of lung cancer.

"When ALK is turned on abnormally, it's like stepping on the gas pedal -- it drives uncontrolled proliferation and survival of cancer cells," says investigator Alice Shaw, MD, PhD, who was formerly director of the Center for Thoracic Cancers at MGH and led the NEJM study. Notably, ALK-positive patients tend to be 10 to 15 years younger than other lung cancer patients. They are also at high risk for developing brain metastasis.

A new class of drugs that block ALK, known as ALK inhibitors, was discovered in 2008. "Turning off ALK with an ALK inhibitor is like putting on the brakes," agrees Justin Gainor, MD, of the Mass General Cancer Center, who worked with Shaw on the study. "It can lead to rapid killing of cancer cells and cause tumors to shrink dramatically." Both first and second generation ALK inhibitors have been developed, including crizotinib (Xalkori), alectinib (Alecensa), and brigatinib (Alunbrig), which can be very effective, but patients eventually relapse. What's more, patients treated with these drugs can still develop metastatic spread of cancer to the brain.

Lorlatinib belongs to a third-generation of this drug class and is even more effective at blocking ALK. It's currently approved by the Food and Drug Administration for treating ALK-positive patients whose cancer has progressed despite taking older-generation ALK inhibitors.

Shaw and her co-investigators wanted to know if lorlatinib improved the likelihood of long-term remission in ALK-positive patients when administered as first-line therapy. To find out, she and colleagues at 104 medical centers in 23 countries recruited 296 patients with advanced, previously untreated ALK-positive NSCLC. Half of the patients received lorlatinib, while the remainder were treated with crizotinib, which was the standard of care for these patients when the trial began.

The results were striking. Compared to patients who received crizotinib, those given lorlatinib had a 72% reduction in the risk of cancer progression or death. Importantly, lorlatinib also reduced the risk of new or recurrent brain metastases by 93%. Serious side effects were more common in the lorlatinib group, but more than half were increases in blood cholesterol and triglycerides, which were manageable with medication.

The investigators will continue to follow patients in this study to track their long-term outcomes, but "these results support lorlatinib as a potential first-line option for ALK-positive patients," says Shaw.

Shaw is now global head of Translational Clinical Oncology at the Novartis Institutes for BioMedical Research

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

Early treatment with lorlatinib improves survival in some lung cancer patients: Lung cancer patients with a specific genetic alteration lived longer and were protected against metastasis to the brain when treated early with lorlatinib -- ScienceDaily

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

FDA Approves Rozlytrek (entrectinib) for People With ROS1-Positive, Metastatic Non-Small Cell Lung Cancer and NTRK Gene Fusion-Positive Solid Tumors

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY),  announced  the U.S. Food and Drug Administration (FDA) has approval of  Rozlytrek (entrectinib) for the treatment of adults with ROS1-positive, metastatic non-small cell lung cancer (NSCLC). The FDA has also granted accelerated approval to Rozlytrek for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory alternative therapy.

These approvals are based on results from the integrated analysis of the pivotal Phase II STARTRK-2, Phase I STARTRK-1 and Phase I ALKA-372-001 trials, and data from the Phase I/II STARTRK-NG study. In the integrated analysis, Rozlytrek was studied in several solid tumor types, including breast, cholangiocarcinoma, colorectal, gynecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma and thyroid cancers. In ROS1-positive, metastatic NSCLC, Rozlytrek shrank tumors in 78% of people with the disease (overall response rate [ORR]; N=51) and the duration of response (DoR) ranged from 1.8 to 36.8+ months (N=40 out of 51). Rozlytrek also shrank tumors in more than half of people with NTRK gene fusion-positive, locally advanced or metastatic solid tumors (ORR=57%; N=54), and objective responses were observed across 10 tumor types (DoR ranged from 2.8 to 26.0+ months; N=31 out of 54). Objective responses to Rozlytrek were seen in people with central nervous system (CNS) metastases at baseline.

“Rozlytrek’s FDA approval for two rare types of cancer is an important advance for patients, combining a targeted medicine and genomic testing to bring this new treatment option to patients who are waiting,” said Sandra Horning, M.D., chief medical officer and head of Global Product Development. “Rozlytrek is the first FDA-approved treatment that selectively targets both ROS1 and NTRK fusions, and, importantly, has also shown responses in these rare cancer types that have spread to the brain.”

“The identification of actionable biomarkers like ROS1 has brought about significant progress in the treatment of lung cancer. This approval brings further hope to people with this rare type of the disease,” said Janet Freeman-Daily, co-founder of The ROS1ders, a group of patients and caregivers affected by ROS1-positive lung cancer. “Up to 40% of people with ROS1-positive non-small cell lung cancer have tumors that have spread to the brain, so now there is a new treatment option for those patients.”

The most common adverse reactions (≥20 percent) with Rozlytrek were fatigue, constipation, altered sense of taste (dysgeusia), swelling (edema), dizziness, diarrhea, nausea, nervous system disorders (dysesthesia), shortness of breath (dyspnea), muscle pain (myalgia), cognitive impairment, increased weight, cough, vomiting, fever (pyrexia), joint pain (arthralgia) and vision disorders.

The FDA’s Accelerated Approval Program allows conditional approval of a medicine that fills an unmet medical need for a serious or life-threatening disease or condition. The accelerated approval of Rozlytrek for NTRK gene fusion-positive solid tumors is based on tumor response rate and durability of response, and continued approval may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Biomarker testing for ROS1 in NSCLC and NTRK gene fusions across all solid tumors is the only way to identify people who are eligible for treatment with Rozlytrek. Genentech is leveraging its expertise in developing personalized medicines and advanced diagnostics, in conjunction with Foundation Medicine, to help identify people with ROS1 and NTRK gene fusions. Foundation Medicine will submit Foundation®One CDx to the FDA for approval as a companion diagnostic for Rozlytrek. An FDA-approved companion diagnostic for Rozlytrek is not available at this time.

Rozlytrek is now available in the United States for adults and children 12 years of age and older. For those who qualify, Genentech offers patient assistance programs for people prescribed Rozlytrek by their doctor through Genentech Access Solutions. Please contact Genentech Access Solutions at (866) 422-2377 or visit http://www.Genentech-Access.comfor more information.

About the Integrated Analysis

This approval is based on an integrated analysis including data from 51 people with ROS1-positive NSCLC and 54 people with locally advanced or metastatic NTRK gene fusion-positive solid tumors (10 tumor types, >19 histopathologies) from the Phase II STARTRK-2, Phase I STARTRK-1 and Phase I ALKA-372-001 trials. This approval is also based on data from the Phase I/II STARTRK-NG study in pediatric patients. The studies enrolled people across 15 countries and more than 150 clinical trial sites. Safety was assessed from an integrated analysis of 355 people across these four trials.

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

https://pubchem.ncbi.nlm.nih.gov/compound/Entrectinib#section=2D-Structure

FDA Approves Tagrisso (osimertinib) as First-Line Treatment for EGFR-Mutated Non-Small Cell Lung Cancer

In continuation of my update on Osimertinib, AstraZeneca,announced that the US Food and Drug Administration (FDA) has approved Tagrisso (osimertinib) for the 1st-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) mutations (exon 19 deletions or exon 21 L858R mutations), as detected by an FDA-approved test. The approval is based on results from the Phase III FLAURA trial, which were presented at the European Society of Medical Oncology 2017 Congress and published in the New England Journal of Medicine.

Dave Fredrickson, Executive Vice President, Head of the Oncology Business Unit at AstraZeneca, said: “Today’s FDA approval of Tagrisso in the 1st-line setting is an exciting milestone for patients and our company. Tagrisso delivered unprecedented median progression-free survival data across all pre-specified patient subgroups, including patients with or without CNS metastases, and could prolong the lives of more patients without their tumors growing or spreading.”

Dr. Suresh S. Ramalingam, Principal Investigator of the FLAURA trial, from Winship Cancer Institute of Emory University, Atlanta, said: “The approval of osimertinib (Tagrisso) in the 1st-line setting represents a major advance in the treatment of patients with EGFR mutations and a significant change in the treatment paradigm. Osimertinib (Tagrisso) provides robust improvements in progression-free survival with no unexpected safety signals compared to the previous generation of EGFR inhibitors.”

The FLAURA trial compared Tagrisso to current 1st-line EGFR tyrosine kinase inhibitors (TKIs), erlotinib or gefitinib, in previously untreated patients with locally advanced or metastatic EGFR-mutated (EGFRm) NSCLC. Tagrisso met the primary endpoint of progression-free survival (PFS) (see table below). PFS results with Tagrisso were consistent across all pre-specified patient subgroups, including in patients with or without central nervous system (CNS) metastases. Overall survival data were not mature at the time of the final PFS analysis.

*Confirmed responses

Safety data for Tagrisso in the FLAURA trial were in line with those observed in prior clinical trials. Tagrisso was generally well tolerated, with Grade 3 or higher adverse events (AEs) occurring in 34% of patients taking Tagrisso and 45% in the comparator arm. The most common adverse reactions (≥20%) in patients treated with Tagrisso were diarrhea (58%), rash (58%), dry skin (36%), nail toxicity (35%), stomatitis (29%), fatigue (21%) and decreased appetite (20%).

In the US, Tagrisso is already approved for the 2nd-line treatment of patients with metastatic EGFRm NSCLC, whose disease has progressed on or after a 1st-line EGFR-TKI therapy and who have developed the secondary T790M mutation, as detected by an FDA-approved test. In 2017, Tagrisso was granted Breakthrough Therapy and Priority Review designations by the US FDA in the 1st-line treatment setting. Tagrisso is under regulatory review in the European Union and Japan for use in the 1st-line treatment setting with regulatory decisions anticipated in the second half of 2018.

Tagrisso received its first approval for 1st-line use based on the FLAURA data in Brazil in patients with metastatic EGFRm NSCLC on April 16, 2018.

FDA Approves Tagrisso (osimertinib) as First-Line Treatment for EGFR-Mutated Non-Small Cell Lung Cancer

FDA Approves New Indication for Gilotrif (afatinib) in EGFR Mutation-Positive NSCLC

In continuation of my update on afatinib...

Boehringer Ingelheim  announced that the U.S. Food and Drug Administration (FDA) has approved a supplemental New Drug Application (sNDA) for Gilotrif (afatinib) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant epidermal growth factor receptor (EGFR) mutations as detected by an FDA-approved test. The new label includes data on three additional EGFR mutations: L861Q, G719X and S768I. The FDA granted Priority Review status to Gilotrif in evaluating this application.

Gilotrif, an oral, once-daily tablet, was previously approved in the U.S. for the first-line treatment of patients with NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations. In addition, Gilotrif is approved in the U.S. for patients with squamous cell carcinoma of the lung whose disease has progressed after treatment with platinum-based chemotherapy.

“With this expanded indication for Gilotrif, NSCLC patients whose tumors have certain EGFR mutations now have an approved therapy that specifically targets these mutations,” said Sabine Luik, M.D., senior vice president of Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “This approval is a result of our company’s commitment to delivering meaningful treatment advances in areas with high unmet medical need and reflects the tireless efforts of physicians, researchers and patients who participated in our studies.”

The sNDA approval is based on a pooled analysis of three studies from the LUX-Lung clinical trial program (Phase II LUX-Lung 2 study and Phase III studies LUX-Lung 3 and LUX-Lung 6) that examined Gilotrif in NSCLC patients whose tumors have EGFR mutations, including L861Q, G719X or S768I. This analysis showed that Gilotrif was active in these EGFR mutations based on objective response rate, duration of response, disease control, progression-free survival and overall survival.

“Compared with other EGFR mutations, L861Q, G719X or S768I substitution mutations are associated with a poorer prognosis and limited treatment options,” said Edward Kim, M.D., Levine Cancer Institute, Carolinas HealthCare System. “The approval of Gilotrif as a targeted therapy for these additional non-resistant EGFR mutations significantly alters the treatment strategy for this population.”

To determine if a patient is eligible for Gilotrif, physicians must conduct a test for genetic mutations – also known as biomarker testing – to determine the type of EGFR mutation present.

“This approval is more welcome news for our lung cancer community,” said Laurie Fenton Ambrose, president and CEO of Lung Cancer Alliance. “These types of advances are helping expand access to treatment options for patients who might benefit from targeted therapies to fight their specific type of lung cancer.”

Ref : https://www.drugs.com/mtm/afatinib.html

FDA Approves New Indication for Gilotrif (afatinib) in EGFR Mutation-Positive NSCLC