Starting in August 2023, the Free ME from Lung Cancer Research Fund is supporting a research project being led by Jia Luo, MD, an Instructor in Medicine at Harvard Medical School and physician in the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute.

Project Abstract

The recent discovery of effective targeted therapies has led to dramatic improvements in life expectancy for lung cancer. However, such advances have not been realized in the most aggressive and underrecognized subtype of lung cancer, NUT carcinoma (NC). NC develops due to a random mutation event, where the NUT gene becomes fused to a gene that reads DNA code. The resulting mutated NUT protein supercharges activating DNA codes that drive cells to divide uncontrollably. This discovery led to the first targeted treatment for NC, BET bromodomain inhibitors (BBDi), which prevent mutant NUT protein from reading DNA. Only 25% of NCs respond to these medicines.

A major finding for NC came from studies in mice and laboratory grown cancer cells within our group which identified that a molecule known as enhancer of zeste homolog 2 (EZH2) is activated due to stress from BBDis. EZH2 keeps cancer cells alive and decreases the effectiveness of BBDis, presenting a potential strategy for treating NC. Other discoveries we will utilize to further our understanding of NC include the largest registry of NC cases and a new mouse model developed for the study of NC.

Leveraging these discoveries, we will use registry samples and mouse model to test combination EZH2 inhibition with tazemetostat and BBDi with ZEN-3694. This will allow us to develop a clinical trial combining tazemetostat and ZEN-3694 as treatment for patients with NC. If successful, this approach has the potential to become the first FDA approved therapy for this cancer.

Dr. Jia Luo’s Bio

Jia Luo, MD, is a medical oncologist in the Thoracic Oncology Program at the Dana-Farber Cancer Institute in Boston. Her research has focused on oncogene-driven lung cancers and developing tools to understand responses to immunotherapy. She has first and co-authored papers in journals such as Cancer Discovery, Annals of Oncology, Nature Reviews Clinical Oncology, Cell Reports and Clinical Cancer Research. She has received both foundation and NIH grants for her research.

Dr. Luo grew up in Madison, WI. She received her BS from University of Wisconsin; MD from Stanford University School of Medicine; internal medicine residency, including a chief year, at Oregon Health & Science University; and medical oncology fellowship at Memorial Sloan Kettering Cancer Center in New York. In her free time, she likes to read, draw, and cook.

Developmental Research Project Awards in Lung Cancer Research

Title: Immunotherapy super-responders in oncogene-driven non-small cell lung cancer
PI: Julia Rotow, MD

Most patients with EGFR-mutant lung cancer do not respond to immunotherapies—treatments that encourage the patient’s own immune system to attack and eliminate cancer cells. However, a small group of super-responders benefit from such treatments. Julia Rotow, MD hopes to determine why these patients respond by examining the genetic and molecular characteristics of their tumors and studying their anti-tumor immune responses. While immunotherapy responders are uncommon in this patient population the identification of these rare immunotherapy responders highlights that a treatment response is still possible for these patients. The data emerging in the study’s cohort offers insight into those patients where immunotherapy should be more readily considered rather than reserved for last line therapy when all other options have been excluded, or for whom immunotherapy-based clinical trial options should be more readily considered. Results from this work could help researchers identify other patients who are likely to benefit from immunotherapies and could lead to the development of new strategies to make EGFR-mutant lung tumors more responsive to such treatments.

Progress to date: The initial phase of this project addressed cohort development and identification of clinicopathologic and genomic features which may predict for response to checkpoint inhibitor immunotherapy among patient populations expected to have low overall immunotherapy response rates. Here Dr. Rotow focused on patients with oncogenic driver mutations traditionally associated with nonsmoking status and on patients without history of tobacco use. Preliminary evaluation of clinicopathologic features associated with response to immunotherapy treatment in patients with traditionally non-immunotherapy responsive driver mutations has highlighted several clinical features that may suggest patient populations where it may be reasonable to incorporate immunotherapy agents earlier in the treatment course. The next phase of this project, currently underway, is to evaluate the immunologic tumor microenvironment in the responding versus nonresponding driver oncogene positive patient populations. This will allow for initial clarification of cytotoxic and immunosuppressive elements within the microenvironment and their association with immunotherapy response in this population enriched for rare immunotherapy responders.

My Research: Since almost 10 years my research focus has been on preclinical imaging techniques such as magnetic resonance imaging (MRI) and nuclear medical imaging (positron emission tomography (PET), SPECT, CT) and applying those imaging methods in the field of Cancer Research.

Being a member of Assistant Professor Claudio Scafoglio’s team now, I am focusing and using the Chorion allantois membrane assay (fertilized chicken eggs are used to grow and analyze early-stage lung cancer specimen) in order to work on my project entitled "A novel biomarker for diagnosis and treatment of lung pre-malignancy".

I started my scientific career as a research assistant in biology (equivalent to BSc) at the German Cancer Research Center, Heidelberg (Germany) and gained work experience in genetics by characterizing genetic alterations in neuroblastoma and breast cancer patient material. I then completed my PhD degree in Biotechnology and Medical Sciences at the Ludwig Institute for Cancer Research in Melbourne (Australia) and gained considerable expertise in molecular and cellular biology. During my 4-year postdoctoral work at the Department of Diagnostic and Interventional Radiology in Hamburg, Germany I focused on the generation of tumor xenograft models suitable for imaging with PET and MRI and was involved in the establishment of a preclinical PET/MRI scanner. I gained experience in the generation of tumor xenograft mouse models and NIS-based imaging and therapy and worked intensively with a preclinical 7T MRI. I continued my postdoctoral work at the Department of Nuclear Medicine at Charité Berlin, Germany. I was involved as a research associate and principal investigator at the German Cancer Research Centre Heidelberg and the Berlin Experimental Radionuclide Imaging Centre, Charité Berlin in a national funded, collaborative oncology research association (DKTK). The focus of this collaborative consortium is the translational aspect, in which scientific investigations become fast forward from bench to bedside. I gained extended experience in the establishment of clinically relevant tumor xenograft models such as orthotopic models of prostate cancer, neuroendocrine tumors of the pancreas and hepatocellular carcinoma. I also focussed on multimodal preclinical imaging techniques such as PET, SPECT, CT, and MRI using state-of-the-art hybrid scanners.

By receiving the FMFLC/IASLC fellowship I received the opportunity to start a scientifically challenging project "A novel biomarker for diagnosis and treatment of lung pre-malignancy" in the department of Pulmonary Disease and Critical Care under the supervision of Assistant Professor Claudio Scafoglio. Science is international by nature. Scientific exchange and international mobility are essential for the training of scientists in general and international collaboration has been directly linked to high-quality science and innovation. Being now part of a well-established group under the supervision of Assistant Professor Claudio Scafoglio, working on lung cancer premalignancy, I broadened my scientific know-how immensely. Also, being able to attend already two major conferences, the IASLC world conference on lung cancer and just recently the Keystone Symposium on tumor metabolism, where I presented my first results, exposed me to state-of-the-art science, which is of utmost importance to reach my project goals and further inspired me for potential future projects.

Honors

• 2002 DAAD, Referat Internationaler Praktikantenaustausch, Bonn.
  • INTERSTIP, travel scholarship University of Applied Sciences, Mannheim
• 2005 Gottlieb Daimler&Karl Benz Foundation, Ladenburg, Germany
  • Fellowship Program "Research Abroad", PhD thesis
• 2006 Aventis Foundation Study Fund, Frankfurt/Main, Germany
  • Scholarship granted to aspiring young scientists, research topic:  "Nanotechnology in Medicine"
• 2017 YING (young investigator grant), Novartis, Nürnberg, Germany
  • Therapieresistenzen in Neuroendokrinen Neoplasien
• 2018 Poster Award, category ‘New tools for cancer imaging’
  • European Society for Molecular Imaging (ESMI2018)
• 2018 FMFLC and IASLC Foundation Joint Fellowship Award
  • 2-year fellowship for the Early Detection of Lung Cancer:  Project title: "A novel biomarker for diagnosis and treatment of lung pre-malignancy" based at UCLA, Division of Pulmonary and Critical Care, Los Angeles, USA, PI: Assistant Prof. Claudio Scafoglio

– First FDA-approved treatment designed to target both ROS1 and NTRK that also shows response in cancer that has spread to the brain –

– Genentech’s first FDA-approved tumor-agnostic medicine –

SOUTH SAN FRANCISCO, Calif. – August 15, 2019 – Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that the U.S. Food and Drug Administration (FDA) has approved 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.com for 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.

About Lung Cancer

According to the American Cancer Society, it is estimated that more than 228,000 Americans will be diagnosed with lung cancer in 2019, and NSCLC accounts for 84 percent of all lung cancers. It is estimated that approximately 60 percent of lung cancer diagnoses in the United States are made when the disease is in the advanced stages. While the ROS1 gene fusion can be found in any person with NSCLC, young never-smokers have the highest incidence of ROS1-positive NSCLC. NTRK gene fusions have been identified in a broad range of solid tumor types, with a higher incidence in certain tumor types including NSCLC.

About NTRK Gene Fusion-Positive Cancer

Neurotrophic tyrosine receptor kinase (NTRK) gene fusion-positive cancer occurs when the NTRK1/2/3 genes fuse with other genes, resulting in altered TRK proteins (TRKA/TRKB/TRKC) that can activate signaling pathways involved in the proliferation of certain types of cancer. NTRK gene fusions are present in tumors irrespective of site of origin. These fusions have been identified in a broad range of solid tumor types, including breast, cholangiocarcinoma, colorectal, gynecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma and thyroid cancers.

About Rozlytrek™

Rozlytrek (entrectinib) is an oral medicine for the treatment of adults with ROS1-positive, metastatic non-small cell lung cancer (NSCLC), as well as 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. It is a selective tyrosine kinase inhibitor designed to inhibit the kinase activity of the TRK A/B/C and ROS1 proteins, whose activating fusions drive proliferation in certain types of cancer. Rozlytrek can block ROS1 and NTRK kinase activity and may result in the death of cancer cells with ROS1 or NTRK gene fusions.

Rozlytrek™ U.S. Indication (pronounced roz lye’ trek)

Rozlytrek is a prescription medicine used to treat:

• Adults with non-small cell lung cancer (NSCLC) that has spread to other parts of the body and is caused by an abnormal ROS1 gene
• Adults and children 12 years and older with solid tumors (cancer) that:
• Are caused by certain abnormal NTRK genes and
• Have spread or if surgery to remove their cancer is likely to cause severe complications, and
• There is no satisfactory alternative treatment option or the cancer grew or spread on other treatment

It is not known if Rozlytrek is safe and effective for use in children less than 12 years of age.

Rozlytrek was approved in NTRK gene fusion-positive solid tumors through a faster FDA review process based on the percentage of patients whose tumor size shrank or disappeared after treatment and how long that response lasted. There are ongoing studies to confirm benefit of Rozlytrek for this use.

Important Safety Information

Rozlytrek may cause serious side effects, including:

• Congestive heart failure. Rozlytrek may cause congestive heart failure or make the congestive heart failure that a patient already has worse. Patients should tell their healthcare provider right away if they have any of the following signs and symptoms of congestive heart failure:
  • persistent coughing or wheezing
  • increasing shortness of breath
  • trouble breathing when lying down
  • tiredness, weakness, or fatigue
  • sudden weight gain
  • swelling in ankles, feet, or legs
• Central nervous system (CNS) effects. Rozlytrek may cause dizziness, changes in mood, or may affect how a patient thinks and cause confusion, hallucinations, and problems with concentration, attention, memory, and sleep. Patients should tell their healthcare provider right away if they have any of these symptoms.
• Bone fractures. Rozlytrek may increase the risk of bone fractures. Bone fractures may happen with or without a fall or other injury. Patients should tell their healthcare provider if they have pain, changes in movement, or bone abnormalities.
• Liver problems (hepatotoxicity). A healthcare provider will do blood tests to check a patient’s liver function during treatment with Rozlytrek. Patients should tell their healthcare provider right away if they develop symptoms of liver problems including: loss of appetite, nausea or vomiting, or pain on the upper right side of the stomach area. A healthcare provider may temporarily stop treatment, decrease the dose, or permanently stop Rozlytrek if a patient develops liver problems with Rozlytrek.
• Increased uric acid level in the blood (hyperuricemia). Rozlytrek may cause an excess of uric acid in the blood. A healthcare provider may do tests before and during a patient’s treatment with Rozlytrek to check the uric acid level in the blood. A healthcare provider may prescribe medications if a patient has high blood uric acid levels.
• Changes in the electrical activity of the heart called QT prolongation. QT prolongation can cause irregular heartbeats that can be life-threatening. A healthcare provider will do tests before and during treatment with Rozlytrek to check the electrical activity of the heart and body salts (electrolytes). Patients should tell their healthcare provider right away if they feel faint, lightheaded, dizzy, or feel their heart beating irregularly or fast while taking Rozlytrek. These may be symptoms related to QT prolongation.
• Vision problems. Rozlytrek may cause vision problems. Healthcare providers may stop Rozlytrek and refer to an eye specialist if a patient develops severe vision problems during treatment with Rozlytrek. Patients should tell their healthcare provider right away if they have any loss of vision or any change in vision, including:
  • double vision
  • seeing flashes of light
  • blurry vision
  • light hurting the eyes
  • new or increased floaters

Before taking Rozlytrek, patients should tell their healthcare provider about all their medical conditions, including if they:

• have liver or kidney problems.
• have any heart problems, including a condition called long QT syndrome.
• have nervous system (neurological) problems.
• have or have had eye or vision problems.
• are pregnant or plan to become pregnant. Rozlytrek can harm an unborn baby. Patients should tell their healthcare provider right away if they become pregnant during treatment with Rozlytrek or think they may be pregnant.
• If patients are able to become pregnant, their healthcare provider will do a pregnancy test before they start treatment with Rozlytrek.
• Females who are able to become pregnant should use effective birth control during treatment with Rozlytrek and for at least 5 weeks after the final dose.
• Males who have female partners that are able to become pregnant should use effective birth control during treatment with Rozlytrek and for 3 months after the final dose.
• Are breastfeeding or plan to breastfeed. It is not known if Rozlytrek passes into breast milk. Do not breastfeed during treatment with Rozlytrek and for 7 days after the final dose of Rozlytrek. Patients should talk to their healthcare provider about the best way to feed their baby during this time.

Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, or herbal supplements.
Certain other medicines may affect how Rozlytrek works causing side effects. Patients should know the medicines they take. Patients should keep a list of them to show to their healthcare provider and pharmacist when they get a new medicine.

The most common side effects of Rozlytrek include:

These are not all the possible side effects of Rozlytrek. For more information, patients should ask their healthcare provider or pharmacist.

Patients should call their doctor for medical advice about side effects.

Report side effects to the FDA at (800) FDA-1088 or http://www.fda.gov/medwatch. Report side effects to Genentech at (888) 835-2555.

Please see http://www.Rozlytrek.com for the full Prescribing Information, including Patient Information.

About Genentech in lung cancer

Lung cancer is a major area of focus and investment for Genentech, and we are committed to developing new approaches, medicines and tests that can help people with this deadly disease. Our goal is to provide an effective treatment option for every person diagnosed with lung cancer. We currently have five approved medicines to treat certain kinds of lung cancer and more than 10 medicines being developed to target the most common genetic drivers of lung cancer or to boost the immune system to combat the disease.

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.

Julia Rotow, MD focuses her research on understanding treatment resistance in oncogene-driven lung cancers, including EGFR-mutated lung cancer. In addition to running clinical trials evaluating the use of personalized combination targeted therapy strategies at acquired resistance to EGFR-targeted therapies, she studies several challenges facing treatment for oncogene-driven lung cancer. These include the survival of persistent dormant tumor cells, and resistance to immunotherapy-based treatments for patients with oncogene-driven tumors.

Title: Immunotherapy super-responders in oncogene-driven non-small cell lung cancer
PI: Julia Rotow, MD

Most patients with EGFR-mutant lung cancer do not respond to immunotherapies—treatments that encourage the patient’s own immune system to attack and eliminate cancer cells. However, a small group of super-responders benefit from such treatments. Julia Rotow, MD hopes to determine why these patients respond by examining the genetic and molecular characteristics of their tumors and studying their anti-tumor immune responses. While immunotherapy responders are uncommon in this patient population the identification of these rare immunotherapy responders highlights that a treatment response is still possible for these patients. The data emerging in the study’s cohort offers insight into those patients where immunotherapy should be more readily considered rather than reserved for last line therapy when all other options have been excluded, or for whom immunotherapy-based clinical trial options should be more readily considered. Results from this work could help researchers identify other patients who are likely to benefit from immunotherapies and could lead to the development of new strategies to make EGFR-mutant lung tumors more responsive to such treatments.