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Not all EGFR Mutations Are the Same
By Ivy Elkins, Co-Founder of EGFR Resisters
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Many of you understand the importance of having biomarker testing when you are diagnosed with lung cancer. This biomarker testing may indicate that you have an EGFR-positive mutation. But what does that mean?
What does EGFR mean?
First of all, EGFR stands for epidermal growth factor receptor, which is a protein found on the surface of cells in the body. EGFR is a normal part of the body’s functioning and helps cells grow and divide. When an EGFR mutation occurs, this means that there is an error in the gene that tells EGFR how to work. The mutation results in an abnormally large number of signals being sent to tell cells to grow and divide, leading to cancer cells dividing rapidly and forming a tumor.
There are different ways a mutation in EGFR can happen depending on what part of the EGFR gene develops an error. According to a recent study “more than 70 different EGFR mutations have been identified in patients.”1 It is important to ask your doctor the subtype of your EGFR mutation because not all medications work the same for all subtypes of mutations.
Types of EGFR mutations
The most common types of EGFR mutations are exon 19 deletions and exon 21 L858R point mutations. These are considered the “classical” EGFR mutations and are usually very responsive to EGFR targeted therapy drugs such as osimertinib. If you do not have one of these mutations, you may have an exon 20 insertion mutation or an “atypical” mutation (S768I, L861Q, G719X) that might respond better to drugs approved or in clinical trials specifically for these indications. This definitely is something to talk to your doctor about.
It is also useful to know if you have any co-mutations, which are mutations that may occur along with your EGFR mutation. Many people with EGFR-positive lung cancer have mutations in TP53, which is a tumor suppressor gene. In fact, TP53 mutations are common throughout lung cancer and even in different types of cancer in general. Although these mutations are studied often, there is currently a lack of consensus on how or if these mutations can be treated. However, EGFR mutations accompanied by both a TP53 mutation and a mutation in another tumor suppressor gene, RB1, can indicate a chance of future transformation to small cell lung cancer.2 If this is the case, it would be a good idea to discuss possible up-front treatment options with your doctor.
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How to Read Biomarker Test Results
From LUNGevity
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Biomarker testing is used among diagnosed patients with non-small cell lung cancer (NSCLC) to determine the presence of specific mutations or proteins associated with cancer. It ensures that patients get matched to the right treatment at the right time, based on their biomarker test results. The results can also provide a complete overview of the therapies and clinical trials available to them specific to their biomarker(s). It should be noted that biomarker test reports are not the same across all labs that run them. This booklet, therefore, will cover the general information that most biomarker test reports contain. It explains the different biomarkers that cancers are tested for, what the results mean, how available therapy options are reported, and how to evaluate the clinical trial options in partnership with your healthcare provider.
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Available on Demand: #TogetherSeparately: Surviving Survivorship
From the Lung Cancer Research Foundation
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Dr. Isabel Preeshagul was joined by Dr. Marleen Meyers and EGFR Resisters co-founder Jill Feldman for the LCRF Lung Cancer Community Talk. Topics focused on ways to manage physical and emotional side effects, including coping with anxiety and fear, and a discuss on social and financial challenges that may arise following cancer treatment.
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What is Meant by “Informed Consent”?
By Ivy Elkins, Co-Founder of EGFR Resisters
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Unless you have participated in a clinical trial, you might not be familiar with the term “informed consent,” commonly used to refer to the document that patients are given when they are considering signing up for a trial. This document contains information about the trial, discusses risks of participating, and includes details about the experimental treatment and required tests. Patients need to sign the document before beginning a clinical trial.
What is informed consent?
The National Cancer Institute (NCI), however, defines informed consent as “a process in which patients are given important information, including possible risks and benefits, about a medical procedure or treatment, genetic testing, or a clinical trial. This is to help them decide if they want to be treated, tested, or take part in the trial. Patients are also given any new information that might affect their decision to continue. Also called consent process.”1 This leads to an important question: Is informed consent a process, as the NCI definition indicates, or is it merely a document?
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"U.S. Clinical Trials After Osimertinib" Spreadsheet Now Available
Includes clinical trials organized by the following: EGFR common/uncommon mutations, Exon 19 with C797X, Exon 20, MET, HER2, No new resistance mechanisms/HER3, Leptomeningeal Disease/Brain Mets, and SCLC Transformation. Updated regularly.
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This project was the brainchild of Linda Tweini, a caregiver to her mother who recently died and was an EGFR Resister. She wanted to do something to help others like her mother and brought this project's attention to the EGFR Resisters. Linda meticulously resourced appropriate clinical trials from clinicaltrials.gov and then she teamed up with Laura Book to get it completed. Both Linda and Laura put in many hours of work to make this spreadsheet as comprehensive and easy to use as possible to help us navigate treatments in the U.S. It will be updated periodically.
If you know of a new or a clinical trial missing from the list on the spreadsheet, please contact Laura Book at laurabbook@gmail.com . Linda and Laura would also like to compile a list of people participating on these trials so that we generate a list of patient contacts for others interested in their trial experience to talk to. For those who are or have participated on any of these trials, please email your name, phone number, trial number to Laura Book at laurabbook@gmail.coma
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Being Courageous Is A Real Choice
By Lalaine Alfaro for Lungcancer.net
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How can you get ready to do something though being scared to death or most frightened? Despite fear you still have the ability to be useful. There are moments I feel a great deal of fear and anxiety about the situations or choices when living with lung cancer. Sometimes I can overcome them but there are times it is hard.
Fear of metastases and treatment unknowns
My lung cancer had developed into a brain tumor. I am grateful to my target therapy treatment my brain MRI has been clear so far. In some situations, metastatic cancer can be cured however not the primary site of cancer. Lung cancer has the tendency to commonly spread to the brain, bone, and liver. Sometimes there are many metastases in one or both lungs such as the edges of the lungs, in the lower lobes, and outside the lungs like the pleura. With the new development of different targeted therapy treatments, I am in good hands for survival.
My targeted therapy treatment can only control my lung cancer. My oncologist says I am staying on my current TKI as long as possible. Research studies have shown there are second drivers and new bypass mechanisms after findings of resistance. Later treatment options are available depending on other genetic testing results. This is good news down the line.
The realities of scanxiety
Every computed tomography (CT) scan shows the location, size, and shape of the lung cancer tumor. My scans are the chest-abdomen-pelvic CT and the semi-annual brain magnetic resonance imaging (MRI). I have taken my targeted therapy pills for more than a year now. Both of my scans are showing good results. I remind myself scans are routine check-ups. These are important for my survival.
One of the serious side effects of my ALK-positive TKI is anemia and liver toxicity. My blood tests frequency of once a month has not changed. Subsequently, my oncologist monthly discusses the results with me, mostly over the phone due to Covid-19 restrictions. A complete blood count (CBC) is done to see my complete health during my treatment. Another way of looking after my overall health.
Worries about serious side effects
When I first received my prescription for my ALK-positive TKI, the cancer pharmacist gave me a booklet of side effects and tips to overcome them. However, there are serious ones that involve dose reduction and stoppage of prescription in order to reduce toxicity. Quite a scary condition but health safety is a priority for health care providers.
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Talking to kids about cancer can be tough. We're partnering with Pickles Group to bring you a live webinar on September 18 to help.
Pickles Group’s mission is to provide free peer-to-peer support and resources to kids affected by their parent or guardian’s cancer.
You’ll hear from their Chief Clinical Program Officer, Kelsey Mora, an expert in supporting families through illness. You'll also learn more about upcoming programs and resources for families affected by cancer.
This webinar is perfect for adults who want to be able to better communicate with kids about a cancer diagnosis and ongoing treatment in ways that support kids' social-emotional wellbeing.
Please join the conversation on September 18th at 7:00 pm ET here.
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FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer
From FDA
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On August 11, 2022, the Food and Drug Administration granted accelerated approval to fam-trastuzumab deruxtecan-nxki (Enhertu, Daiichi Sankyo, Inc.) for adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating human epidermal growth factor receptor 2 HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. This is the first drug approved for HER2-mutant NSCLC.
FDA also approved the Life Technologies Corporation’s Oncomine™ Dx Target Test (tissue) and the Guardant Health, Inc.’s Guardant360® CDx (plasma) as companion diagnostics for Enhertu. If no mutation is detected in a plasma specimen, the tumor tissue should be tested.
Enhertu was evaluated at a 6.4 mg/kg dose (n=152) across multiple trials and at a 5.4 mg/kg dose (n=102) in a randomized dose-finding trial. Response rates were consistent across dose levels. Increased rates of interstitial lung disease/pneumonitis were observed at the higher dose. The efficacy results of the approved recommended dose of 5.4 mg/kg given intravenously every 3 weeks are described below.
Efficacy for accelerated approval was based on DESTINY-Lung02, a multicenter, multi-cohort, randomized, blinded, dose-optimization trial. Eligible patients were required to have unresectable or metastatic HER2-mutant non-squamous NSCLC with disease progression after prior systemic therapy. Patients were selected for treatment with Enhertu based on the presence of activating HER2 (ERBB2) mutations in a tumor specimen. Patients received Enhertu 5.4 mg/kg by intravenous infusion, every 3 weeks until unacceptable toxicity or disease progression.
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EGFR Tyrosine Kinase Inhibitor Sequencing Revisited: From the Revival of Old Tools to the Integration of New Agents
From Journal of Thoracic Oncology
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In this issue of the Journal of Thoracic Oncology, Piccirillo et al. report the results of the BEVERLY trial, a randomized phase 3 study that reveals the progression-free survival (PFS) benefit of bevacizumab to erlotinib as first-line treatment for Italian patients with metastatic NSCLC with common EGFR mutations. In this large study, after a median follow-up of 36.3 months, median investigator-assessed PFS was 15.4 months with erlotinib plus bevacizumab and 9.6 months with erlotinib alone (hazard ratio = 0.66, 95% confidence interval: 0.47–0.92). These results add further evidence to that provided by previously reported randomized studies, mostly conducted in Asian patients, that investigated combinations of first-generation EGFR TKIs and antiangiogenic agents, including JO25567, NEJ026, CTONG-1509, and other trials with erlotinib and bevacizumab, and the RELAY trial with erlotinib and ramucirumab. Taken together, these studies reported on median PFS ranging from 16.4 to 19.4 months.
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WCLC 2022 Research Highlights
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WCLC (World Conference on Lung Cancer) 2022 Wrap Up
From IASLC
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It’s a wrap! Catch up on key highlights of the IASLC 2022 World Conference on Lung Cancer with Dr. Narjust Florez and Dr. Stephen Liu as they discuss the science, social engagement and notable abstracts with Dr. Ben Levy.
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Survey: 77% of Women With Lung Cancer Report Sexual Dysfunction
From MEDPAGE TODAY
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A total of 77% of women with lung cancer surveyed reported moderate to severe sexual dysfunction, according to results of the SHAWL study presented at the World Conference on Lung Cancer.
Of the 127 participants who noted sexual activity in the previous 30 days, 75 (59%) reported significant issues with vaginal dryness, and 63 (26%) reported vaginal pain or discomfort during sexual activity, said Narjust Florez (Duma), MD, of Dana-Farber Cancer Institute and Harvard Medical School in Boston.
In addition, she said, marked differences were noted before and after participants' lung cancer diagnosis in decreased sexual desire/interest (15% vs 31%, P<0.001) and vaginal pain/discomfort (13% vs 43%, P<0.001).
The most common reasons given that negatively affected participants' satisfaction with their sex life ("very much" to "somewhat") included the following, Florez said:
- Fatigue: 95 patients (40%)
- Feeling sad/unhappy: 66 patients (28%)
- Issues with partner: 52 patients (22%)
- Shortness of breath: 36 patients (15%)
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Dr. Spira on the Further Investigations of Lazertinib/Amivantamab in EGFR-Mutant NSCLC
From OncLive
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Alexander I. Spira, MD, PhD, FACP, research institute director, Thoracic and Phase 1 Trial Program, Virginia Cancer Specialists Research Institute, Virginia Cancer Specialists, clinical assistant professor, Johns Hopkins University, discusses additional studies investigating the use of lazertinib (Leclaza) and amivantamab-vmjw (Rybrevant) in EGFR-mutated non–small cell lung cancer (NSCLC).
The combination of lazertinib and amivantamab could have a role in several indications for patients with EGFR-mutated NSCLC, such as the in the treatment-naïve setting or the refractory setting, Spira says. The two agents could also be evaluated in combination with chemotherapy before or after treatment with osimertinib (Tagrisso), and they could potentially replace osimertinib, Spira notes.
The phase 3 MARIPOSA-2 trial (NCT04988295) is investigating the combination of lazertinib and amivantamab plus chemotherapy vs chemotherapy alone for patients with EGFR-mutated, locally advanced or metastatic NSCLC who failed treatment on osimertinib. Amivantamab plus chemotherapy is also being compared with chemotherapy alone as a frontline treatment for patients with advanced or metastatic NSCLC harboring EGFR exon 20 insertions in the phase 3 PAPILLON trial (NCT04538664).
Since lazertinib/amivantamab has demonstrated the ability to overcome osimertinib resistance, investigators want to continue exploring optimal settings for the combination’s use, Spira continues. An additional area of exploration could come in the adjuvant setting, Spira concludes.
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BBT-176, a 4th Generation EGFR TKI for Progressed NSCLC after EGFR TKI Therapy PK, Safety and Preliminary Efficacy from Phase 1 Study
From Dr. Sun Min Lim's presentation at WCLC
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Strategies to Treat EGFR C797S
From Dr. Pasi Janne's presentation at WCLC
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Incidence of C797X Mutations Following Osimertinib
From Dr. Ramalingam's presentation at WCLC
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Frequency of EGFR+ NSCLC Is Higher in Latin Americans and Varies by Country of Origin
From Dr. Ticiana Leal's presentation at WCLC
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Dynamic Mutation Profiles of SCLC Transformation in NSCLC Patients Harboring Concurrent EGFR/TP53/RB1 Mutations
From WCLC Abstract presented by Dr. Jie Huang
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Introduction: Small cell lung cancer (SCLC) transformation remains one of the unsettled resistant mechanisms for lung adenocarcinoma (LUAD), of which co-occurring TP53 and RB1 mutations defined a subgroup of patients with increased risk of SCLC transformation. Our study aimed to uncover genomic features and identify clinically high-risk patients of SCLC-transformed LUAD with EGFR/TP53/RB1 alterations.
Methods: The study was performed in 58 LUAD patients harboring concurrent mutations in EGFR/TP53/RB1. Capture-based targeted sequencing covering 76 genes related to LUAD were performed at baseline and after SCLC transformation to obtain genomic profiles. A decision tree integrating clinical and genomic features was constructed to predict SCLC transformation.
Results: Of 58 patients, 30 were pathologically confirmed as SCLC-transformed LUAD while 28 remained LUAD. In addition to TP53 and RB1, we also identified alterations in PIK3CA (12%), PTEN (12%), and copy number variations (CNVs) in CCNE1 (10%), IL7R (10%), MET (10%), MYC (10%) and TERT (10%). Comparable mutation counts were observed between SCLC transformed group and control group but EGFR 19del mutation and CNVs were more frequently presented in transformed group (p<0.05). Patients with SCLC transformation were diagnosed with LUAD at younger age than control group (p<0.05). The overall median time to SCLC transformation was 27.43 months. In transformed group, less mutation count at LUAD diagnosis was independently associated with less time to transformation (p<0.05). The presence of PTEN mutation was also associated with less time to transformation (p<0.05) while CNVs in IL7R and TERT were associated with longer time to transformation (p<0.05). From baseline to SCLC transformation, the overall trends of mutation counts tended to increase in transformed group but decrease in control group (p<0.001). The second sequencing after SCLC transformation observed that gain of CNVs in genes including PIK3CA, AKT1 and MYC was the key factor underlying increased mutation counts. In addition, EGFR mutations featured by absence of CNVs occurred more frequently in transformed group than control (p<0.05). A decision-tree based model was constructed to predict SCLC transformation using CNV≥2, age≤56.5 years and positive EGFR 19del mutation with sensitivity of 76% and specificity of 71%.
Conclusions: In LUAD patients with concurrent EGFR/TP53/RB1 mutations, SCLC transformed patients showed different mutation profiles featured by gain of CNVs. The combination of clinical and molecular features might be used to predict SCLC transformation of LUAD.
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Go2 Foundation's Lung Cancer Living Room via Facebook Live or YouTube Live
#TogetherSeparately: Women & Lung Cancer, September 12, 2022 at 12:00 noon to 1 pm ET
Join Dr. Narjust Florez from Dana-Farber Cancer Institute and Dr. Isabel Preeshagul, for a Lung Cancer Community Talk. Register here
Talking to Kids About Cancer, Pickles Group, September 18 at 7 pm ET
Please join this conversation sponsored by ALKtALK and EGFR Resisters here. (Zoom Meeting Room #763 789 7683)
IASLC North American Conference on Lung Cancer, September 23-25 in Chicago
Registration is free to patients/advocates. Register here.
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Resources for Hope, Coping, and Inspiration
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The Big Ordeal, Cynthia Hayes
Coping with cancer is hard. It is an emotional ordeal as well as a physical one, with known and somewhat predictable psychological responses. And yet, patients often feel isolated and alone when dealing with the stress, anxiety, depression, and existential crises so typical with a cancer diagnosis. The Big Ordeal, written in collaboration with a psychologist and two oncologists, tackles the emotional side of the experience head-on, to help newly diagnosed patients and their loved ones anticipate, understand, and deal with the psychological turmoil ahead.
Cancer: The Journey from Diagnosis to Empowerment, Dr. Paul Anderson
Drawing on decades of experience, Dr. Anderson offers practical advice to demystify the healing process, empower patients, and teach loved ones how to provide effective support.
Healing Your Grieving Heart After a Cancer Diagnosis: 100 Practical Ideas for Coping, Surviving, and Thriving (The 100 Ideas Series), Alan D. Wolfelt, PhD and Kirby J. Duvall, MD
This empathetic guide coauthored by cancer survivor Dr. Alan Wolfelt helps individuals understand and cope with the many difficult thoughts and feelings to which a cancer diagnosis can give rise, assisting them as they find ways to experience peace and joy throughout their journey. Among the 100 ideas for surviving and thriving in this book are those that explain the basic principles of grief and mourning and how they apply to a life-altering, life-threatening, or terminal medical diagnosis.
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