For a probing discussion detailing the Lung Association’s recently released 2024 “State of Lung Cancer” report, we are joined by esteemed thoracic medical oncologist Dr. Jacob Sands of Dana-Farber Cancer Institute and Harvard Medical School. Offering insight into actionable targeted mutations, Dr. Sands addresses how precision oncology is fundamentally changing lung cancer diagnosis and treatment. The novel immunotherapy drugs, though proven to be safe and effective with significant improvements in response and survival rates, have challenges as well—this episode covers the gamut.
Dr. Albert Rizzo:
Welcome back to Lungcast, the monthly respiratory health podcast series from the American Lung Association and medical news site HCP Live.com. I'm your host, Dr. Albert Rizzo, Chief Medical Officer of the American Lung Association.
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The patient diagnosed with lung cancer today often has a much different journey in their care than those diagnosed 15 to 20 years ago. One major change has been the initiation of low-dose lung cancer screening, shifting the diagnosis to earlier, more curable, and treatable stages. Additionally, there has been an explosion of new therapies, including targetable mutations and immunotherapy.
Today's discussion will focus on actionable targeted mutations. This aspect of precision oncology has fundamentally changed how we diagnose and treat lung cancer. This transformation in the management of lung cancer patients has been driven by what's called oncogene-addicted advanced-stage non-small cell lung cancers (NSCLC), which are identified by the presence of specific biomarkers.
The term “oncogene addiction” refers to a phenomenon in which tumor cells become dependent on a single oncogenic protein or pathway to sustain their malignant properties. This dependency allows the oncogene to fuel and support the malignant phenotype of the tumor cells. Increasingly identifiable oncogenes have led to the development of molecular targeted drugs, including small-molecule tyrosine kinase inhibitors (TKIs), monoclonal antibodies, and antibody-drug conjugates. These targeted therapies have shown significant improvements in response rates, progression-free survival, and overall survival compared to traditional chemotherapy.
Today, we hope to address this category of drugs—their mechanisms, toxicities, resistance, and some of the hurdles in using them. To address this topic, our guest is:
Dr. Albert Rizzo:
Please welcome Dr. Jacob Sands, MD.
Dr. Jacob Sands:
Thank you so much for having me.
Dr. Albert Rizzo:
Dr. Sands is a thoracic medical oncologist at Dana-Farber Cancer Institute and Assistant Professor of Medicine at Harvard Medical School. He joined Dana-Farber in 2017, where he sees patients with lung cancer and leads the small cell lung cancer clinical research program. Dr. Sands has published numerous manuscripts on lung cancer and is leading many active clinical trials. He is a member of the National Comprehensive Cancer Network (NCCN) guidelines committee on small cell lung cancer and lung screening. Despite keeping busy with patients and research, he also volunteers as a National Medical Spokesperson for the American Lung Association.
Thank you, Dr. Sands, for being here today and for all you do with the American Lung Association. It's such a pleasure to chat with you.
Dr. Jacob Sands:
Thank you.
Dr. Albert Rizzo:
Let's start with the NCCN guidelines for lung cancer. They emphasize the importance of tumor testing, or biomarker testing, when treating lung cancer. The most commonly recommended biomarkers include EGFR (epidermal growth factor receptor), ALK, ROS1, BRAF V600E, MET exon 14 skipping mutation, RET, and KRAS G12C. New oncogenic drivers continue to be identified almost weekly, which can lead to potential targeted therapies.
Could you explain to our listeners how these biomarkers are obtained and discuss next-generation sequencing, including the pros and cons of tissue versus blood-based biomarkers?
Dr. Jacob Sands:
Absolutely. This is a great question. We often refer to these as genomic alterations because they include mutations and fusions, which are mistakes in the DNA of cancer cells. These are not inherited—they arise in the cells and drive the cancer.
A pivotal study in 2009, the IPASS trial, focused on nonsquamous NSCLC and a targeted therapy for EGFR mutations. It showed that targeted therapy was overwhelmingly effective in tumors with EGFR mutations compared to chemotherapy. This marked a major shift in targeted therapies for lung cancer.
In the last 15 years, we now have approved drugs targeting EGFR, ALK, RET, BRAF V600E, MET exon 14 skipping, and KRAS G12C. These therapies are often newly developed within the last 5–10 years, reflecting rapid scientific advancement.
To identify these mutations, we analyze DNA from tumor cells using techniques like next-generation sequencing (NGS), which allows us to identify both common and rare mutations in one sample. We can test tissue directly or use blood-based testing, known as a “liquid biopsy,” which captures tumor DNA shed into the bloodstream. Both methods have benefits and limitations, and they can complement each other to give a fuller picture of the tumor's genetic profile.
Dr. Albert Rizzo:
What about patient responses to these targeted mutations? I understand response rates are around 70–80%, but resistance can develop. How do you approach patients who develop resistance?
Dr. Jacob Sands:
That's correct. A partial response is defined as tumor volume shrinking by at least 30%. Even when tumors don’t shrink as much, they can still be controlled for long periods. Most patients experience years of disease control with targeted therapies, which are generally oral and less toxic than chemotherapy.
Resistance can arise through secondary mutations or tumor heterogeneity. Blood-based tests help identify new mutations at progression, guiding subsequent therapy. If a mutation is not detectable in blood, a tissue biopsy may be needed. Localized tumor growth may sometimes be treated with radiation or surgery while systemic therapy continues.
Dr. Albert Rizzo:
Targeted therapies were initially presumed to be non-toxic, but chronic use can cause side effects. Can you explain “on-target” and “off-target” toxicities?
Dr. Jacob Sands:
On-target toxicity occurs when the drug affects normal cells that share the same receptor as the cancer cells, while off-target toxicity affects unrelated pathways. For example, EGFR inhibitors like osimertinib are highly specific, resulting in fewer side effects than earlier drugs. Antibody-drug conjugates deliver chemotherapy directly to cancer cells, but some drug can enter the bloodstream, causing broader toxicities.
Dr. Albert Rizzo:
Shifting gears, as the American Lung Association spokesperson, you help highlight the State of Lung Cancer report. Can you summarize key findings related to biomarker testing?
Dr. Jacob Sands:
The report highlights gaps in insurance coverage for comprehensive biomarker testing. Only 15 states require coverage, five states have partial coverage, and 30 states plus DC have no requirement. Around 40–50% of NSCLC patients may be candidates for targeted therapies, but only about 70% are tested. Infrastructure, resources, and insurance coverage remain major hurdles, especially in community centers.
Dr. Albert Rizzo:
Some pulmonologists defer biomarker testing to oncologists due to lack of resources or infrastructure. Is that your experience?
Dr. Jacob Sands:
Yes, that’s common. Oncologists prefer to have upfront testing completed so treatment decisions can be immediate. In urgent cases, chemotherapy may start while awaiting genomic results, but targeted therapies require this testing first to maximize safety and efficacy.
Dr. Albert Rizzo:
In conclusion, the future of thoracic oncology is clearly shifting toward increased molecular testing and targeted therapies. Dr. Sands, any closing comments?
Dr. Jacob Sands:
This is a huge advance. Over the past 10–15 years, we’ve seen multiple FDA-approved targeted therapies, immunotherapies, and antibody-drug conjugates. The field is moving rapidly, and these advances are providing patients with more effective, better-tolerated treatments.
Dr. Albert Rizzo:
Thank you again for your time and for your work with the American Lung Association.
Outro:
To our listeners, if you want to hear more about respiratory health, we have an extensive archive of discussions. Subscribe and rate Lungcast on your preferred platform and visit Lung.org and HCP Live.com for more news and resources. Until next time, I’m Dr. Albert Rizzo reminding you: if you can’t breathe, nothing else matters.
Brought to you by the American Lung Association and HCPLive
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