Lung Cancer’s White Elephant: Never-Smokers with Lung Cancer

It’s time to address the elephant in the room. Lung cancer in never-smokers (LCINS) has enough cases diagnosed each year to rank in?the top 15 ?of all cancer types in the US and accounts for?25% of lung cancer ?cases worldwide. Despite LCINS occurring more than ovarian, stomach, and brain/nervous system cancers, most people don’t realize that never-smokers can develop lung cancer.

A recent?New York Post article , and newly published research in?Nature , are testaments to the unfortunate reality that in the US,?10-20% ?of all lung cancer cases diagnosed each year are found in people who have smoked less than 100 cigarettes in their lifetime. LCINS is fundamentally different from other types of lung cancer from when it is diagnosed, to who it affects, what genetic changes drive its growth, and how it responds to existing therapies. Lantern understands that LCINS is unique—?that’s why we launched the?Harmonic? ?trial (NCT05456256 ) for our drug candidate LP-300 specifically for never-smokers with non-small cell lung cancer (NSCLC).?

The?New York Post ?article tells the story of Natasha Loveridge,?an active and health-conscious 49-year-old woman who was shockingly diagnosed with stage IV lung cancer despite never smoking. Her experience?is a salient example of what is arguably one of the most challenging aspects of LCINS: an unexpected late-stage cancer diagnosis. Never-smokers experiencing early lung cancer symptoms such as chest pain, wheezing, or coughing are often dismissive of these symptoms or sent home from their doctor without a chest scan because their history does not include smoking. A non-diagnosis can lead to extended periods of time before a tumor mass is discovered, giving the cancer time to grow and progress further than if a chest scan were performed upon the first appearance of symptoms. If she had known that she was at risk for lung cancer even as a never-smoker, Natasha may have discovered her cancer months earlier at the onset of her first symptoms.

A unique and under-addressed aspect of LCINS is that it disproportionately affects women. Women have double the risk of being diagnosed when compared to men, and the increased occurrence is even more pronounced for East Asian women who are never smokers. For example, LCINS accounts for?82.7% ?of all lung cancer cases in Chinese women. In the US, there are several advocacy groups and initiatives attempting to address and raise awareness of these gaps in the never-smoker cancer community, including?Breath of Hope Kentucky , the?White Ribbon Project , and the?Female Asian Never Smokers (FANS) Study ?at the University of California San Francisco. Research is currently ongoing to investigate why women are disproportionately affected by LCINS. A better understanding of demographic, environmental, and genetic risk factors will allow for the advancement of early detection and treatment options for LCINS patients.

The specific genetic changes that cause LCINS are distinct from the mutations that drive lung cancer in smokers and are detectable through routine NGS biomarker panels. The?key genetic mutations ?driving LCINS are in the EGFR, ALK, ROS1, and MET genes. These belong to a family of genes known as tyrosine kinase receptors (TKRs) and are targets for our drug candidate LP-300, which acts by binding to and inactivating TKRs. The aforementioned?Nature ?research article specifically links EGFR-driven lung cancers to inhalable air pollutants in the environment. Such mutations in EGFR are the most common mutations found in LCINS patients at almost?60% , whereas the key drivers of lung cancer in smokers are KRAS and TP53. Similarly, mutations in ROS1 and MET are found at extremely low mutation frequencies when examining lung cancer as a whole but are found at a much higher frequency in LCINS patients. Due to these genetic differences, never-smokers do not respond to therapies used to treat lung cancer in smokers, such as?PD-L1 inhibitors , creating a need for different targeted treatment options that are tailored to them. Identification of the genetics involved in LCINS is a key step in designing such targeted therapies, as biomarker-guided clinical treatments like Lantern’s LP-300 are?up to?12x more likely to succeed.?

Despite there being?20,000 to 40,000 cases ?diagnosed in the US annually and the unique biomarker profile of this cancer, no approved therapies have been developed specifically for LCINS patients. Lantern is hoping to change this paradigm with our drug candidate LP-300. In a previous?Phase 3 clinical trial ?for all lung cancer patients, a subset of never-smoker NSCLC patients who received LP-300 with chemotherapy showed a significant increase in overall and two-year survival of 91% and 125% respectively. Our Harmonic? trial (NCT05456256 ) for never-smokers with NSCLC is now enrolling patients at?multiple sites ?across the US in areas including Southern California, New York City, and Dallas.

Dr. Edward S. Kim , physician-in-chief of City of Hope Orange County, recently spoke about the potential of LP-300 in an?OncLive podcast -??“In the landscape of NSCLC and especially in this population [LCINS patients] where we have biomarker-based approaches which are really taking precision medicine to, I think, one of the highest levels in the entire oncology field, we have to continue to investigate different targets, different mechanisms, and drugs like LP-300”.?

Lung cancer is different in never-smokers; treatment for it should be too. If you, or someone you know, are a never-smoker with NSCLC, please visit?harmonictrial.com ?to learn more, or consult your cancer care team about whether the Harmonic? trial could be an option for you.

The following articles contain more stories of never-smokers diagnosed with lung cancer:

This blog post is written by Liliann DeVos , communications and clinical trial outreach intern of Lantern Pharma