Tagged: Lung Cancer

Amivantamab Monotherapy in Rare EGFR-Mutated Advanced NSCLC

August 26, 2025

“Amivantamab, an anti-EGFR/MET bispecific antibody, shows efficacy in EGFR-mutated NSCLC, but its role in rare EGFR alterations and CNS involvement, including leptomeningeal disease (LMD), remains insufficiently characterized.“

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality. While the development of targeted therapies has improved outcomes for many patients with EGFR-mutated NSCLC, those with rare EGFR variants often face limited treatment options, especially when the disease involves the central nervous system (CNS).

A recent research paper, titled “Durable complete response in leptomeningeal disease of EGFR mutated non-small cell lung cancer to amivantamab, an EGFR-MET receptor bispecific antibody, after progressing on osimertinib” published in Volume 16 of Oncotarget, describes a patient with NSCLC harboring two uncommon EGFR mutations—G719A and A289V—who experienced a prolonged and clinically significant response to amivantamab monotherapy, after prior treatments had failed.

Rare EGFR Mutations and Leptomeningeal Spread

EGFR mutations are present in a subset of NSCLC cases, with most data and drug approvals focused on common variants such as exon 19 deletions and L858R. Mutations like G719A and A289V are far less common and have limited clinical evidence to guide treatment.

The presence of leptomeningeal disease (LMD)—a late-stage manifestation involving the membranes surrounding the brain and spinal cord—further complicates treatment, given the difficulty many therapies face in crossing the blood-brain barrier.

Case Overview: Advanced NSCLC with Leptomeningeal Disease

This case, reported by Jinah Kim from the University of Vermont Medical Center, Young Kwang Chae from Feinberg School of Medicine and colleagues, involved a 67-year-old man with stage IV NSCLC and no history of smoking. Genetic testing identified the presence of EGFR G719A and A289V mutations. Initial therapy with osimertinib, followed by chemotherapy and immunotherapy, failed to control disease progression, which eventually involved both the brain and spinal fluid.

Given his declining performance status, combination therapies were not feasible. As an alternative, clinicians initiated amivantamab monotherapy, a bispecific antibody targeting EGFR and MET receptors. While amivantamab is currently approved in combination regimens, its activity as a single agent in rare EGFR mutations and CNS disease is not well established.

The Results: Response to Amivantamab

Within six weeks of starting amivantamab treatment, imaging showed a 32% reduction in lung tumor size. By six months, Magnetic resonance imaging confirmed complete resolution of brain metastases and LMD. In parallel, blood tests showed a molecular response. Circulating tumor DNA carrying the EGFR mutations dropped from detectable levels to undetectable. The patient, previously wheelchair-bound, recovered the ability to walk and manage activities of daily living. As of the latest follow-up, 19 months into treatment, the disease remained stable, with no signs of recurrence in either the lungs or CNS.

The Breakthrough: Monotherapy in Rare EGFR-Mutated NSCLC

This case challenges several prevailing views in the treatment of EGFR-mutated NSCLC. Amivantamab demonstrated activity against two rare mutations—G719A and A289V—that are poorly characterized and lack established treatment protocols.

The drug was administered as monotherapy, which diverges from current standard use involving combination regimens. Most notably, the clinical response included resolution of CNS involvement, suggesting that amivantamab may possess a degree of blood-brain barrier penetration not typically expected of large antibody-based therapies.

The Impact: A Potential Strategy for Patients with Limited Options

This case shows that amivantamab might be effective in more patients than previously thought, including those with rare mutations and brain metastases. It also raises the possibility of using the drug alone in patients who cannot tolerate combination therapies. These findings are especially significant because current clinical trials often exclude patients with untreated brain metastases, leaving a gap in NSCLC care.

Future Perspectives and Conclusion

This case provides a detailed example of amivantamab monotherapy being associated with sustained disease control in a patient with advanced NSCLC, rare EGFR mutations, and leptomeningeal involvement. Although it reflects a single patient’s experience, the outcome raises important questions for further research.

Key areas for investigation include the mechanism by which amivantamab may cross the blood-brain barrier—a longstanding challenge in treating CNS metastases. Additional studies are also needed to evaluate its efficacy against other rare EGFR mutations and to determine whether monotherapy could be a feasible option for patients who are unable to tolerate standard combination regimens.

While limited in scope, this case underscores the need for broader clinical data and suggests that amivantamab may have a role in complex, treatment-resistant NSCLC presentations.

Click here to read the full research paper in Oncotarget.

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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com.

Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Cigarette Smoke and Weak DNA Repair: A Double Hit Behind Lung Cancer Risk

August 11, 2025

“Lung cancer remains the leading cause of cancer-related fatalities in the United States and worldwide, with cigarette smoking the most well-established risk factor for lung cancer.“

Lung cancer, particularly non-small cell lung cancer (NSCLC), is the deadliest cancer worldwide. Cigarette smoking is one of the main causes, but not every smoker develops the disease. This suggests that other biological factors help determine who develops cancer.

Researchers from the Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indianapolis, and from the Richard L. Roudebush Veterans Affairs Medical Center have now found that cigarette smoke, combined with a weakened DNA repair system, can trigger the early stages of lung cancer, particularly NSCLC. This work, led by first author Nawar Al Nasralla and corresponding author Catherine R. Sears, was recently published in Volume 16 of Oncotarget.

Understanding the Link Between Cigarette Smoke and DNA Repair

NSCLC develops through a mix of genetic and environmental factors, with tobacco smoke as a major driver. Cigarette smoke contains thousands of harmful chemicals, many of which can damage DNA in the cells covering the airways. The body has natural systems to repair DNA damage and keep cells healthy. For example, one key protein, Xeroderma Pigmentosum Group C (XPC), detects specific types of DNA damage and starts the repair process, helping to maintain cellular genetic stability.

When DNA repair does not work properly, damaged DNA can remain in cells. Over time, these alterations may accumulate and lead to uncontrolled cell growth, raising the risk of NSCLC, and other lung diseases, such as chronic obstructive pulmonary disease (COPD).

The Study: Investigating the Relation Between DNA Repair and Lung Cancer Development

In the paper “Cigarette smoke and decreased DNA repair by Xeroderma Pigmentosum Group C use a double hit mechanism for epithelial cell lung carcinogenesis,” the research team investigated how cigarette smoke affects DNA repair when XPC function is reduced and whether this combination accelerates lung disease and cancer development.

They studied both healthy lung cells and lung cancer cells to compare how each type reacted to cigarette smoke exposure. By analyzing these differences, the team aimed to better understand how weakened DNA repair systems might set the stage for NSCLC and other lung diseases.

The Results: XPC Reduction is Part of NSCLC Development

The study found major differences between healthy lung cells and lung cancer cells when DNA repair was compromised. In healthy bronchial cells, cigarette smoke reduced DNA repair ability, increased DNA damage, and caused more cell death. These effects became stronger when XPC levels were lower.

Lung cancer cells responded differently, showing greater resistance to cigarette smoke. They required higher exposure to cause similar DNA damage, and lowering XPC had little effect on their survival, suggesting they rely on other mechanisms to manage the damage.

The researchers also examined genomic instability—signs that DNA is becoming dangerously unstable. In healthy cells, reduced XPC made cigarette smoke damage more likely to produce micronuclei, small DNA fragments that indicate higher cancer risk. In lung cancer cells, lowering XPC did not significantly change these markers.

Finally, in human NSCLC tumor samples, both lung adenocarcinomas and squamous cell carcinomas had much lower XPC levels than nearby healthy tissue. This was true regardless of smoking history, indicating that XPC loss is part of tumor biology rather than simply a result of cigarette smoke.

The Breakthrough: A Double Hit Driving Lung Disease Development

The findings point to a dangerous partnership between cigarette smoke and weakened DNA repair. Cigarette smoke delivers the first hit by directly damaging DNA. Reduced XPC delivers the second hit by limiting the cell’s ability to repair that damage. Together, these effects allow genetic errors to accumulate, increasing the probability that lung cells become cancerous. This “double hit” mechanism may help explain why some smokers develop lung diseases while others do not.

The Impact: Lung Cancer Prevention and Care

Testing for DNA repair capacity, especially XPC levels, could help identify people at higher risk for lung cancer, even before symptoms appear. Such screening could guide targeted prevention strategies for smokers and previous smokers.

Future Perspectives and Conclusion

This research highlights the importance of protecting cells’ DNA repair systems, particularly XPC, to reduce lung cancer risk. The next step will be to understand why XPC levels drop in lung cells. Identifying and addressing the causes could lead to prevention strategies for people exposed to cigarette smoke, including those who have already quit but remain at risk. Preserving or restoring XPC function could be a therapeutic strategy to slow or even prevent the earliest stages of NSCLC caused by cigarette smoke.

Overall, when cigarette smoke and reduced DNA repair act together, they can cause severe damage to lung cells, increase genetic instability, and raise the chances of developing NSCLC.

Click here to read the full research paper in Oncotarget.

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A Rare Genetic Shift That Helped Lung Cancer Evade Treatment

March 12, 2025

“This case adds to the literature on bypass signaling as a mechanism of resistance to lorlatinib, providing evidence for RET activation as a novel escape mechanism […]”

What if a cancer treatment worked—until it suddenly didn’t? A new case report, “Acquired RUFY1-RET rearrangement as a mechanism of resistance to lorlatinib in a patient with CD74-ROS1 rearranged non-small cell lung cancer: A case report,” published in Oncotarget, reveals how a non-small cell lung cancer (NSCLC) patient developed drug resistance through a rare genetic alteration, allowing the cancer to evade therapy. This unexpected finding highlights the importance of advanced genetic testing and personalized cancer treatments.

Non-Small Cell Lung Cancer, Targeted Therapy and Drug Resistance

Non-Small Cell Lung Cancer is the most common type of lung cancer, accounting for nearly 85% of all cases. Some patients with NSCLC have genetic mutations, such as ROS1 gene fusions, that drive tumor growth. These patients often respond well to targeted therapies like lorlatinib, a ROS1 inhibitor that blocks cancer growth.

However, cancer is constantly evolving. Over time, it can develop resistance to targeted therapies, leading to treatment failure. Understanding these resistance mechanisms is crucial for precision oncology, the approach of tailoring cancer treatment based on a patient’s unique genetic profile.

The Case Report That Changed Our Understanding

Dr. Jenny L. Wu from Vanderbilt University School of Medicine and Dr. Wade T. Iams from Vanderbilt-Ingram Cancer Center describe a rare case of drug resistance in a 42-year-old man with advanced NSCLC (stage IV) carrying a ROS1 gene rearrangement. Initially, the patient responded to multiple treatments, including entrectinib and later lorlatinib, both FDA-approved ROS1 inhibitors.

After six months on lorlatinib, his cancer began progressing again. To determine why the treatment stopped working, clinicians performed RNA next-generation sequencing (NGS), a diagnostic tool used to detect genetic mutations in cancer cells.

A Hidden Genetic Mutation

The NGS revealed a previously unknown mutation: a RUFY1-RET gene fusion, which had never been linked to lorlatinib resistance before. RET fusions are commonly associated with thyroid cancer and lung adenocarcinoma, but this was the first documented case where a RET fusion emerged as a mechanism of resistance to ROS1 inhibitors.

This discovery suggests that NSCLC can activate alternative survival pathways when ROS1 inhibitors are used, making precision medicine strategies even more critical for advanced lung cancer patients.

A New Treatment Approach

After detecting the RET fusion, clinicians adjusted the patient’s treatment plan by introducing pralsetinib, a RET inhibitor, alongside lorlatinib to target both mutations.

Initially, the combination therapy showed promise. Scans revealed tumor shrinkage, and the patient responded positively. Unfortunately, the response lasted only four months before the cancer progressed again. The patient passed away shortly thereafter, highlighting the urgent need for more durable treatment options for drug-resistant lung cancer.

The Importance of This Case

This is the first documented case of a RET fusion emerging as a resistance mechanism to lorlatinib. It challenges previous assumptions about how NSCLC adapts to targeted therapies and emphasizes the importance of RNA sequencing in detecting hidden resistance mutations.

Standard DNA testing did not detect the RET fusion; only RNA sequencing revealed it. This finding suggests that more sensitive genetic testing should be used when patients develop treatment resistance.

This case also raises new questions about therapy combinations. While the mix of lorlatinib and pralsetinib provided temporary disease control, it was not enough for long-term remission. New strategies are needed to develop more long-lasting treatment combinations for patients who develop resistance.

Future Perspectives and Conclusion

Treatment resistance remains a major challenge in lung cancer care. While targeted therapies have revolutionized treatment, they must continuously adapt to stay ahead of the disease.

Although the combination of pralsetinib and lorlatinib initially showed some effectiveness, the response did not last. In the future, scientists must investigate why some RET fusions make drugs less effective and whether finding these genetic alterations earlier could help change treatment plans before resistance fully sets in.

By uncovering new resistance mechanisms, this case highlights the importance of advanced genetic testing and contributes to the growing field of precision oncology. The more we understand how cancer adapts, the better we can develop smarter, more effective treatments and improve survival rates for lung cancer patients.

Click here to read the full case report in Oncotarget.

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Small Cell Lung Cancer: Advancing Precision Medicine with Biomarker Research

December 4, 2024

“Precision medicine is an innovative approach to disease prevention and treatment that considers differences in people’s genes, injuries, environments, and lifestyles to target the right therapies to the right patients at the right time.”

Could a deeper understanding of one of the deadliest lung cancers lead to more effective treatments? Recent research offers a promising way forward, aiming to improve patient outcomes and provide clinicians with valuable insights.

Small Cell Lung Cancer (SCLC) is a particularly aggressive form of lung cancer. It spreads fast and does not always respond well to conventional therapies such as chemotherapy. Although SCLC accounts for around 15% of all lung cancer cases, survival rates are extremely low. Only less than 5% of patients live more than five years after diagnosis. These alarming statistics highlight the critical need for new treatments. A team of researchers from the Federal University of Ceará, working together with collaborators from Argentina and Spain, may have found part of the solution.

The Study: Finding Clues in Tumor Biomarkers

Published in Oncotarget Volume 15 on October 11, 2024, the study is titled “Relationship between the expressions of DLL3, ASC1, TTF-1 and Ki-67: First steps of precision medicine at SCLC.” Led by corresponding author, Dr. Fabio Tavora, the research team analyzed tumor samples from 64 adult patients diagnosed with SCLC between 2022 and 2024. Their focus was on specific biomarkers, molecules that reveal the unique biology of a tumor, and that could lead to better ways to improve diagnosis and treatment for SCLC.

The Challenge: Why Current Treatments Are Not Enough

Current treatments for SCLC, like chemotherapy, are based on a “one size fits all” approach. While chemotherapy can initially decrease tumor size, its effects are often temporary, in addition to the harsh side effects that the patients can experience. This type of universal treatment overlooks each tumor’s specific biological characteristics, which is one of the main reasons chemotherapy has such low long-term success rates for SCLC patients.

To address this problem, the researchers studied the presence of distinct biomarkers. Since these molecules usually differ from tumor to tumor, they can provide valuable insights into tumor behavior. The goal was to discover new ways to personalize treatments, making them more efficient.

Technology: Using Digital Tools for Precision

In addition to standard techniques like immunohistochemistry, the researchers used QuPath, a novel digital pathology tool. QuPath enabled the researchers to evaluate tumor samples with unprecedented precision and resolution, revealing differences in biomarker expression between patients and between tumors, thus demonstrating that no two tumors are identical. This highlighted the importance of tailored treatment options.

The Results: Two Important Biomarkers

The study revealed two key biomarkers with the potential to improve SCLC treatment: Delta-like ligand 3 (DLL3) and Thyroid Transcription Factor-1 (TTF-1).

The Breakthrough: DLL3 and TTF-1 as Game-Changing

DLL3, a protein identified almost exclusively on the surface of SCLC tumor cells, has emerged as a potential therapeutic target. In this study, DLL3 was found in more than 70% of the SCLC tumors and its expression was tumor-specific. This finding makes it a suitable target for precision medicine, as treatments can target DLL3-positive cells while avoiding healthy tissue.

TTF-1, traditionally used as a diagnostic marker for lung cancer, showed potential as a prognostic biomarker in this study. Patients with TTF-1-positive tumors demonstrated better survival rates. The study also discovered a link between the expressions of TTF-1 and DLL3, suggesting that these two biomarkers could be used together to help choose treatments.

Therapeutic Potential: Toward Personalized Treatments

Unlike traditional therapies, which take a generic approach, biomarker-based treatments are tailored to the unique characteristics of each tumor. This personalization could make treatments more effective while reducing the side effects that patients experience.

Samuel Silva, the study’s first author, during an interview, emphasized the importance of the relationship between TTF-1 and DLL3. TTF-1 serves as both diagnostic and survival prediction tool, while DLL3 creates new opportunities for targeted therapy. Together, these biomarkers offer hope for more effective and individualized treatments for SCLC.

One promising development is the recent FDA approval of Tarlatamab, a therapeutic compound that uses the body’s immune system to target and destroy DLL3-positive tumor cells. This is an example of how biomarkers like DLL3 can be successfully translated into clinical settings.

Looking Ahead: What’s Next for SCLC Research

While this study represents a significant step forward on SCLC treatment, there is still more work to be done. In his interview, Silva explained that his team plans “… to look into the genomics and transcriptomics landscapes and the interactions of all these molecules,” aiming to better understand the molecular mechanisms driving SCLC and to further refine the therapeutic strategies.

Future clinical trials will be necessary to validate these findings and assess how effective and reliable DLL3 and TTF-1 are in guiding treatment for SCLC patients. With continued research, the ultimate goal is to make precision medicine a standard option for all SCLC patients.

Conclusion

SCLC is one of the most challenging cancers to treat, but this study offers hope. QuPath played a key role in showing how biomarkers like DLL3 and TTF-1 can guide more personalized and effective treatments. By focusing on these biomarkers, researchers are leading the way for better ways to diagnose and treat this aggressive disease. Precision medicine, which tailors treatments to each patient’s unique needs, promises to improve survival rates and quality of life for those facing SCLC.

Click here to read the full research paper in Oncotarget.

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Dr. Blagosklonny’s Strategy: From Osimertinib to Preemptive Combinations

June 6, 2024

This article dissects Dr. Mikhail V. Blagosklonny’s paradigm-shifting perspective on preemptive combinations for treating EGFR-mutant non-small cell lung cancer.

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In the relentless battle against non-small cell lung cancer (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations, the development of resistance has long been a formidable obstacle. Historically, first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) like gefitinib, erlotinib, afatinib, and dacomitinib have faced a significant hurdle: the emergence of the T790M point mutation in approximately 50% of patients, rendering the tumor resistant to these therapies.

This resistance stems from a sobering reality – before treatment, a small subset of cancer cells already harbor the T790M mutation, conferring no selective advantage initially. However, once treatment commences, these rare mutated cells proliferate selectively, eventually dominating the tumor population and diminishing the effectiveness of first- and second-generation TKIs.

The Rise of Osimertinib: A Beacon of Hope

In 2015, the FDA approved osimertinib, a third-generation EGFR TKI, as a second-line therapy for NSCLC patients with the T790M mutation. This approval recognized that untreated tumors are typically T790M-negative, with the mutation potentially present in only a single cell initially. Moreover, approximately 50% of patients do not harbor this mutation at all, underscoring the rationale for administering osimertinib after resistance to first- or second-generation TKIs emerges.

However, a paradigm shift was on the horizon. Osimertinib’s ability to target the T790M mutation, coupled with its potential to eliminate the rare resistant cells before they proliferate, paved the way for a groundbreaking approach: administering osimertinib as a first-line treatment, without waiting for resistance to develop.

Preemptive Combinations: A Multifaceted Strategy

In a seminal 2018 clinical trial, osimertinib demonstrated its prowess as a first-line treatment, significantly extending median progression-free survival (PFS) compared to first-generation EGFR inhibitors (18.9 months vs. 10.2 months). Remarkably, while the objective response rates were similar between the two groups, the duration of response was nearly doubled with osimertinib (17.2 months vs. 8.5 months).

Capitalizing on these findings, Dr. Mikhail V. Blagosklonny introduced the concept of “preemptive combinations” – a multi-pronged approach to not only induce a therapeutic response but also eliminate the few resistant cells harboring pre-existing mutations. By combining osimertinib with first- or second-generation EGFR inhibitors like gefitinib and afatinib, these preemptive combinations could potentially prevent on-target resistance mechanisms, thereby extending PFS and overall survival (OS) for a substantial proportion of patients. On March 15, 2024, Dr. Blagosklonny’s research perspective was published in Oncotarget’s Volume 15, entitled, “From osimertinib to preemptive combinations.”

Expanding the Armamentarium: Comprehensive Preemptive Combinations

While osimertinib addresses the T790M mutation, other resistance mechanisms remain a concern. Approximately 50% of resistance cases involve on-target secondary mutations within EGFR, such as L718, G724, L792, G796, and C797, which can be targeted by first- or second-generation EGFR inhibitors. Additionally, off-target mechanisms like MET and HER2 amplifications contribute to resistance.

To combat this multifaceted challenge, Dr. Blagosklonny proposed a comprehensive preemptive combination comprising osimertinib, afatinib (or a first-generation EGFR inhibitor), and capmatinib (a potent MET inhibitor). This triple-threat approach could potentially prevent up to 75% of resistance mechanisms, dramatically extending median PFS from 18 months with osimertinib alone to an estimated 40 months.

Addressing Heterogeneity: The Bittersweet Reality

While osimertinib undoubtedly improves median PFS and OS compared to first-generation TKIs, a sobering reality emerges: approximately 20% of patients may experience a shortened PFS due to pre-existing mutations like C797S, which render the tumor resistant to osimertinib but sensitive to first-generation TKIs. In these cases, osimertinib inadvertently selects for resistant clones, potentially harming a subset of patients.

The solution, as proposed by Dr. Blagosklonny, lies in the simplicity of preemptive combinations. By combining osimertinib with gefitinib, or even a triple combination with afatinib, the risk of selecting for resistant clones is mitigated, ensuring that no patient is inadvertently harmed by the superior TKI.

Transient Combinations: A Flexible Approach

For clinicians who may be hesitant about administering three- or four-drug combinations, Dr. Blagosklonny suggests a flexible approach: a sequence of transient two-drug combinations. This strategy involves alternating between different combinations, such as osimertinib and gefitinib, followed by osimertinib and afatinib, and so on, effectively covering all potential resistance mechanisms while maintaining a manageable treatment regimen.

Extending the Paradigm: MET-Driven NSCLC

The insights gleaned from EGFR-driven NSCLC can be applied to other molecular subtypes, such as MET exon 14 skipping mutation (METex14)-driven NSCLC. Dr. Blagosklonny’s personal experience with this condition underscores the importance of preemptive combinations in this setting as well.

While the selective MET inhibitor capmatinib demonstrated remarkable efficacy in treating Dr. Blagosklonny’s brain metastases, resistance tends to emerge within a year, often driven by secondary mutations like D1228 and Y1230. To combat this, a preemptive combination of capmatinib, afatinib (to target EGFR and HER2 alterations), and cabozantinib (a type II MET inhibitor effective against resistance mutations) could potentially prevent up to 50% of resistance mechanisms, prolonging progression-free survival for a significant proportion of METex14-driven NSCLC patients.

Overcoming Hurdles: The Path Forward

Despite the promise of preemptive combinations, challenges remain. The development of novel targeted therapies and the exploration of immune checkpoint inhibitors in combination with these regimens offer exciting avenues for future research. Additionally, refining clinical trial designs to incorporate precision medicine approaches and tailored combination strategies will be crucial in translating these concepts into tangible benefits for patients.

Conclusion: A Paradigm Shift in Cancer Care

Dr. Blagosklonny’s perspective on preemptive combinations represents a paradigm shift in the treatment of lung cancer and potentially other malignancies. By proactively targeting resistance mechanisms before they can take hold, this approach offers a glimmer of hope for prolonging progression-free survival and improving outcomes for patients grappling with this disease. As research continues to unravel the complexities of cancer resistance, preemptive combinations may pave the way for a future where we can stay one step ahead of cancer.

Click here to read the full research perspective in Oncotarget.

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Oncotarget is an open-access, peer-reviewed journal that publishes primarily oncology-focused research papers. These papers are available to readers (at no cost and free of subscription barriers) in an open-access and continuous publishing format at Oncotarget.com.

Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Antitumor Effects of Sacituzumab Govitecan Plus Platinum-Based Chemotherapy

March 14, 2024

In this study, researchers investigated the antitumor effects of Sacituzumab govitecan in combination with platinum-based chemotherapy.

The relentless search for effective cancer therapies has led to numerous breakthroughs in drug discovery and development. Advancements have emerged in recent years through the promising avenue of combination therapy, where two or more drugs are used synergistically to enhance their collective therapeutic effect. This strategy has shown significant potential in overcoming drug resistance, reducing side effects, and improving patient survival rates.

In a new study, researchers Thomas M. Cardillo, Maria B. Zalath, Roberto Arrojo, Robert M. Sharkey, Serengulam V. Govindan, Chien-Hsing Chang, and David M. Goldenberg from Gilead Sciences and the Center for Molecular Medicine and Immunology demonstrated the significant antitumor effects of Sacituzumab govitecan, an anti-Trop-2-SN-38 antibody-drug conjugate, in combination with platinum-based chemotherapy. On February 22, 2024, their research paper was published in Oncotarget, entitled, “Sacituzumab govitecan plus platinum-based chemotherapy mediates significant antitumor effects in triple-negative breast, urinary bladder, and small-cell lung carcinomas.”

Sacituzumab Govitecan & Platinum-Based Chemotherapy

Sacituzumab govitecan is an innovative drug that has gained prominence in recent years due to its unique mechanism of action and remarkable antitumor effects. It is an antibody-drug conjugate composed of an anti-Trop-2-directed antibody linked with the topoisomerase I inhibitory drug, SN-38, via a proprietary hydrolysable linker. Trop-2 is a transmembrane glycoprotein that is highly expressed in various solid tumors, making it an attractive target for cancer therapy. SN-38, the active metabolite of the chemotherapy drug irinotecan, is a potent topoisomerase I inhibitor that triggers DNA damage and apoptosis in cancer cells.

Platinum-based chemotherapy, primarily cisplatin and carboplatin, is a cornerstone of cancer treatment. These drugs work by interfering with DNA replication in cancer cells, leading to cell death. However, their use is often limited by drug resistance and toxic side effects.

“Using multiple drugs to treat cancer may allow for direct activity against multiple targets simultaneously or may indirectly affect the same target through different mechanisms of action [16].”

The Study

The combination of Sacituzumab govitecan and platinum-based chemotherapy has the potential to overcome these limitations. In the current study, the researchers found this combination to produce significant antitumor effects in various cancer models, including triple-negative breast, urinary bladder, and small-cell lung carcinomas. They found that the combination treatment resulted in additive growth inhibitory effects in vitro. The combination led to significant down-regulation of anti-apoptotic proteins and up-regulation of pro-apoptotic proteins, suggesting a shift towards pro-apoptotic signaling.

The in vivo efficacy of the combination therapy was further confirmed in mice bearing human tumor xenografts. The combination of Sacituzumab govitecan and carboplatin or cisplatin resulted in significant tumor regressions in all tested models. Importantly, the combination therapy was well tolerated by the animals, indicating a favorable safety profile.

Conclusions

The findings from this study represent a significant leap forward in the field of chemotherapy combination therapy drug discovery. The team provided strong evidence to support the clinical investigation of Sacituzumab govitecan in combination with platinum-based chemotherapy for the treatment of various solid tumors. Future studies should investigate the optimal dosing and sequencing of this combination therapy to maximize its efficacy and minimize potential toxicities. Additionally, the exploration of potential biomarkers could help identify patients who are most likely to benefit from this combination therapy.

In summary, the combination of Sacituzumab govitecan (SG) and platinum-based chemotherapy holds great promise as a potent antitumor therapy. It represents a novel approach that could potentially revolutionize the treatment of various solid tumors and improve patient outcomes.

“Importantly, these data demonstrate significantly greater antitumor effects of SG plus carboplatin or cisplatin in tumor-bearing mice than monotherapies, and that they were well tolerated by the animals. Based on these results, SG plus platinum-based chemotherapeutics merit clinical investigation.”

Click here to read the full research paper in Oncotarget.

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The Obesity Paradox, Metformin and Lung Cancer

July 27, 2023

In a new editorial, researchers from Instituto Nacional de Cancerología discuss the obesity paradox and its potential therapeutic opportunities in the context of lung cancer.

The Obesity Paradox, Metformin and Lung Cancer

The strong correlation between obesity and a myriad of life-limiting diseases and conditions, including type 2 diabetes, is widely recognized and acknowledged in the research community. A less defined correlation is that between obesity, diabetes and lung cancer. Whether this association is directly causal or if there are underlying contributing factors is not yet clear.

“Although obesity and type 2 diabetes mellitus (T2DM) have been associated with lung cancer (LC) development, several confounding factors, such as chronic inflammation, high insulin levels, microbiome, as well as the oncogenic potential of growth and sexual hormones, have introduced uncertainty and avoid the fully recognition of this relationship [1, 2].”

Given the existence of this association, scientists are testing therapeutic regimens that may have the potential to fight all three issues — together. Metformin, a drug commonly prescribed to treat type 2 diabetes, helps lower blood sugar levels by improving insulin sensitivity and reducing glucose production in the liver. The metabolic-modifying properties of metformin aid in treating diabetes and obesity. Metformin has also garnered attention for its potential anti-aging properties and may hold promise for treating age-related diseases, including cancer. Lately, there has been growing interest in testing metformin in combination therapies to combat cancer-promoting conditions induced by obesity.

The “Obesity Paradox”

While the link between morbidity and obesity may seem cut-and-dry, researchers have discovered a surprising trend. The “obesity paradox” suggests that, in certain instances, individuals classified as overweight or mildly obese seem to fare better or have a survival advantage compared to those with normal weight or even underweight counterparts. This paradox has been particularly observed in certain chronic illnesses, such as heart failure, chronic kidney disease, and even in the context of aging. Researchers are still striving to understand the underlying mechanisms driving this phenomenon.

In a new editorial, researchers Pedro Barrios-Bernal, Norma Hernández-Pedro, Luis Lara-Mejía, and Oscar Arrieta from Instituto Nacional de Cancerología in Mexico City, Mexico, discuss the obesity paradox and its potential therapeutic opportunities in the context of lung cancer. Their editorial paper was published in Oncotarget on July 1, 2023, and entitled, “Obesity paradox and lung cancer, metformin-based therapeutic opportunity?” They suggest that metformin may have potential therapeutic effects for both obesity and lung cancer. The researchers explore the mechanisms by which metformin may modify tumor metastatic properties and promote an antitumor immune response. They also discuss the potential implications of the obesity paradox in the context of lung cancer treatment and the potential benefits of metformin use in combination with antineoplastic therapies.

In a 2019 study, the researchers conducted a phase 2 randomized clinical trial investigating the effect of metformin combined with tyrosine kinase inhibitors (TKIs) (compared to TKIs alone) in patients with epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma. They found that the addition of metformin to standard EGFR-TKI therapy in patients with advanced lung adenocarcinoma significantly improved progression-free survival. In their 2022 s tudy, the researchers performed a secondary analysis of the same study, now measuring the association of body mass index (BMI). This time, they reported that the survival outcome in patients with EGFR-mutated lung adenocarcinoma was greater with patients with a BMI higher than 24. The findings suggest that this treatment combination has a selective effect in obese populations and a lack of benefit in patients with a BMI less than 24, thus contributing to the obesity paradox.

“These findings suggest a strong sensitization by the addition of metformin in obese population, suggesting that biochemical and molecular differences influence the treatment response [8].”

Reflections & Future Research

In conclusion, the relationship between obesity, type 2 diabetes and lung cancer remains a subject of ongoing research. Metformin shows promise as a potential multipurpose treatment option, exhibiting properties beneficial for diabetes, obesity, aging, and cancer. The obesity paradox adds a layer of complexity to the obesity-cancer relationship, with some studies suggesting better survival rates and treatment response in overweight or mildly obese individuals treated with metformin. The researchers add that further investigation is needed to determine whether any of the proposed mechanisms of metformin have clinically meaningful activity in the treatment of obese patients with lung cancer. The ongoing research surrounding metformin and its interactions with obesity and cancer may lead to improved therapeutic strategies for these interconnected health challenges.

“Until then, we propose that pharmacodynamics, pharmacokinetics, metabolic parameters, tumor biology, biochemical and molecular modifications may be related to the ‘obesity paradox’ and must be taken into account to choose the most appropriate treatment.”

Click here to read the full editorial in Oncotarget.

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Oncotarget

New Target Fights Ferroptosis- and Radio-Resistance in Lung Cancers

November 2, 2022

Researchers published a research perspective about a recent study that uncovered FSP1 as a novel target gene that mediates ferroptosis resistance and radioresistance in lung cancer cells.

Figure 1: KEAP1-NRF2 axis and its molecular effectors in the regulation of ferroptosis. — **Figure 1:** KEAP1-NRF2 axis and its molecular effectors in the regulation of ferroptosis.

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Ferroptosis is a type of cell death caused by the accumulation of iron and lipid peroxides in cells. Cancer cells are often resistant to ferroptosis, which allows them to survive and proliferate. Radioresistance is another common feature of cancer cells that allows them to resist the effects of radiation therapy.

A new research paper (published on April 22, 2022) identified ferroptosis suppressor protein 1 (FSP1) as a novel KEAP1/NRF2 target gene and demonstrated that FSP1 plays an essential role in NRF2-mediated ferroptosis resistance and radioresistance in KEAP1-deficient lung cancer cells.

Recently, researchers Nsengiyumva Emmanuel, Hongen Li, Jing Chen, and Yilei Zhang from Xi’an Jiaotong University, Ruyang People’s Hospital and Shaanxi Jiuzhou Biomedical Science and Technology Group wrote a paper about the implications of these findings. On October 19, 2022, their research perspective was published in Oncotarget’s Volume 13, entitled, “FSP1, a novel KEAP1/NRF2 target gene regulating ferroptosis and radioresistance in lung cancers.”

“In a recent study by Pranavi Koppula et al. from The University of Texas MD Anderson Cancer Center, FSP1 was demonstrated as a novel target of NRF2 and to play a vital role in KEAP1/NRF2-mediated ferroptosis regulation [13], which reveals the important role of genetic regulation of FSP1 in cancer development.”

The KEAP1-NRF2 regulatory pathway is crucial for protecting cells against oxidative damage. In lung cancer cells, KEAP1 mutations lead to NRF2 deregulation and contribute to tumorigenesis. Researchers have been searching for an effective way of targeting this pathway in cancer cells to sensitize them to ferroptosis/radiation-inducing agents. They found that FSP1 is upregulated in KEAP1-mutant lung cancer cells, and its expression is associated with resistance to ferroptosis and radiotherapy. Coenzyme Q10- (CoQ) FSP1 signaling represents a potential target for overcoming resistance to ferroptosis and radiotherapy in KEAP1-mutant lung cancer cells.

“Currently, there are four major ferroptosis-defending systems, while NRF2 could directly control two of them, SLC7A11/GSH/GPX4 axis and CoQ/FSP1 axis.”

This study provides new insights into the role of target genes in the KEAP1-NRF2 pathway and how they contribute to cancer cells’ resistance to ferroptosis and radiotherapy. However, the mechanism by which KEAP1-NRF2 target genes mediate resistance to ferroptosis is not yet fully understood. Fortunately, the identification of FSP1 as a key target gene involved in this process opens up new therapeutic avenues for the treatment of lung cancer.

“Here, Pranavi Koppula and her colleagues’ study indicates that pharmacological targeting of CoQ-FSP1 signaling to overcome KEAP1 deficiency-induced radioresistance could be a potentially effective therapeutic strategy in treating KEAP1 mutant lung cancers.”

Click here to read the full research perspective published by Oncotarget.

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Oncotarget

Trending With Impact: Analysis of Mutational Burden in NSCLC

April 21, 2022

Researchers conducted a multi-site cohort study of tumor mutational burden among hundreds of patients diagnosed with stage IV non-small cell lung cancer (NSCLC).

The Trending With Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Oncotarget.com.

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While a high tumor mutational burden (TMB) may seem unfavorable in the midst of battling non-small cell lung cancer (NSCLC), a higher TMB has been associated with a higher number of neoantigens. The presence of more neoantigens can potentially elicit a stronger immune response. Therefore, TMB may be a viable biomarker of tumor response to immunotherapeutic agents. However, the definitions, parameters and units used to measure high- and low-TMB have been inconsistent over the years. Today, the consensus unit for reporting TMB has shifted to mutations per megabase (mut/Mb). The common cut-off for high- vs. low-TMB from tissue samples is >10 mut/Mb in NSCLC.

“Despite inconsistencies with TMB definition and reporting over time, high TMB has consistently been associated with improved clinical benefit among patients receiving immunotherapy for NSCLC [22].”

Researchers—from University of Utah, University of Minnesota Duluth, Huntsman Cancer Institute, H. Lee Moffitt Cancer Center and Research Institute, Baptist Health Medical Group, MetroHealth Medical Center, Rutgers Cancer Institute of New Jersey, University of Southern California, Saint Luke’s Cancer Institute, University of Kentucky, and Bristol Myers Squibb—used the newest consensus unit and common cut-off parameters for TMB expression to measure TMB’s relationship to treatment response and survival outcomes among metastatic NSCLC patients. Their trending research paper was published in Oncotarget’s Volume 13 on January 31, 2022, and entitled, “Real-world survival analysis by tumor mutational burden in non-small cell lung cancer: a multisite U.S. study.”

“The purpose of this study is to evaluate clinical outcomes by TMB among NSCLC patients treated with immunotherapy containing regimens in the first-line setting.”

The Study

Participants in this large cohort study included 667 patients who had been diagnosed with stage IV NSCLC and treated with any NSCLC-related treatment. Patients were recruited from nine different academic and community cancer centers across the United States. The researchers intended to utilize this “real-world” dataset and hoped it would allow them to realistically assess the role of TMB as a potential biomarker of NSCLC response to treatment.

First, the team collected demographic and clinical characteristics and separated them into two groups: TMB greater or less than 10 mut/Mb. Characteristics included age, sex, race, body mass index, smoking history, PD-L1 expression, comorbidities, Eastern Cooperative Oncology Group performance status (ECOG PS) at diagnosis, histology subtype, Stage at metastatic diagnosis, and site of metasteses. Interestingly, a history of smoking was significantly associated with a TMB greater than 10 mut/Mb.

“Smoking status was significantly associated with TMB >10 with 91% of patients reported as current or former smokers compared to 61% in the TMB <10 cohort (p < 0.01, Table 1).”

The Results

The researchers found no association between TMB and age, PD-L1 expression, tumor histology, or cancer stage at diagnosis. Next, the team assessed for significant associations between TMB and 17 genomic alterations. They found that lower TMB was associated with ALK and EGFR alterations. Higher TMB was associated with TP53 alterations. The researchers investigated the association between TMB and treatment patterns and responses. The overall response rate was very similar in both groups.

A multivariable model was used to analyze overall patient survival and progression-free survival (PFS) for first-line immunotherapy containing regimens based on TMB. The model controlled for the initial patient characteristics and did not demonstrate significantly different results for overall survival in the two groups. However, the researchers found in a subgroup analysis that, of the patients who received TMB testing within 60 days of receiving immunotherapy treatment, those with TMB >10 demonstrated significantly longer overall survival compared to their TMB <10 counterparts. In terms of PFS, they found that PFS was longer among patients with TMB >10 in the cohort and subgroup analyses. PFS was significantly longer when treated with an immunotherapy-containing regimen first-line compared to a first-line treatment of chemotherapy. An association between TMB and PD-L1 expression was not found in this study.

Conclusion

“This study evaluated two broad questions: (1) The distribution of TMB in the real world and its association with baseline clinical and demographic features (n = 677) and (2) the association between TMB and clinical outcomes among NSCLC patients who received first-line immunotherapy (n = 224).”

Results of the study confirmed the association between a higher TMB and smoking history, as well as the benefits of first-line immunotherapy within two months of TMB testing. While the researchers were forthcoming about limitations in their study, metastatic NSCLC patients with TMB>10 who were treated with first-line immunotherapy had improved overall survival and progression-free survival.

“Based on the results in this study and prior research, TMB along with other biomarkers, such as PD-L1, may help identify patients more likely to benefit from first-line immunotherapy.”

Click here to read the full research paper published by Oncotarget.

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Oncotarget

New Study: ALK Rearrangement Among Lung Cancer Patients

November 10, 2021

In Oncotarget’s Volume 12, Issue 23, cover paper, researchers retrospectively assessed the prevalence of anaplastic lymphoma kinase (ALK) gene rearrangement among nearly 20,000 patients with advanced non-small cell lung cancer.

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The identification of an actionable gene mutation or translocation in patients with cancer can give researchers a target for new drug therapies. One such mutation, found in some patients with non-small cell lung cancer (NSCLC), is anaplastic lymphoma kinase (ALK) gene rearrangement. However, the exact population of patients that present with ALK rearrangement has not been fully characterized. Identifying the subpopulation of patients who present with ALK rearrangement may lead to better overall treatment outcomes.

Researchers—from University of Mississippi Medical Center, Roche Information Solutions, Roche Diagnostics Corporation, Genesis Research, and Houston Methodist Hospital—conducted a retrospective study of nearly 20,000 patients with advanced NSCLC (aNSCLC). The researchers assessed ALK rearrangement prevalence in the cohort overall and then categorized the data using patient characteristics. Their paper was published on the cover of Oncotarget’s Volume 12, Issue 23, and entitled, “Anaplastic lymphoma kinase rearrangement prevalence in patients with advanced non-small cell lung cancer in the United States – retrospective real world data”.

“We performed a retrospective study of a database to acquire real-world clinical data on the frequency of the translocation in a large pool of patients drawn primarily from community hospitals and practices.”

The Study

This cross-sectional, observational study used de-identified data from Flatiron Health’s database, which included 19,895 patients who were diagnosed with aNSCLC in the United States between 2015 and 2019. The average age of patients was 68.5, plus or minus 10 years. The distribution of gender was nearly equal, with men comprising 50.4% (10,029) of the patient cohort, and 68.4% of patients were Caucasian. A large proportion of patients had a non-squamous histology type (80.5%) and smoking history (85.5%).

“Prevalence of ALK rearrangement was assessed overall and then stratified by patient characteristics such as age, gender, race, smoking status and histology.”

The researchers used descriptive statistics to summarize patient characteristics. Characteristics included age, gender, race, geographic location, smoking status, histology, practice type (community or academic), PD-L1 status, prevalence of ALK rearrangement and other biomarkers.

“Regardless of documented histology, a higher ALK rearrangement rate (8.9%) was observed among patients who had no smoking history compared to patients with a smoking history (1.5% ALK positivity) which represent the largest number of patients in this cohort (17,003).”

Conclusion

Results from the study concluded that ALK rearrangement was present in 2.6% of the total cohort, or 517 patients. The researchers found that ALK rearrangement prevalence varied based on the patients’ demographic characteristics. The rate of ALK rearrangement was the highest among patients younger than 40 years old, and decreased with age. Researchers found no significant difference in ALK rearrangement between men and women. However, when compared to other patients, Asian patients had a higher ALK rearrangement rate (39 out of 623, or 6.3%). Interestingly, the ALK positivity rate was greatest (9.3%) among non-smoking patients with non-squamous histology.

“In summary, this retrospective review of nearly 20,000 patients with aNSCLC and tested for ALK in the United States confirms that ALK rearrangements are found more commonly in younger nonsmokers and patients of Asian descent.”

Click here to read the full research paper, published by Oncotarget.

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