General Comments / Chat, page-13327

"Non-small cell lung cancer (NSCLC) has the largest population of patients eligible for competing ICIs, which are used as SOC at multiple treatment stages. However, more than 65% of these patients develop acquired resistance and as a result lack effective therapeutic options. Because 5-year survival rates are so critically low, therapies like Bisantrene that could either resensitize a resistant cancer or be used concurrently with SOC to maintain sensitivity to treatment have the potential to increase that number significantly." Mason Hill @Mason14
Gemini AI

Let's break down the statement:

1. "Non-small cell lung cancer (NSCLC) has the largest population of patients eligible for competing ICIs, which are used as SOC at multiple treatment stages."

• True. NSCLC is the most common type of lung cancer, accounting for approximately 84% of lung malignancies. Immune checkpoint inhibitors (ICIs) have become a standard of care (SOC) for advanced NSCLC at various stages, either as monotherapy or in combination with chemotherapy.

2. "However, more than 65% of these patients develop acquired resistance and as a result lack effective therapeutic options."

• Largely True, but with nuances.

  • Acquired Resistance: Studies show a high rate of acquired (secondary) resistance to ICIs in NSCLC patients who initially respond. One pooled analysis found up to 65% of initial responders developed progressive disease at 4 years. Another retrospective study found 78% of patients who acquired an initial response to PD-1 inhibitors developed secondary resistance. Primary resistance (no initial response) is also significant, ranging from 7-27% in first-line treatment and higher in second-line.

  • Lack of Effective Therapeutic Options: While acquired resistance presents a significant challenge, research is actively exploring and developing strategies for patients who progress on ICIs. These include:

    • Combining ICIs with other therapies (e.g., chemotherapy, targeted therapies, other immunotherapies).

    • Investigating novel agents and combinations.

    • Retreatment with ICIs in specific cases.

    • Local treatments like stereotactic radiotherapy for oligoprogression.

  • So, while the lack of effective options is a critical unmet need, it's not entirely accurate to say there are no effective options, as research continues to identify new strategies. The statement could be interpreted as "lack of sufficiently effective" options, which aligns more closely with the reality.

3. "Because 5-year survival rates are so critically low, therapies like Bisantrene that could either resensitize a resistant cancer or be used concurrently with SOC to maintain sensitivity to treatment have the potential to increase that number significantly."

• Partially True and a Reasonable Conclusion.

  • Critically Low 5-year Survival Rates for NSCLC: This is True. While survival rates vary significantly by stage, the overall 5-year relative survival rate for NSCLC is still relatively low. For distant (metastatic) NSCLC, 5-year survival rates can be as low as 5.5% to 12%. Even for all stages combined, it's around 28-32%.

  • Bisantrene's Potential:

    • Mechanism: Bisantrene is an old chemotherapy agent with anthracycline-like activity (DNA intercalation, topoisomerase II inhibition). More recently, it has been identified as a potent and selective inhibitor of the FTO protein, an m6A RNA demethylase.

    • Relevance to Resistance/Sensitization: Inhibition of FTO has been shown in preclinical studies to potentially overcome anticancer drug resistance and synergize with other anticancer treatments. This directly addresses the need for therapies that could resensitize resistant cancers or maintain sensitivity.

    • Clinical Data (Limited in NSCLC for this specific use): Bisantrene has been evaluated in various cancers, including leukemia, breast, and ovarian cancer, with some positive results in the past. It has also shown promise in acute myeloid leukemia (AML) where it is currently in clinical trials, including some focused on combinations.

    • Potential to Increase Survival Rates: Given the high rate of acquired resistance and the low 5-year survival rates, any therapy that can effectively address resistance or maintain sensitivity would indeed have the potential to significantly improve patient outcomes. The premise that Bisantrene, with its proposed mechanisms, could achieve this is a reasonable scientific hypothesis. However, specific clinical evidence directly demonstrating Bisantrene's ability to resensitize ICI-resistant NSCLC or maintain ICI sensitivity in concurrent use in NSCLC patients is still emerging or would require further dedicated research. Current clinical trials involving Bisantrene are predominantly in AML or broader solid tumors with doxorubicin combinations, not specifically focused on ICI resistance in NSCLC at this time.

Overall Conclusion:

The statement is largely True in its core assertions regarding NSCLC, ICI resistance, and low survival rates. The potential role of a drug like Bisantrene to address these issues is a scientifically plausible and actively researched area. However, the claim about Bisantrene's potential is based on its known mechanisms of action and preclinical data, rather than established clinical efficacy specifically in overcoming ICI resistance or maintaining sensitivity in NSCLC patients.

Therefore, the statement is a largely accurate representation of the challenges in NSCLC treatment and a well-reasoned hypothesis for the potential utility of drugs like Bisantrene, though the specific clinical validation of Bisantrene for overcoming ICI resistance in NSCLC is still an area of ongoing investigation.