While platinum chemotherapy is considered the standard treatment after a patient progresses on a first-line ADC-IO combination, experts admit this is a standard "based on nothing." There is no clinical trial data to prove its efficacy in this specific setting; it serves only as a placeholder for new clinical trials.

Unlike traditional cytotoxic agents, the DLL3-targeting T-cell engager tarlatumab demonstrates consistent overall survival benefits in third-line SCLC regardless of the patient's chemotherapy-free interval from first-line therapy. This indicates it works via a distinct mechanism that bypasses conventional chemoresistance pathways, representing a new treatment paradigm.

Lurbinectedin's effectiveness in second-line SCLC is highly dependent on the chemotherapy-free interval after first-line treatment. Patients with a longer interval (>90 days) show significantly better response rates and disease control, reinforcing that "platinum sensitivity" acts as a proxy for broader cytotoxic drug sensitivity.

Real-world data suggests that using one antibody-drug conjugate (ADC) immediately after another is often ineffective. A potential strategy to overcome this resistance is to administer a different class of chemotherapy before starting the second ADC.

The investigator-led PLUTO trial found docetaxel chemotherapy provided a better overall survival benefit than lutetium in first-line mCRPC. This result directly confronts the common clinical bias against chemotherapy ("chemophobia"), proving that older treatments can still outperform newer targeted agents and should not be prematurely abandoned.

The failure of the concurrent chemo-immuno-radiation approach has not stalled progress. Instead, new clinical trials are actively exploring novel strategies like SBRT boosts, dual checkpoint inhibitors, radiosensitizing nanoparticles, and induction immunotherapy to improve upon the current standard of care.

Actuate employed a master protocol that tested their drug alongside eight different standard-of-care chemotherapies in patients who had already failed them. This design efficiently demonstrated the drug's ability to reverse chemo-resistance across multiple histologies, informing their Phase 2 strategy.

The TRILINX trial revealed Xevinapant's toxicity was so high that it forced reductions in standard, effective treatments like cisplatin and radiation. This compromised the foundational therapy, leading to worse patient outcomes and demonstrating a key risk in adding novel agents to established regimens.

For N2+ EGFR-mutant NSCLC, clinicians now face a choice. Combining neoadjuvant osimertinib with chemotherapy is potent and gets treatment done upfront, but osimertinib monotherapy is better tolerated, reducing the risk of toxicity that could prevent a patient from reaching their planned surgery.