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Polyclonal Resistance — SCE Medical Oncology MCQ

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HardLung CancerPolyclonal ResistanceSCE Medical Oncology

A 65-year-old man with NSCLC on third-generation EGFR TKI (osimertinib) progresses. Comprehensive molecular profiling at progression shows no single dominant resistance mechanism but multiple low-level alterations. What does this pattern suggest?

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Correct answer: C — Polyclonal resistance — multiple distinct resistance mechanisms arising simultaneously, making single-targeted therapy unlikely to be effective; platinum-based chemotherapy ± continuation of osimertinib is often the pragmatic approach

Polyclonal resistance (multiple concurrent resistance mechanisms at low allelic frequency) is increasingly recognised as a common pattern at TKI progression, found in approximately 30-50% of cases. Unlike monoclonal resistance (single dominant mechanism amenable to next-line targeted therapy), polyclonal resistance is difficult to target with any single agent. Pragmatic management typically involves platinum-based chemotherapy ± osimertinib continuation (COMPEL trial concept), as the backbone EGFR-mutant population may still derive partial benefit from continued TKI.

Reference: ESMO 2024 NSCLC; Oxnard et al Cancer Discov 2018