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Spectrum of Resistance Mechanisms to ALK TKIs in NSCLC: Largest Single-Center Experience from India
Ullas Batra1, Shrinidhi Nathany2, Mansi Sharma1
1Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Center, New Delhi, India.
Introduction:
Anaplastic lymphoma kinase (ALK) rearranged non-small cell lung carcinoma (NSCLC) has emerged as a distinct entity with growing number of potent ALK tyrosine kinase inhibitors (TKIs). Despite showing durable responses and promising survival rates, resistance to these ensue. This is the largest series of repeat biopsies from patients of ALK-positive NSCLC progressing on ALK-directed therapy from this part of the world. Using a combinatorial approach of genomics and histology, we describe the spectrum of various resistance mechanisms encountered.
Methods:
This is a cross-sectional study recruiting ALK-positive NSCLC cases who have progressed on any line ALK TKI and have undergone repeated biopsies followed by genomic sequencing by next-generation sequencing (NGS).
Results:
Thirty-two ALK-positive NSCLC patients progressed on TKI were enrolled. Median age was 53 years (range: 36-75 years) with a male predilection (male:female 1.3:1). Twenty-seven (84.4%) cases harbored an additional resistance mechanism. Eighteen of these harbored an on-target ALK alteration, with L1196M gatekeeper mutation being the most common, in 11 cases, and G1202 alteration in 3 cases. In 9 cases an off-target alteration was detected, the most frequent being TP53 mutation in 8 cases, KRAS mutation in 4 cases and MET amplification in 3 cases. Four patients underwent sequential NGS testing and allele frequency changes in ALK fusion and resistance mechanisms were demonstrated. Sixteen patients have been offered lorlatinib therapy, the median progression-free survival of which has not yet been reached.
Conclusion:
This is the largest series depicting ALK resistance mechanisms from a single center to date. The SPACEWALK study which demonstrated ALK TKI resistance mechanisms using plasma-based genotyping was a multicentric study. The spectrum encountered in this study is distinct from the rest of the world, thus highlighting heterogeneity within ALK-rearranged tumors. Comprehensive clinical evaluation at disease progression coupled with NGS-based genotyping will pave the way for lucid understanding of disease biology, thus aiding in the institution of optimal therapy.
Insights
Resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) is common. This study details the genomic and histologic resistance mechanisms in ALK-positive NSCLC patients, highlighting distinct patterns and aiding optimal therapy selection.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC) is a distinct subtype treated with ALK tyrosine kinase inhibitors (TKIs).
- Despite initial efficacy, resistance to ALK-TKIs is a significant clinical challenge, necessitating a deeper understanding of underlying mechanisms.
- Identifying resistance mechanisms is crucial for guiding subsequent treatment strategies in ALK-positive NSCLC.
Purpose of the Study:
- To investigate and characterize the spectrum of resistance mechanisms in ALK-positive NSCLC patients progressing on ALK-directed therapy.
- To analyze genomic alterations and histological changes associated with TKI resistance using repeat biopsies and next-generation sequencing (NGS).
- To highlight the heterogeneity of resistance mechanisms, particularly in a specific geographic region.
Main Methods:
- A cross-sectional study involving 32 ALK-positive NSCLC patients who progressed on ALK TKI therapy.
- Collection of repeat biopsies from patients for comprehensive genomic profiling using next-generation sequencing (NGS).
- Analysis of both on-target (ALK alterations) and off-target (other gene mutations/amplifications) resistance mechanisms.
Main Results:
- Eighty-four percent (84.4%) of patients exhibited an additional resistance mechanism beyond the initial ALK alteration.
- On-target ALK alterations included L1196M (11 cases) and G1202 (3 cases). Off-target alterations frequently involved TP53 (8 cases), KRAS (4 cases), and MET amplification (3 cases).
- Sequential NGS testing demonstrated dynamic changes in allele frequencies of resistance mechanisms. Sixteen patients were initiated on lorlatinib, with median progression-free survival not yet reached.
Conclusions:
- This study represents the largest series detailing ALK TKI resistance mechanisms from a single center, revealing distinct patterns compared to global data.
- The encountered spectrum of resistance mechanisms underscores the heterogeneity within ALK-rearranged NSCLC.
- Integrated clinical evaluation and NGS-based genotyping are essential for understanding disease biology and optimizing therapeutic strategies for patients with resistant ALK-positive NSCLC.
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