Genomic instability in advanced non-small cell lung cancer (NSCLC) treated with maintenance durvalumab in the UNICANCER SAFIR02-Lung/ IFCT1301 trial.
Authors: Dall'Olio Filippo Gustavo , Zrafi Wael , Mamann Aaron , Job Bastien , Michiels Stefan , Tomasini Pascale , Raimbourg Judith , Daniel Catherine , Janicot Henri , Madroszyk Anne , Audigier Valette Clarisse , Bieche Ivan , Mazieres Julien , MORO SIBILOT Denis Lucien , Jimenez Marta , Westeel Virginie , Tran-Dien Alicia , Barlesi Fabrice , Besse Benjamin 
Published: August 2024

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Background: Genomic instability is a hallmark of cancer that has been associated to immune evasion, cancer progression and multidrug resistance. In SAFIR02-Lung, advanced NSCLC pts were enrolled to receive a platinum-based chemotherapy. After 4 cycles, pts with no targetable alterations were oriented to the immunotherapy sub-study, and if stable or in response, were randomized between maintenance durvalumab or Standard of Care (SoC) (PMID 35802649). Durvalumab prolonged survival only in the PD-L1 ≥ 1% subgroup. In this study we investigated a genomic instability score based on somatic copy number alterations as determined by Comparative Genomic Hybridization (CGH) array as a biomarker for maintenance immunotherapy. Methods: SAFIR02-Lung (NCT02117167) is a multicentric, randomized phase 2 clinical trial. Tissue samples were obtained before induction chemotherapy. Extracted DNA from fresh frozen tumor was analyzed using high-resolution Affymetrix Cytoscan arrays, DNA from FFPE samples was analyzed using the Affymetrix Oncoscan CNV platform. The absolute copy-number (ACN) profile was generated by ASCAT v3.1 through EaCoN v0.3.6 ( https://github.com/gustaveroussy/EaCoN , PMID 36669143 ) on R v4.1.1 and then the genomic instability score was estimated as the sum of the segment length multiplied by the absolute difference between segment copy number and the ASCAT estimated sample ploidy. This sum is reported to the reference genome length. Progression Free Survival (PFS) was the primary endpoint, defined as the time from randomization until the date of objective radiological disease progression, clinical progression or death. The secondary endpoint was Overall Survival (OS). Results: CGH array data were available for 79 patients out of 183, 56 randomized to durvalumab and 23 to SoC. 47 were men, 72 had non-squamous histology and 12 had brain and 10 had liver metastasis. We divided patients in tertiles according to instability (INS) score. No correlation was seen between INS score and PD-L1 positivity (p = 0.5), or liver and brain metastasis. Pts with high INS had lower median PFS of 2.5 months (m) (95% CI 1.4 – 5.2) vs 4.3m (95% CI 2.6 – 13.7) for those with intermediate INS and 6.1m for those with low INS (95% CI 1.9 – 21.2), p 0.012. Similarly, low INS patients had longer OS of 29.6 m (95% CI 15.4 – NR) vs 17.9m for intermediate INS (95% CI 10 – NA) and 12.1m for high INS (95% CI 10.2 – 19.5), p = 0.039. No difference was seen in the control group (p=0.25 for PFS and p=0.4 for OS). A multivariable model showed that high INS was independently associated worse PFS (HR 2.60, 95% CI 1.36 - 4.98, p 0.004) and OS (HR 2.90, 95% CI 1.33 - 6.35, p 0.008). Conclusions: Genomic instability score based on CGH array-based copy number alterations profile is associated with worse PFS and OS in patients under response to chemotherapy who received durvalumab maintenance. Clinical trial information: NCT02117167 .