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P. Saintigny



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    MO18 - NSCLC - Targeted Therapies IV (ID 116)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO18.06 - BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 1949)

      16:45 - 16:50  |  Author(s): P. Saintigny

      • Abstract
      • Presentation
      • Slides

      Background
      Effective therapeutic strategies for mutant KRAS and other biomarkers of resistance in refractory NSCLC remain an unmet medical need, while a personalized medicine approach is increasingly adopted in NSCLC guided by tumor molecular profiling. The BATTLE-2 clinical study is using EGFR, PI3K/AKT and MEK inhibitors and is designed to identify biomarkers for optimal patient selection for these therapies (ClinicalTrials.gov NCT01248247).

      Methods
      This is a four-arm, open-label, multi-center, biopsy-driven, adaptive randomization, phase II clinical trial in NSCLC pts that failed at least 1 prior line of therapy. Patients are adaptively randomized to 4 arms: erlotinib, erlotinib plus the AKT inhibitor MK-2206, MK-2206 plus the MEK inhibitor selumetinib, and sorafenib. The primary objective is 8-week disease control rate (DCR). The trial is conducted in 2 stages. In Stage 1, 200 evaluable pts are adaptively randomized (AR) based on observed 8-week DCR and KRAS mutation status while predictive biomarkers are being developed by means of gene expression profiling, targeted next generation sequencing and protein expression. EGFR sensitizing mutations and EML4/ALK translocation in pts that are erlotinib and crizotinib naïve are exclusion criteria, while erlotinib resistant patients are excluded from erlotinib monotherapy. In Stage 2, the AR model is refined to include the most predictive biomarkers tested in Stage 1, with subsequent Stage 2 AR based on the new algorithm, to a total of 400 evaluable pts. Selection of Stage 2 single and/or composite markers follows a rigorous, internally and externally reviewed statistical analysis that follows a training, testing methodology with validation in stage 2 of the trial. All Stage 1 and 2 randomization biomarker assays are CLIA-certified.

      Results
      286 pts have been enrolled, 236 biopsies performed,172 pts randomized, and 167 pts treated. 144 pts are evaluable for the 8-week DCR endpoint. Within the randomized pts group KRAS mutation rate is 22.8%, and EGFR mutation rate 14.8%, while 36.3% patients have been previously treated with erlotinib. Treatment is well tolerated with no unanticipated toxicity.

      Conclusion
      Accrual updates, demographics, and further details will be presented at the meeting. (Supported by NCI R01CA155196-01A1)

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    P2.10 - Poster Session 2 - Chemotherapy (ID 207)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-009 - Intrinsic and acquired resistance patterns in non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy (ID 853)

      09:30 - 09:30  |  Author(s): P. Saintigny

      • Abstract

      Background
      Platinum-based chemotherapy (PBC) yields clinical benefit in some but not all patients with advanced NSCLC. All patients eventually become resistant to treatment. We assessed degree and timing of onset of tumor regression (TR) and tumor growth (TG) as a surrogate indicator of sensitivity and resistance patterns.

      Methods
      In 130 NSCLC patients on PBC, we assessed percent change in tumor diameter (TG or maximum TR on treatment) compared to pre PBC, and also assessed incremental percent further TR or TG in serial scans compared to the most recent prior scan on treatment.

      Results
      Of the 130 patients, 32 (25%) had intrinsic resistance, with TG at 1[st] repeat scan after 2 cycles of PBC. Only 1 patient with initial TG had later TR on PBC. Among those with TR at 1[st] re-evaluation, pattern of onset of acquired resistance varied: 81 had a 2[nd] repeat scan after 4 cycles of PBC, of whom 20 (25%) had TG. Of 41 patients with earlier TR who then had a 3[rd] repeat scan <4 weeks post PBC cycle 6, 13 (32%) had TG compared to prior scans. In 76% of those with TR, the greatest TR compared to most recent prior scan was seen at the first re-evaluation, with TG or a lower percent TR on later scans. 26 patients had progressive further TR over each of >4 re-evaluation scans, of whom 11 had initial rapid TR at 1[st] re-evaluation, with subsequent more gradual further TR over later scans (a pattern that we designated as “Incremental TR pattern 1”). The other 15 patients with progressive TR over >4 re-evaluation scans had modest initial TR followed by greater TR on a later scan (a pattern that we designated as “Incremental TR pattern 2”). By Spearman coefficients, maximum percent TR from pre PBC (with TG coded as a negative value for TR) correlated with OS (r=0.46, p<0.0001), time to progression (TTP) (r=0.69, p<0.0001) and post-progression survival (PPS) (r=0.30, p=0.001). OS also correlated with TTP (r=0.63, p<0.0001), and PPS correlated with TTP (r=0.44, p<0.0001), and with OS (r=0.95, p<0.0001). Median OS was 11.0 months, and varied with TR pattern (p<0.0001): for patients with first TG at 1[st], 2[nd], 3[rd] and 4[th] repeat scans, median OS was 5.9, 10.8, 10.5 and 15.1 months, respectively. Median OS was 18.2 months in patients with “Incremental TR pattern 1”, and was 30.5 months in patients with “Incremental TR pattern 2”. Median OS with RECIST partial response (23% of patients), minor TR (52%), minor TG (13%) and RECIST progressive disease (13%) was 16.9, 12.4, 9.8 and 4.0 months, respectively (p<0.0001).

      Conclusion
      Intrinsic resistance was noted in 25% of patients. Degree of TR vs TG and patterns of intrinsic and acquired resistance correlated strongly with OS, TTP and PPS, with longest median OS in patients with “Incremental TR pattern 2”. Our observations require confirmation. While numerous biological factors correlate with resistance preclinically, it remains unclear which are most relevant clinically, and it is also unclear what factors may be responsible for the different patterns of clinical resistance observed.