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Rita Chiari



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    OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
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      OA14.04 - Five-Year Outcomes From the Randomized, Phase 3 Trials CheckMate 017/057: Nivolumab vs Docetaxel in Previously Treated NSCLC (ID 894)

      11:30 - 13:00  |  Author(s): Rita Chiari

      • Abstract
      • Slides

      Background

      Historically, outcomes for advanced non-small cell lung cancer (NSCLC) have been poor, with 5-year survival rates < 5% with conventional chemotherapy. Nivolumab, a programmed death-1 (PD-1) inhibitor, was approved in 2015 for patients with previously treated advanced NSCLC based on two randomized phase 3 trials, CheckMate 017 (NCT01642004; squamous) and CheckMate 057 (NCT01673867; non-squamous), which demonstrated improved overall survival (OS) vs docetaxel. We report 5-year pooled efficacy and safety from these trials, representing the longest survival follow-up for randomized phase 3 trials of an immune checkpoint inhibitor in advanced NSCLC.

      Method

      Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG performance status (PS) ≤ 1, and progression during or after first-line platinum-based chemotherapy, were randomized 1:1 to nivolumab 3 mg/kg Q2W or docetaxel 75 mg/m2 Q3W until progression or unacceptable toxicity. After completion of the primary analyses, patients in the docetaxel arm no longer receiving benefit could cross over to receive nivolumab. OS was the primary endpoint for both studies.

      Result

      At 5-year follow-up, 50 nivolumab patients and 9 docetaxel patients were alive. Baseline characteristics of 5-year survivors in both arms were similar to the overall population and patients who survived < 1 year, except for a higher percentage of patients with ECOG PS 0 or tumor programmed death ligand-1 (PD-L1) expression ≥ 1% on nivolumab and ECOG PS 0 and Stage IIIB NSCLC on docetaxel. Nivolumab continued to show long-term OS and progression-free survival (PFS) benefit vs docetaxel with 5-year OS rates 13% vs 3% (HR, 0.68 [95% CI, 0.59–0.78]) and PFS rates 8% vs 0% (0.79 [0.68–0.92]). OS benefit with nivolumab vs docetaxel was observed across subgroups including patients with tumor PD-L1 expression < 1%, baseline liver and adrenal metastases, neutrophil-to-lymphocyte ratio < median, lactate dehydrogenase ≥ upper limit of normal or no baseline proton-pump inhibitor use. Among patients with an objective response to nivolumab (20%) or docetaxel (11%), 32% remained in response at 5 years vs none on docetaxel, with a median duration of response of 19.9 vs 5.6 months, respectively. Of the 5-year nivolumab vs docetaxel survivors, 36% vs 0% were on study drug, 20% vs 67% received subsequent immunotherapy (on or off study), and 10% vs 0% were off study drug, progression free, with no subsequent therapy. No new safety signals were observed with longer follow-up. Between 3 and 5 years’ follow-up, 8 of the 31 (26%) nivolumab-treated patients reported a treatment-related adverse event, 1 (3%) grade 3–4. The most common select adverse events (events with a potential immunological cause) were related to skin, in 4 (13%) patients, none of which were grade 3–4.

      Conclusion

      CheckMate 017 and 057 are the first phase 3 trials to report 5-year outcomes for a PD-1 inhibitor in previously treated advanced NSCLC, demonstrating a greater than 4-fold increase in 5-year OS rates with nivolumab (13%) over docetaxel (3%). Nivolumab remained well tolerated with no new safety signals.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-84 - Interaction of Lorlatinib with CYP2B6, CYP2C9, UGT, and P-gp Probe Drugs in Patients with Advanced Non-Small Cell Lung Cancer (ID 293)

      09:45 - 18:00  |  Author(s): Rita Chiari

      • Abstract
      • Slides

      Background

      Lorlatinib is a small-molecule anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of patients with ALK-positive advanced non-small cell lung cancer (NSCLC). Because lorlatinib is an inducer and inhibitor of various cytochrome P450 (CYP) enzymes and transporters, an evaluation of its effect on these substrates at steady state is warranted. A drug-drug interaction (DDI) sub-study was conducted in patients with advanced NSCLC to evaluate the net effect of these interactions.

      Method

      Probe drugs utilized included bupropion for CYP2B6, tolbutamide for CYP2C9, acetaminophen for uridine 5'-diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase, UGT), and fexofenadine for P-glycoprotein-1 (P-gp). Thirty-two patients (to have at least 6 evaluable patients per probe drug) were administered a single dose of a probe drug alone on Day −2 to determine plasma exposure of the probe drug alone. Starting on Cycle 1 Day 1, patients began lorlatinib tablets 100 mg daily. On Cycle 1 Day 15, another single dose of the same probe drug was administered concurrently with lorlatinib.

      Result

      Co-administration of lorlatinib 100 mg with bupropion, a sensitive CYP2B6 probe drug, decreased bupropion geometric mean plasma AUCinf and Cmax by 25% and 27%, respectively. For tolbutamide, a sensitive CYP2C9 probe drug, lorlatinib decreased tolbutamide AUCinf and Cmax by 43% and 15%, respectively. Likewise, for acetaminophen, a sensitive UGT substrate, lorlatinib decreased acetaminophen AUCinf and Cmax by 45% and 28%, respectively. Finally, for fexofenadine, a sensitive P-gp substrate, lorlatinib decreased fexofenadine AUCinf and Cmax by 67% and 63%, respectively.

      Conclusion

      Critical steady-state–based DDI evaluations can be conducted in patients with cancer in carefully designed studies. Per FDA guidance, strong, moderate, and weak inducers are drugs that decrease the AUC of sensitive index substrates by ≥80%, ≥50% to <80%, and ≥20% to <50%, respectively. Based on these criteria, lorlatinib behaved as a net weak inducer of CYP2B6, CYP2C9, and UGT; and a net moderate inducer of P-gp. The results of this sub-study can help guide recommendations for dose modifications when lorlatinib is given concomitantly with drugs that are metabolized by these enzymes or transporters. Based on the current results, only drugs that are P-gp substrates of narrow therapeutic index may require dose adjustments when used concomitantly with lorlatinib.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-03 - Molecular Determinants for Lorlatinib Activity in ROS1 Positive NSCLC: Results of the Prospective PFROST Trial (ID 1566)

      09:45 - 18:00  |  Author(s): Rita Chiari

      • Abstract

      Background

      Lorlatinib, an ALK/ROS1 inhibitor, demonstrated activity in ROS1+ NSCLC pretreated with crizotinib. However, molecular events predictive for tumor response during lorlatinib treatment are largely unknown.

      Method

      PFROST was a prospective phase II trial designed to include ROS1+ NSCLC refractory to crizotinib. Eligible patients were treated with lorlatinib at the daily dose of 100 mg until disease progression. Primary end point was response rate (RR). For all included patients pre-lorlatinib tumor tissue or blood sample collection was mandatory. At the time of lorlatinib failure liquid biopsy was recommended. The samples were then run with the NEOliquid assay, specifically designed for liquid biopsies, or NEOselect, a panel optimized for formalin-fixed paraffin-embedded (FFPE) tumor tissue, covering 39 cancer related genes.

      Result

      From June 2017 to April 2019, 22 ROS1+ crizotinib refractory lung adenocarcinoma patients were included in 10 Institutions. Median age was 56 years (range 39-82); male/female: 8/14; ECOG PS 0 (N=8; 36.4%), PS1 (N=14; 63,6%); The majority had brain metastases at baseline (N=15; 68.1%), were never smokers (N=13; 59.1%) and received lorlatinib as third line therapy (N=16; 72.7%). In all cases crizotinib was the last therapy line before lorlatinib. At the time of the present analysis, trial completed its accrual and 13 patients are still receiving therapy. A total of 18 patients were evaluable for response and 7 had confirmed complete (N=1) or partial (N=6) responses for an overall RR of 38.8%. In 4 patients, response to therapy was not yet evaluated. A total of 10 tissue biopsies and 20 blood samples obtained after crizotinib and before lorlatinib therapy were collected. For 7 samples analyses are ongoing. Among responders, no patient harbored a secondary ROS1 mutation. Conversely, no response was observed among patients with secondary ROS1 mutations (N= 1 ROS1S1861I, N=1 ROS1 V2054A, N=3 ROS1G2032R). All patients harboring the ROS1G2032R mutation rapidly progressed and maintained this aberration in liquid biopsy at the time of radiological evidence of lorlatinib failure.

      Conclusion

      In our study lorlatinib confirmed its efficacy in crizotinib resistant ROS1+ NSCLC. Molecular profile of refractory patients suggests reduced efficacy in individuals developing secondary ROS1 mutations after crizotinib failure.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-84 - NSCLC Survival Expectancy for Patients Treated with Docetaxel/Nintedanib in the SENECA Trial and Previous Immunotherapy (ID 807)

      10:15 - 18:15  |  Author(s): Rita Chiari

      • Abstract
      • Slides

      Background

      The phase IIb SENECA trial was an Italian real-world experience recently ended, which demonstrated similar progression free survival (PFS) and overall survival (OS) in non-squamous non-small cell lung cancer (nsNSCLC) patients treated with second-line docetaxel/nintedanib, regardless the relapsing-time from end of first-line chemotherapy and the docetaxel schedule employed (weekly or q3wks), with a slightly higher toxicity-trend in the q3wks arm. During accrual period (January 2016-April 2018), no therapeutic alternative to the use of docetaxel was available for patients with recurrent nsNSCLC until April 2017, when the first immune-checkpoint inhibitor was approved and reimbursed in Italy in this setting. At that point, the study was amended allowing enrolment of patients previously treated with immunotherapy (IT). Because of the lack of data about the optimal therapeutic algorithm in this context, aim of the present evaluation is to investigate if survival expectancy of patients treated with docetaxel/nintedanib could positively influenced when previously treated with IT.

      Method

      In the SENECA trial, 212 nsNSCLC patients, progressing after first-line chemotherapy, were treated with docetaxel plus continuous oral nintedanib, with the possibility of maintenance in case of stabilization or response. This evaluation focus on 16 patients previously treated with IT and compares them to the rest of patient population. Survival analysis is performed using Kaplan Meier curves; Hazard Ratios (HR) with 95% Confidence Interval (95%CI) are reported to compare the two groups.

      Result

      Patients treated with IT (2 combined with first-line chemotherapy, 14 alone) correspond to 7.5% of the entire study population; they were 9 males and 7 females, with a median age of 62.5 years, mainly current or former-smokers, with an ECOG-performance status 0 in 93.7% of cases. At the cut-off date (December 25th, 2018), after a median follow-up of 35.5 months, no significant differences appear between patients previously treated with IT and the other ones in terms of PFS (5.84 vs 4.31 months, respectively; HR 0.564 [95% CI 0.283-1.122], p-value=0.1029), and OS (9.37 vs 9.02 months, respectively; HR 1.108 [95% CI 0.393-3.123], p-value=0.8456). No significant differences have been observed also in disease-control rates (80.0% vs 66.7%, p-value=0.5436).

      Conclusion

      Despite this report does not show a greater survival expectancy for patients treated with docetaxel/nintedanib and previous IT, it's likely that the small sample size may affect this result. The longer PFS and greater disease-control rate are attractive hints for future evaluations with larger sample sizes, supposing a new therapeutic algorithm for recurrent nsNSCLC patients.

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