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Hidetoshi Hayashi
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MA03 - Clinomics and Genomics (ID 119)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Heather A Wakelee, Wilfried Ernst Erich Eberhardt
- Coordinates: 9/08/2019, 10:30 - 12:00, Colorado Springs (1994)
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MA03.11 - Chemotherapy After PD-1 Inhibitors Versus Chemotherapy Alone in Patients with Non–Small Cell Lung Cancer (WJOG10217L) (Now Available) (ID 409)
10:30 - 12:00 | Author(s): Hidetoshi Hayashi
- Abstract
- Presentation
Background
Studies have suggested that chemotherapy after immune checkpoint inhibitors may confer an improved response in patients with non–small cell lung cancer (NSCLC). However, potential selection bias in such studies has not been addressed. We therefore applied propensity score analysis to investigate the efficacy of subsequent chemotherapy after PD-1 inhibitors (CAP) compared with chemotherapy alone.
Method
We conducted a multicenter retrospective cohort study for patients with advanced or recurrent NSCLC who were treated at 47 institutions across Japan between 1 April 2014 and 31 July 2017 with chemotherapy (docetaxel with or without ramucirumab; S-1; or pemetrexed) either after PD-1 inhibitor therapy (CAP cohort) or alone (control cohort). The primary end point was objective response rate (ORR). Inverse probability weighting (IPW) was applied to adjust for potential confounding factors, including age, sex, smoking status, performance status, histology, EGFR or ALK genetic alterations, brain metastasis, and recurrence after curative radiotherapy.
Result
A total of 1439 patients (243 and 1196 in the CAP and control cohorts, respectively) was available for unadjusted analysis. Several baseline characteristics—including age, histology, EGFR or ALK alterations, and brain metastasis—differed significantly between the two cohorts. After adjustment for patient characteristics with the IPW method, ORR was 18.9% for the CAP cohort and 10.8% for the control cohort (ORR ratio, 1.75; 95% confidence interval [CI], 1.25–2.45; P = .001). Median PFS was 3.5 and 2.6 months for the CAP and control cohorts, respectively (hazard ratio [HR], 0.862; 95% CI, 0.743–0.998; P = .048). The PFS rate at 3, 6, and 12 months was 53.3%, 28.5%, and 4.6%, respectively, for the CAP cohort, and 44.3%, 19.7%, and 6.1% for the control cohort. Median OS was 9.8 months for the CAP cohort and 10.3 months for the control cohort (HR, 0.979; 95% CI, 0.813–1.179; P = .822).
Conclusion
After adjustment for selection bias using propensity score–weighted analysis, CAP showed a significantly higher ORR and longer PFS compared with chemotherapy alone, with the primary end point of ORR being achieved. However, these results did not translate into an OS advantage, and no PFS benefit was apparent at 12 months despite the improvement observed at 3 and 6 months. Our findings suggest that prior administration of PD-1 inhibitors may result in a synergistic antitumor effect with subsequent chemotherapy, but that such an effect is transient. CAP therefore does not appear to achieve durable tumor control or confer a lasting survival benefit.
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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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P1.01-103 - Preliminary Results of Brigatinib in Japanese Patients (Pts) Who Previously Received Alectinib: Brigatinib-2001 Study (ID 1180)
09:45 - 18:00 | Author(s): Hidetoshi Hayashi
- Abstract
Background
Brigatinib is a next-generation ALK inhibitor with broad preclinical activity against ALK resistance mutations. To evaluate efficacy and safety of brigatinib in Japanese pts, a single-arm, multicenter, phase 2 study of brigatinib in pts with ALK-positive NSCLC (NCT03410108) in Japan is ongoing, with the primary endpoint of objective response rate (ORR) by independent review. This study has a safety evaluation lead-in phase to confirm the tolerability and pharmacokinetics of brigatinib with a small number of Japanese pts prior to the expansion phase. Here we report the preliminary results from pts in the safety lead-in phase who had been heavily pre-treated with ALK tyrosine kinase inhibitors (TKIs), including alectinib and ceritinib.
Method
Stage IIIB, IIIC, or IV NSCLC with documented ALK rearrangements were enrolled. Up to 4 ALK TKIs (alectinib, ceritinib, crizotinib and lorlatinib) and 3 lines of prior other systemic anti-cancer treatment were allowed only for the safety evaluation lead-in phase. Brigatinib of 180 mg QD with 90 mg QD lead-in for the first 7 days (90→180mg QD) was administered and efficacy was evaluated every 8 weeks.
Result
All 9 pts previously received prior alectinib, of whom 6 received 2 or more prior ALK TKIs. The standard dose of 90→180mg QD was well tolerated among Japanese pts. Only 1 dose-limiting toxicity (DLT) was observed: grade 3 lipase increase without clinical evidence of pancreatitis. The most common AEs were increased blood creatine phosphokinase (n=7), increased aspartate aminotransferase (n=6), and hypertension (n=5). By investigator assessment, 5 of 9 pts (56%) had confirmed partial response by the end of cycle 6. Tumor samples from 5 pts were collected prior to the start of brigatinib treatment, and 2 cases had secondary mutation, including one pt with a G1202R mutation who had a confirmed partial response to brigatinib by investigator assessment. Intensive PK sampling data in Japanese pts are comparable with those in non-Japanese pts.
Conclusion
Standard dose of brigatinib 90→180mg is tolerable in Japanese pts and show promising preliminary anti-tumor activity in the post-alectinib setting.
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P1.04 - Immuno-oncology (ID 164)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.04-40 - Serum Perforin Levels During the First Cycle of Anti-PD-1 Antibody Therapies in Non-Small Cell Lung Cancer (ID 1662)
09:45 - 18:00 | Author(s): Hidetoshi Hayashi
- Abstract
Background
Blockade of PD-1 pathways by anti-PD-1 antibodies restore the function of exhausted T cells and release perforin and granzyme B which induce cytotoxic activity against tumor cells. We examined serum perforin and granzyme B as biomarkers of response to nivolumab and pembrolizumab in non-small cell lung cancer (NSCLC) patients.
Method
Advanced NSCLC patients treated with nivolumab or pembrolizumab were studied. Serum were collected on days 1, 2, 8 and 15 for nivolumab and on days 1, 2, 8, 15 and 22 for pembrolizumab. Concentration of perforin and granzyme B was determined by enzyme-linked immunosorbent assay (ELISA). Best objective response was evaluated by Evaluation Criteria in Solid Tumors (RECIST) 1.1.
Result
Sera from 40 patients with nivolumab and 26 patients with pembrolizumab were analyzed. Optimal cutoff levels for baseline concentration of perforin (day 1) were determined by efficacy. The calculated optimal cutoff levels were 5450.46 pg/ml with nivolumab (area under the receiver-operating-characteristic curve [AUC], 0.703) and 6631.16 pg/ml with pembrolizumab (AUC, 0.806). With nivolumab, median progression-free survival (PFS) was 6.8 months (95% confidence interval [CI], 2.8 to 3.7) in high concentration group (85%) versus 0.7 months (95% CI, 0.13 to not reached) in low concentration group (15%; hazard ratio [HR] for disease progression or death, 0.24; 95% CI, 0.09 to 0.68, p=0.007). Median overall survival (OS) was 14.9 months (95% CI, 10.2 to not reached) in high concentration group versus 1.8 months (95% CI, 0.13 to not reached) in low concentration group (HR for death, 0.19, 95% CI, 0.05 to 0.78, p=0.022). With pembrolizumab, median PFS was 6.7 months (95% CI, 3.5 to not reached) in high concentration group (73%) versus 0.7 months (95% CI, 0.37 to 5.7) in low concentration group (26%; HR for disease progression or death, 0.31; 95% CI, 0.11 to 0.89; p=0.03). Median OS was not reached (95% CI, 7.9 to not reached) in high concentration group versus 2.1 months (95% CI, 0.57 to not reached) in low concentration group (HR for death, 0.2; 95% CI, 0.05 to 0.77; p=0.018). Ratios of sequential perforin levels to baseline levels were analyzed, however, their AUC were not high enough, considered as low predictive power. Serum granzyme B was difficult to measure by ELISA.
Conclusion
With anti-PD-1 antibody therapies, in patients with advanced NSCLC, higher baseline serum perforin levels before treatment were associated with significantly longer progression-free and overall survival.
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P2.14 - Targeted Therapy (ID 183)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.14-15 - Impact of Coexisting Gene Mutations in EGFR-Mutated Non–Small Cell Lung Cancer Before Treatment on EGFR T790M Mutation Status After EGFR-TKIs (ID 1347)
10:15 - 18:15 | Author(s): Hidetoshi Hayashi
- Abstract
Background
The T790M secondary mutation of epidermal growth factor receptor gene (EGFR) is the most common mechanism of acquired resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). We investigated the association between gene mutation profile in EGFR mutation–positive non–small cell lung cancer (NSCLC) before EGFR-TKI treatment and T790M status after treatment.
Method
A total of 57 EGFR mutation–positive NSCLC patients who had undergone a repeat biopsy (tissue or liquid) after failure of treatment with a first- or second-generation EGFR-TKI and who had sufficient tumor tissue available from before treatment for genetic analysis was enrolled. The gene mutation profile of tumor tissue obtained before EGFR-TKI treatment was evaluated by next-generation sequencing with a comprehensive cancer gene panel (409 genes). The number of potentially damaging nonsynonymous mutations was predicted with PolyPhen-2 software.
Result
Progression-free survival during EGFR-TKI treatment did not differ significantly between patients who developed T790M-mediated resistance and those who developed T790M-independent resistance. The predicted number of damaging nonsynonymous mutations in pretreatment tumor tissue was significantly lower in patients who developed T790M-mediated resistance than in those with T790M-independent resistance (P = 0.024).
Conclusion
Coexisting mutations in tumor tissue before EGFR-TKI treatment may contribute to the emergence of cell clones responsible for development of T790M-dependent or T790M-independent TKI resistance in patients with EGFR-mutated NSCLC. Multiplex genomic testing of pretreatment tumor tissue may thus provide a means of identifying patients likely to develop T790M-mediated TKI resistance and therefore inform treatment selection.
