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Ryo Toyozawa
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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): Ryo Toyozawa
- 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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PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)
- Event: WCLC 2019
- Type: Plenary Session
- Track:
- Presentations: 1
- Now Available
- Moderators:Giorgio Vittorio Scagliotti, Ramon Rami-Porta
- Coordinates: 9/09/2019, 08:00 - 10:15, Barcelona (2005)
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PL02.08 - Registrational Results of LIBRETTO-001: A Phase 1/2 Trial of LOXO-292 in Patients with RET Fusion-Positive Lung Cancers (Now Available) (ID 964)
08:00 - 10:15 | Author(s): Ryo Toyozawa
- Abstract
- Presentation
Background
No targeted therapy is currently approved for patients with RET fusion-positive non-small cell lung cancer (NSCLC). LOXO-292 is a highly selective RET inhibitor with activity against diverse RET fusions, activating RET mutations and brain metastases. Based on initial data from LIBRETTO-001, LOXO-292 received FDA Breakthrough Designation for the treatment of RET fusion-positive NSCLC in August 2018.
Method
This global phase 1/2 study (87 sites, 16 countries) enrolled patients with advanced RET-altered solid tumors including RET fusion-positive NSCLC (NCT03157128). LOXO-292 was dosed orally in 28-day cycles. The phase 1 portion established the MTD/RP2D (160 mg BID). The phase 2 portion enrolled patients to one of six cohorts based on tumor type, RET alteration, and prior therapies. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints included DoR, CNS ORR, CNS DoR, PFS, OS, safety and PK.
Result
As of 17-June 2019, 253 RET fusion-positive NSCLC patients were treated. The primary analysis set (PAS) for LOXO-292 registration, as defined with the US FDA, consists of the first 105 consecutively enrolled RET fusion-positive NSCLC patients who received prior platinum-based chemotherapy; 58 patients (55%) also received prior anti PD-1/PD-L1 agents. The majority of PAS responders have been followed for ≥6 months from first response. Of the remaining 148 patients, 79 had previously been treated with platinum-based chemotherapy, 55 did not receive prior platinum-based chemotherapy and 14 did not have measurable disease at baseline.
Conclusion
Among PAS patients, the investigator-assessed ORR was 68% (95% CI 58-76%, n=71/105, 2 PRs pending confirmation). Responses did not differ by fusion partner or the type or number of prior therapies, including chemotherapy, anti PD-1/PD-L1 agents and multikinase inhibitors with anti-RET activity. The median DoR was 20.3 months (95% CI 13.8-24.0) with a median follow-up of 8 months; as evidenced by the wide confidence interval, this DoR estimate is not statistically stable due to a low number of events (16 of 69 confirmed responders). The intracranial ORR was 91% (n=10/11: 2 confirmed CRs, 8 confirmed PRs) for patients with measurable brain metastases at baseline.
The ORR in efficacy evaluable treatment naïve RET fusion-positive NSCLC patients was 85% (95% CI 69-95%, n=29/34, 7 PRs pending confirmation). In the safety data set of all 531 patients, 5 treatment-related AEs occurred in ≥15% of patients: dry mouth, diarrhea, hypertension, increased AST and increased ALT. Most AEs were grade 1-2. Only 9 of 531 (1.7%) patients discontinued LOXO-292 for treatment-related AEs.
LOXO-292 had marked antitumor activity in RET fusion-positive NSCLC patients and was well tolerated. These data will form the basis of an FDA NDA submission later this year.
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