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Lecia V. Sequist
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FP01 - Early Stage/Localized Disease (ID 111)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP01.05 - The ASCENT Trial: A Phase II Study of Neoadjuvant/Adjuvant Afatinib, Chemoradiation +/- Surgery for Stage III EGFR-Mutant NSCLC (ID 3752)
00:00 - 00:00 | Author(s): Lecia V. Sequist
- Abstract
Introduction
The ADAURA trial showed benefit to adjuvant osimertinib in stage III EGFR-mutant (EGFRm) NSCLC, but the role of TKI induction is unknown. In 2011, we began ASCENT, a phase II trial of neoadjuvant and adjuvant afatinib in addition to standard of care (SOC) curative-intent therapy for EGFRm stage III NSCLC (NCT01553942). The study closed early for slow accrual. This is the final analysis.
Methods
ASCENT enrolled patients with EGFRm, stage IIIA/B (AJCC 7th ed.) NSCLC amenable to curative-intent chemoradiation therapy (CRT) ± surgery. Resectability was determined by the treating multidisciplinary team at diagnosis. Patients received neoadjuvant afatinib 40mg QD x 2 months, then concurrent CRT (up to 4 cycles of cisplatin/pemetrexed and 3D conformal RT or intensity-modulated RT personalized to tumor size, site, operability) +/- surgery and an optional 2 years of adjuvant afatinib. The primary outcome was objective response rate (ORR) to neoadjuvant afatinib. Major pathologic response (MPR) was defined as < 10% residual tumor at resection, complete pathologic response (CPR) as no residual tumor.
Results
19 patients (14F/5M), median age 56 (range 34-75) were enrolled. 12 had EGFR del19, 7 L858R. 10 were classified as potentially resectable stage IIIA at diagnosis, 9 as unresectable IIIA/B. All completed two months of neoadjuvant afatinib; 5 (26%) required afatinib dose reduction. The ORR after neoadjuvant afatinib was 11/19 (58%; 95% CI, 33-80%). 1 patient initially deemed inoperable became a surgical candidate based on response to neoadjuvant afatinib; 2 patients progressed on neoadjuvant afatinib or exhibited findings that clarified their presenting stage as IV; both discontinued the protocol. The remaining 17 patients proceeded to CRT with pre-op median radiotherapy dose of 54 Gy (range 45-66; n=10), definitive median dose of 67 Gy (range 63-72; n=7). Among 10 patients who underwent resection (all via lobectomy), the MPR rate was 70% (6 MPR, 1 CPR). 13 (68%) patients started adjuvant afatinib after surgery (7) or definitive CRT (6); 4 completed 2 years, 3 discontinued early (median 1.5 months), 2 recurred during adjuvant afatinib and 4 remain on adjuvant therapy. Key grade 3/4 toxicities included rash (n=6), diarrhea (5), esophagitis (3), nausea (3), pneumonitis (2) and febrile neutropenia (1); there were no treatment-related deaths. With median follow-up of 30.6 months (range 3.1-96.3), 9 (47%) patients have recurred, with 5/9 having CNS-only recurrence. Recurrences occurred in 3/10 surgical patients and 5/7 definitive CRT patients. Median PFS was 34.6 months (95% CI 16.9-66.1) and median OS was 69.1 months (95% CI 29.4-NR). 2-year OS is 88% (95% CI 59-97%).
Conclusion
In stage III EGFRm NSCLC, 2 months of neoadjuvant afatinib is associated with an ORR comparable to that seen in advanced disease and does not impair receipt of SOC chemoradiotherapy ± surgery. PFS and OS are favorable in this single-arm study. The high rate of CNS-only recurrence highlights a potential for improved outcomes with more CNS-penetrant EGFR TKIs. Along with the interim results of ADAURA, these results support genotype-directed therapies in stage III EGFRm NSCLC, though the optimal sequence of TKI therapy will need to be defined.
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FP14 - Targeted Therapy - Clinically Focused (ID 252)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP14.03 - Osimertinib + Savolitinib in pts with EGFRm MET-Amplified/Overexpressed NSCLC: Phase Ib TATTON Parts B and D Final Analysis (ID 3312)
00:00 - 00:00 | Author(s): Lecia V. Sequist
- Abstract
- Presentation
Introduction
Preliminary data from TATTON (NCT02143466, a multi-arm, multi-drug combination study) suggested that savolitinib, a potent and highly selective MET-tyrosine kinase inhibitor (TKI), plus osimertinib, a third-generation, irreversible, oral epidermal growth factor receptor (EGFR)-TKI, that potently and selectively inhibits T790M and EGFR mutations (EGFRm), may overcome MET-based resistance to EGFR-TKIs in NSCLC. We present the final data from two TATTON expansion cohorts (TATTON Parts B and D); data cutoff 4 March 2020.
Methods
Adult patients with locally advanced/metastatic, MET-amplified/overexpressed, EGFRm NSCLC, and disease progression on a prior EGFR-TKI. Most patients had retrospective, central confirmation of MET status by local fluorescent in-situ hybridisation (MET gene copy ≥5 or MET/CEP7 ratio ≥2), next-generation sequencing or immunohistochemistry (+3 in ≥50% of tumour cells). In Part B, patients received osimertinib 80 mg plus savolitinib 600 mg orally once daily; after a protocol amendment, patients ≤55 kg received savolitinib 300 mg. In Part D, patients who had received no prior third-generation EGFR-TKI and were T790M-negative, received osimertinib plus savolitinib 300 mg. The primary endpoint was safety/tolerability; secondary endpoints included objective response rate (ORR), progression-free survival (PFS) and pharmacokinetics.
Results
In Parts B and D, 138 and 42 patients respectively, received treatment. Grade ≥3 adverse events (AEs) were reported in 62% and 50% of patients, in Parts B and D respectively; serious AEs were reported in 49% and 38% of patients, respectively. AEs led to discontinuation of savolitinib in 49 (36%) and 15 (36%) patients, and osimertinib in 24 (17%) and 8 (19%) patients, for Parts B and D, respectively. In Part B, seven patients died due to AEs; two cases were possibly treatment-related. In Part D, two patients died due to AEs; neither was considered treatment-related. PFS and ORR results are included in the Table. Pharmacokinetics of savolitinib and osimertinib were consistent with other patient populations in TATTON and previous studies.
Conclusion
Osimertinib plus savolitinib was generally well tolerated and the safety profile was in-line with that previously reported. Our results support that osimertinib plus savolitinib may overcome MET-based resistance in patients with NSCLC whose disease has progressed on prior EGFR-TKI. Further exploration of the osimertinib plus savolitinib combination is underway in the SAVANNAH (NCT03778229) and ORCHARD (NCT03944772) studies.
Table
Part B: osimertinib 80 mg + savolitinib 600/300* mg
Part D: osimertinib 80 mg + savolitinib 300 mg
Endpoint
Previously treated with a 3G EGFR-TKI
No prior 3G EGFR-TKI, T790M-negative
No prior 3G EGFR-TKI, T790M-positive
No prior 3G EGFR-TKI, T790M-negative
n=69
n=51
n=18
n=42
ORR†, n (%)
[95% CI]
23 (33)
[22.4, 45.7]
33 (65)
[50.1, 77.6]
12 (67)
[41.0, 86.7]
26 (62)
[45.6, 76.4]
Median PFS, months
[95% CI]5.5
[4.1, 7.7]9.1
[5.5,12.8]11.1
[4.1,22.1]9.0
[5.6, 12.7]Total PFS events, n (%)
51 (74)
36 (71)
12 (67)
29 (69)
* Most patients were enrolled to 600 mg savolitinib, prior to weight-based dosing implementation, but following a protocol amendment, the final 21 patients enrolled in Part B were dosed with savolitinib by body weight as follows: patients who weighed ≤55 kg (n=7) received 300 mg daily and those weighing >55 kg (n=14) received 600 mg daily
†All confirmed responses were partial response.
3G, third generation; CI, confidence interval; ORR, objective response rate; PFS, progression-free survival
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