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David Kozono
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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): David Kozono
- 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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P79 - Immunotherapy (Phase II/III Trials) - Immunotherapy Plus Chemotherapy (ID 256)
- Event: WCLC 2020
- Type: Posters
- Track: Immunotherapy (Phase II/III Trials)
- Presentations: 2
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P79.01 - TCR Sequencing to Identify Responders in Patients with Stage III NSCLC Treated with Atezolizumab with Chemoradiation (AFT-16) (ID 3201)
00:00 - 00:00 | Author(s): David Kozono
- Abstract
Introduction
Immune checkpoint therapies have significantly enhanced overall survival for non-small cell lung cancer (NSCLC), but whether a specific patient will respond to therapy remains difficult to predict. We propose an approach of using T cell receptor (TCR) sequencing to address this uncertainty by comparing the T cell immune repertoires of patients with partial response (PR) to the repertoires of patients with progressive disease (PD), based on RECIST criteria.
Methods
We conducted a multi-institutional phase II Alliance Foundation Trials study, AFT-16 (NCT03102242), to explore the safety and efficacy of atezolizumab before and after chemoradiation (CRT). 63 patients with stage IIIA/B NSCLC and performance status 0-1 were enrolled with the plan to receive 4 cycles of neoadjuvant atezolizumab (1200 mg IV q 21 days) with restaging scans after cycles 2 and 4. Non-progressing patients continued on to receive carboplatin and paclitaxel (C/P) weekly with 60 Gy RT in 30 fractions, followed by 2 cycles of C/P consolidation and up to 9 months of additional adjuvant atezolizumab therapy. Peripheral blood mononuclear cell samples were collected before and after neoadjuvant treatment, and genomic DNA was isolated (gDNA). Survey resolution sequencing of the TCR CDR3 region was conducted using the immunoSEQ v3 platform (Adaptive Biotechnologies, Seattle, WA). We focused on blood samples from pre-therapy and after 2 or 4 cycles of atezolizumab. The pre-treatment and post-treatment Simpson clonality, observed richness, productive fraction, and nucleotide to amino acid convergence were calculated for all patients (pre-treatment: 18 PR, 12 PD; post-treatment: 17 PR, 7 PD). Significance was determined using the Mann-Whitney U test. These variables before treatment were used to train a random forest classifier. 100 trees and all four variables were considered at non-leaf nodes. The number of trees and variables were optimized by asymptotically minimizing out-of-bag error. Clonotypes that were significantly expanded or contracted after treatment were identified using a beta-binomial differential abundance model for patients with paired samples (16 PR, 7 PD).
Results
There are no significant differences in the clonality, richness, and convergence between patients who demonstrated PR and PD before or after treatment. The productive fraction was significantly higher for patients demonstrating PD compared to PR before treatment (P = .02), and after treatment (P = .03). The random forest produced a 23.3% out-of-bag error (class errors: PR: 0.17, PD: 0.33; random classifier error: 30%) in predicting outcomes using pre-treatment variables. PR patients demonstrated an average of 3.63 contracted clonotypes while PD patients demonstrated an average of 0.29 (P = 0.046).
Conclusion
Preliminary evidence suggests that there are detectable differences in the immune repertoires of patients demonstrating PR versus PD and that the differences before treatment may be used for early outcome prediction. Current shortcomings include the absence of tumor TCR sequencing, small numbers of patients, and low sequencing resolution that limit predictive machine learning. Future analysis will ideally include tumor TCR sequencing, comparisons of immune repertoires of additional patients, and “deep” sequencing data. We will also correlate TCR sequencing with clinical outcomes once these data are mature.
Support: Alliance Foundation Trials; Genentech. https://acknowledgments.alliancefound.org
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P79.06 - CHIO3: ChEmotherapy Combined with Immune Checkpoint Inhibitor for Operable Stage IIIA/B Non-Small Cell Lung Cancer (AFT-46) (ID 1916)
00:00 - 00:00 | Author(s): David Kozono
- Abstract
Introduction
Stage IIIA/B (T1-3, N2) non-small cell lung cancer (NSCLC) continues to be a clinical challenge with 5‑year survival of 15%-40%. Both local and distant recurrence plagues this population. Optimal management remains uncertain. Intergroup 0139 showed a doubling of survival in the subset of patients treated with chemoradiotherapy (CRT) followed by lobectomy versus CRT alone (36% vs. 18%, 5‑year survival, p=0.002). The addition of immunotherapy to CRT has shown promising results in the PACIFIC trial, in a nonoperative stage III population (HR for overall survival=0.69; 95% CI 0.55-0.86 compared to CRT only). Interest has grown in combining four modes of therapy in a manner that minimizes toxicity; this has potential to transform the historically poor outcomes for operable stage III NSCLC.
The population targeted in this trial is operable stage IIIA/B NSCLC, with histologically documented N2 disease. We seek to assess the feasibility and clinical impact of combined platinum doublet chemotherapy with 1125 mg durvalumab for operable stage III NSCLC as neoadjuvant therapy prior to anatomic resection, followed by postoperative radiation to 50-54 Gy, and subsequently durvalumab 1500 mg IV q 4 weeks for 1 year (Figure).
Methods
Patients with resectable Stage IIIA/B (T1-3 N2) NSCLC with biopsy proven N2 nodal involvement, performance status 0-1, adequate organ function and no contraindication for immunotherapy are potentially eligible. Target enrollment is 55 patients, anticipating 42 will undergo resection. Our hypothesis is that N2 nodal clearance (N2NC) will be higher (50% or greater) for neoadjuvant platinum doublet chemotherapy with durvalumab than historically observed (30% on average) for platinum doublet chemotherapy alone. The N2NC rate is the primary endpoint. In addition there will be a number of secondary endpoints including assessment of pathologic response, safety and tolerability, and overall survival.
Support: AFT, Astra-Zeneca; https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT04062708
