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Julia K Rotow



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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): Julia K Rotow

      • Abstract
      • Slides

      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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      FP14.07 - Combination Osimertinib plus Selpercatinib for EGFR-mutant Non-Small Cell Lung Cancer (NSCLC) with Acquired RET fusions (ID 3402)

      00:00 - 00:00  |  Presenting Author(s): Julia K Rotow

      • Abstract
      • Slides

      Introduction

      Selpercatinib is a highly selective and potent FDA-approved RET inhibitor that has demonstrated marked and durable efficacy in RET fusion-positive NSCLC. While RET fusions are the primary oncogenic driver in ~2% of NSCLC, RET fusions have also been identified as acquired resistance alterations following treatment with EGFR inhibitors, including osimertinib, in EGFR-mutant NSCLC. We sought to evaluate the safety and preliminary efficacy of the combination of osimertinib and selpercatinib in patients progressing on osimertinib.

      Methods

      Patients received selpercatinib in combination with osimertinib across three selpercatinib compassionate access programs: single patient protocols (SPP), named patient programs (NPPs), and an expanded access program (EAP). All patients had advanced EGFR-mutated NSCLC with a RET fusion detected from tissue or plasma following osimertinib therapy. Clinicopathologic and outcomes data were collected retrospectively.

      Results

      Across 12 patients identified, 11 had an EGFR exon 19 deletion (92%) and one had an EGFR L858R mutation (8%). The most common emergent RET fusion was CCDC6-RET (five patients, 42%), followed by NCOA4-RET (four patients, 33%), KIF5B-RET (two patients, 17%), and RUFY2-RET (one patient, 8%). All patients had received prior osimertinib and seven (58%) had also received a 1st or 2nd generation EGFR TKI. Most patients received selpercatinib at 80 mg BID (92%, range 100 mg QD - 120 mg BID) and osimertinib at 80 mg daily (75%, range 40 mg QD - 80 mg BID). Of twelve identified patients, 10 were evaluable for response per RECIST 1.1. Among RECIST evaluable patients five had a response (50%, four confirmed partial responses, one unconfirmed partial response). One patient, unevaluable per RECIST for non-measurable disease at baseline, demonstrated sustained clinical radiographic improvement ongoing at 8.2 months. The second unevaluable patient discontinued treatment prior to reassessment for unrelated clinical events preventing oral medication administration. The median duration of combination treatment across all 12 identified patients was 7.4 months (range 0.6 – 16.7+ months). For patients who achieved a RECIST response, the median treatment duration was 11 months (range 7.4 – 16.7+ months). Treatment was discontinued due to disease progression in seven patients, one patient discontinued for toxicity (grade 2 pneumonitis), one patient for intolerance to oral medication administration, and three patients remained on therapy at data cut-off. In one patient with a response lasting 10 months, plasma sequencing at resistance revealed persistence of EGFR 19del (22% AF) and RET fusion (0.4% AF) plus newly detected second-site resistance mutations in both EGFR (C797S, 0.1%) and RET (G810S, 0.8%), providing additional confirmation of the biologic relevance of the acquired RET fusion.

      Conclusion

      For patients with EGFR-mutant NSCLC with an acquired RET fusion as a mechanism of EGFR inhibitor resistance, the addition of selpercatinib to osimertinib was feasible, with evidence of radiographic responses and durable benefit. These findings support future investigation of this combination, which will be evaluated prospectively as an arm of the phase 2 ORCHARD platform study (NCT03944772). The availability of active combination targeted therapy strategies highlights the need for assessment for genomic mechanisms of resistance following initial EGFR targeted therapy in NSCLC.

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    MA01 - Novel Systemic Treatment in NSCLC (ID 102)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
    • Presentations: 1
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      MA01.02 - Chair (ID 4223)

      11:45 - 12:45  |  Presenting Author(s): Julia K Rotow

      • Abstract

      Abstract not provided

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    P34 - Pathology - Liquid Biopsy (ID 104)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P34.04 - Circulating Tumor DNA (ctDNA) as a Marker of Progressive Disease in Patients with Advanced Lung Cancer  (ID 3421)

      00:00 - 00:00  |  Author(s): Julia K Rotow

      • Abstract
      • Slides

      Introduction

      ctDNA is a novel, non-invasive biomarker that is increasingly investigated and used in the care of patients with cancer. Early applications of this technology relied on its ability to identify the presence of clinically actionable mutations, e.g. the detection of EGFR sensitizing mutation at diagnosis. Recently, there has been growing interest in whether the longitudinal kinetics of this biomarker can predict clinically meaningful endpoints. Ongoing studies are investigating its potential role as a surrogate biomarker of response. However, its ability to predict progression has not been thoroughly investigated, outside of anecdotal data that EGFR T790M concentration levels rise earlier than radiographic progression in some patients progressing on erlotinib. Here, we investigate ctDNA’s ability to predict radiographic progression in advanced lung cancer patients receiving third-generation EGFR TKIs.

      Methods

      Three early-stage clinical trials of third-generation EGFR inhibitors performed at our institution in which patients underwent routine plasma monitoring and standard imaging were studied. Forty patients with detectable EGFR sensitizing mutation (L858R=27.5%; Exon 19 Deletion= 72.5%) in plasma at baseline were analyzed. All patients had stage IV non-small cell lung cancer (NSCLC) and had experienced past progression on EGFR TKI; 92.5% of patients had histopathology-confirmed EGFR T790M mutation at the start of trial. Retrospective analysis was performed to identify date of progressive disease (as defined by RECIST1.1 criteria). ctDNA was assessed via digital droplet PCR and analyzed to identify the date of “plasma progression”, defined as any rise of EGFR sensitizing mutation relative to the prior draw or lack of at least a 50% decrease in ctDNA concentration by the first day of cycle two (21-day cycles).

      Results

      Plasma progression was identified at or before radiographic progression in thirty-three of forty patients (82.5%). Of the ten patients with CNS only progression, plasma progression was identified in 60% of those at or before radiographic progression. Of the thirty patients who had non-CNS progression, plasma progression was identified in 90% of those at or before radiographic progression. Plasma progression occurred at a median of 0.95 months (Range: 0-9.7 months) before radiographic progression in our cohort. Of thirty-two plasma progression events called where a subsequent ctDNA draw was available in the absence of clinical change between results, there were only five “false positives” where the subsequent draw had undetectable ctDNA.

      Conclusion

      These data identify the rise in circulating tumor DNA, “plasma progression”, as a strong predictor of radiographic progressive disease in patients with EGFR mutant NSCLC undergoing targeted therapy with third generation TKIs. Plasma progression was highly sensitive at capturing radiographic progression in non-CNS progression, though its lower performance overall in the subset of patients with CNS only progression is consistent with prior data of low systemic ctDNA shed among CNS tumors (both primary and metastatic). These data lay the groundwork for future studies including the incorporation of ctDNA kinetics into routine clinical care, especially to identify and/or inform progressive disease. Further investigation into early plasma progression relative to radiographic progression may harbour interesting insights about mechanisms of resistance.

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