Virtual Library
Start Your Search
Jyoti D Patel
Author of
-
+
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
-
+
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 | Author(s): Jyoti D Patel
- Abstract
- Presentation
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.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
MA11 - Expanding Targetable Genetic Alterations in NSCLC (ID 251)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/31/2021, 14:15 - 15:15, Scientific Program Auditorium
-
+
MA11.09 - Efficacy and Safety of Larotrectinib in Patients with Tropomyosin Receptor Kinase (TRK) Fusion Lung Cancer (ID 1796)
14:15 - 15:15 | Author(s): Jyoti D Patel
- Abstract
Introduction
Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers that occur in a wide range of tumor types. Larotrectinib, a highly selective Food and Drug Administration and European Medicines Agency approved TRK inhibitor, demonstrated an objective response rate (ORR) of 79% and a median duration of response (DoR) of 35 months across multiple cancers (Hong et al. Lancet Oncol 2020). Here we report updated data for patients with TRK fusion lung cancer assessed by independent review committee (IRC) and investigators (INV).
Methods
Patients with lung cancer harboring an NTRK gene fusion enrolled in two clinical trials (NCT02122913 and NCT02576431) were included in this analysis. Larotrectinib 100 mg twice daily was administered on a continuous 28-day schedule. Response was assessed by IRC and by INV per RECIST v1.1.
Results
As of July 15, 2019, 14 patients with metastatic TRK fusion lung cancer were enrolled: 13 with non-small cell lung cancer (NSCLC) and 1 patient with small cell lung cancer (SCLC). Seven (6 NSCLC, 1 SCLC) patients had baseline central nervous system (CNS) metastases. The median age was 52 years (range 25–76). Eleven patients (79%) had fusions involving NTRK1 and three patients (21%) had fusions involving NTRK3. Patients were heavily pre-treated with a median of three prior therapies (range 1–5). Among 13 IRC-evaluable patients the ORR was 77% (95% confidence interval [CI] 46–95). ORR was 71% (95% CI 42–92) per INV. ORR in patients with CNS metastases was 71% (95% CI 29–96) and 57% (95% CI 18–90) per IRC and per INV, respectively (Table). The overall DoR per IRC ranged from 3.6 to 36.8+ months. The median progression-free survival (PFS) had not been reached (range 1.8 to 30.3+ months), with an estimated PFS rate at 12 months of 69%. Larotrectinib was well tolerated, with treatment-emergent adverse events being mainly Grade 1–2.
ConclusionAll patients
(N=14)Patients with brain
metastases at baseline
(n=7)INV
IRC†
INV
IRC
ORR, % (95% CI)
71 (42–92)
77 (46–95)
57 (18–90)
71 (29–96)
CR, n (%)
1 (7)
2 (15)
0
0
PR, n (%)
9 (64)
8 (62)
4 (57)
5 (71)
SD, n (%)
3 (21)
3 (23)
2 (29)
2 (29)
PD, n (%)
1 (7)‡
0
1 (14)‡
0
†IRC data missing for one patient. ‡Extracranial progression detected.
CI, confidence interval; CR, complete response; INV, investigator assessment; IRC, independent review committee assessment; PD, progressive disease; PR, partial response; SD, stable disease.
In this updated dataset, larotrectinib was shown to be highly active in patients with advanced lung cancer harboring NTRK gene fusions, including those with CNS metastases. The drug has a favorable safety profile. These results support inclusion of NTRK gene fusions in the routine molecular testing of patients with lung cancer.
-
+
OA07 - Immuno-biology and Novel Immunotherapeutics from Bench to Bed (ID 228)
- Event: WCLC 2020
- Type: Oral
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 1
- Moderators:
- Coordinates: 1/30/2021, 10:30 - 11:30, Scientific Program Auditorium
-
+
OA07.01 - Chair (ID 4229)
10:30 - 11:30 | Presenting Author(s): Jyoti D Patel
- Abstract
Abstract not provided
-
+
P14 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Immuno-Biology (ID 153)
- Event: WCLC 2020
- Type: Posters
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
-
+
P14.27 - Pathogenic Genomic Alterations of CDKN2A Predict Immunotherapy Resistance in NSCLC (ID 2353)
00:00 - 00:00 | Author(s): Jyoti D Patel
- Abstract
Introduction
Immune checkpoint blockade (ICB) has improved outcomes for patients with non-small cell lung cancer (NSCLC). However, most patients experience disease progression. There are limited data regarding molecular predictors of progression, particularly in those patients predicted to respond most favorably. We used a next-generation sequencing (NGS) platform to identify genomic aberrations associated with clinical outcomes following ICB in NSCLC.
Methods
We retrospectively reviewed NSCLC patients who received ICB at our institution and underwent NGS with “OncoPlus”, a proprietary 1212-gene hybrid capture genomic sequencing assay. We characterized tumor mutations and copy number variations and investigated their associations with clinical outcome.
Results
139 patients with advanced treatment-naïve or recurrent NSCLC received ICB from 2016-2020 and underwent “OncoPlus” testing. Median age was 66, 87% had adenocarcinoma, and 88% had a smoking history. AJCC 8th edition initial staging: IA/IIB (n=6), IIIA/B/C (n=38), IVA (n=25), and IVB (n=70). 53% of patients (n=73) received ICB in the treatment-naïve, metastatic setting. 82% had PD-L1 staining: unavailable in 25 patients (18%), 0% in 31 (22%), 1-49% in 36 (26%), and ≥50% in 47 (34%).
64% of patients received ICB monotherapy (n=89), 28% of patients received concurrent chemo-ICB (n=39), and the remaining 7% of patients received some combination of molecularly targeted therapies + ICB +/- cytotoxic chemotherapy. ICB included pembrolizumab (n=85, 58%), nivolumab +/- ipilimumab (n=19 monotherapy, n=18 dual blockade, 27%), atezolizumab (n=17, 12%), and durvalumab (n=11, 8%). The majority received radiotherapy to at least 1 lesion (n=104, 75%). Median follow-up after ICB initiation was 11 months (range 0-44); 2-yr PFS and OS for the overall cohort were 21% and 41%, respectively.
The most frequent pathogenic genomic alterations affected TP53 (67%, n=93), KRAS (38%, n=51), STK11 (27%, n=38), and CDKN2A (22%, n=31). We found that tumors with alterations in CDKN2A (mutation/deletion 48%/52%) were associated with inferior median progression-free survival (PFS; 3.4 vs. 7.4 mo., p=0.043) and more markedly median overall survival (OS; 11.6 vs. 22.1 mo., p=0.020) compared to wild-type tumors. On multivariate Cox proportional hazards analysis including age, gender, BMI, ECOG, TMB, PD-L1 status, and ICB indication, CDKN2A loss/mutation was independently associated with a 2.1-fold risk of progression (p=0.015) and a 3.0-fold risk of death (p=0.001). In high TMB NSCLCs (≥ 10 mutations/megabase, n=66), CDKN2A alteration was associated with a trend to worsened OS (median OS 9.4 vs. 16.6 mo., p=0.055). In high PD-L1 NSCLCs (≥50%; n=47), CDKN2A alteration remained negatively associated with OS (median OS 10.4 vs. 22.2 mo., p=0.020). Using RECIST 1.1 criteria, CDKN2A loss-of-function tumors were twice as likely to exhibit progressive disease as their best response to ICB when compared to CDKN2A wild-type tumors (48% vs. 22%, p=0.02).
Conclusion
In a large cohort of NSCLC patients treated with ICB, NGS identified CDKN2A mutation/deletion as a predictor of poor clinical outcomes. In the context of recent evidence for sensitivity to CDK4/6 inhibition of CDKN2A-deficient tumors, our findings raise the possibility of utilizing currently available targeted agents in the treatment of CDKN2A-deficient NSCLCs receiving ICB.
-
+
P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
-
+
P76.62 - RAMOSE: An Open-Label Randomized Phase II Study of Osimertinib with or without Ramucirumab in TKI-Naïve EGFR-Mutant Metastatic NSCLC (ID 3246)
00:00 - 00:00 | Author(s): Jyoti D Patel
- Abstract
Introduction
The third-generation EGFR tyrosine kinase inhibitor osimertinib is currently used as a standard first-line therapy for patients with metastatic EGFR-mutant NSCLC. However, a majority of patients’ cancers will develop resistance to osimertinib in less than 2 years, with a median progression-free survival of approximately 19 months.
Preclinical models demonstrate upregulated VEGF signaling as a mechanism of acquired resistance to EGFR therapies, and improved efficacy when combining VEGF and EGFR inhibition. Ramucirumab, a monoclonal antibody targeting VEGF receptor 2, was recently approved by the US FDA in combination with erlotinib in patients with metastatic untreated EGFR-mutant NSCLC, based on a significant improvement in progression-free survival (PFS) with the combination seen in the RELAY trial.
A phase I study of osimertinib with ramucirumab (NCT02789345) demonstrated safety and feasibility of this combination. With this strong preclinical and clinical evidence, we are conducting a phase 2 trial to evaluate the osimertinib ramucirumab combination’s efficacy in treatment-naïve EGFR-mutant NSCLC.
Methods
RAMOSE (HCRN LUN-18-335; NCT03909334) is a randomized, open-label phase 2 study comparing osimertinib 80mg PO daily + ramucirumab 10 mg/kg IV q3 weeks (O + R) to osimertinib 80mg PO daily monotherapy (O) for initial treatment of metastatic EGFR-mutant NSCLC. Patients are randomized 2:1 to the O+R versus O groups, with stratification based on type of EGFR mutation and presence of CNS metastasis. The trial plans to enroll total of 150 patients, allocating 100 to O+R and 50 to O monotherapy. The primary endpoint is PFS. Secondary endpoints include ORR, OS and DCR, as well as safety/toxicity. Major inclusion criteria include patients with metastatic NSCLC harboring activating EGFR mutations (L858R or Exon 19 del). Major exclusion criteria include prior anti-EGFR or anti-VEGF treatments. Patients with stable CNS metastasis are allowed. We hypothesize an improvement of PFS from 18.9 months to 29.7 months, corresponding to a hazard ratio of 0.65.
The study is currently open at 9 sites in the USA, with additional sites planned. Hoosier Cancer Research Network is facilitating execution of the trial. Analysis by a study Data Safety Monitoring Board (DSMB) is performed annually. In addition, a planned interim analysis for efficacy will be performed after the first 75 subjects are enrolled.
Results
The trial opened to accrual in July 2019. As of July 02, 2020 (the data cutoff for planned DSMB analysis), 29 patients had been accrued. 25 of these patients were randomized (17 to O+R arm and 8 to O arm). Among the patients currently evaluable for toxicity (N=19), grade 3 or higher adverse events (AEs) were reported in 5/14 patients on O+R arm, versus 1/5 patients on O arm. In the O+R arm, grade 3 AEs included hypertension (n=1), pleural catheter infection (n=1), musculoskeletal pain (n=1), neutrophil count decreased (n=1), and dyspnea (n=1).
Conclusion
Early analysis from the RAMOSE trial shows no unexpected signals of toxicity with the combination of O+R. Enrollment for the trial is ongoing.
-
+
P79 - Immunotherapy (Phase II/III Trials) - Immunotherapy Plus Chemotherapy (ID 256)
- Event: WCLC 2020
- Type: Posters
- Track: Immunotherapy (Phase II/III Trials)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
-
+
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): Jyoti D Patel
- 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