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Karen L Reckamp
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ES14 - What First Line in Oncogene Addicted NSCLC (ID 17)
- Event: WCLC 2019
- Type: Educational Session
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:Dolores Isla, Jessica Menis
- Coordinates: 9/08/2019, 15:15 - 16:45, Vancouver (2003)
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ES14.05 - Patients Harbouring a Driven-Mutation: Pro and Patient's Perspective (Now Available) (ID 3234)
15:15 - 16:45 | Presenting Author(s): Karen L Reckamp
- Abstract
- Presentation
Abstract
Patients Harbouring a Mutation-Driven NSCLC—Pro and Patient Perspective
Karen L. Reckamp, MD, MS
City of Hope Comprehensive Cancer Center, Duarte, CA, USA
Genomic alterations in non-small cell lung cancer (NSCLC) define distinct subtypes with specific mechanisms leading to constitutive activity of a gene pathway, and tumor growth and metastasis. Targeted therapy for NSCLC with oncogenic driver mutations or alterations, usually with small molecule tyrosine kinase inhibitors (TKIs), has changed the paradigm for treatment of patients. New genetic alterations continue to be described with potential therapeutic interventions, and over 60% of patients with the adenocarcinoma subtype of NSCLC have a defined molecular alteration1. The perspective of the clinician and patient merges on the ideal that treatment for NSCLC should provide a long duration of cancer control (ideally tumor shrinkage) with limited side effects, and improvement in quality of life. Some aspects of treatment with targeted therapy may be more important to the treating physician, while patients may have a differing viewpoint during care. This will be explored.
From a clinician’s lens, the treatment for patients with NSCLC harbouring an alteration that can be treated with a targeted therapy involves an algorithm that includes the ideal sequencing of therapy. This requires determining the best front line therapy based on progression free survival (PFS) and overall survival while including the toxicity profile into the algorithm, and also assessing possible mechanism of resistance and options for subsequent therapy. A front line option should not be withheld based on second line options, but sequencing of therapy to increase survival and quality of life becomes an important part of the treatment decision (Table 1). This may be best exemplified in the case of EGFR mutant NSCLC, in which osimertinib demonstrated clear PFS benefit over erlotinib or gefitinib.2 In this case, mechanisms of resistance are still being elucidated and subsequent therapy becomes chemotherapy combinations. Recent studies have shown PFS benefit with first generation EGFR TKIs in combination with ramucirumab or chemotherapy, but were not directly compared to osimertinib. Furthermore, the toxicity with the combination therapy was also increased. Therefore, the choice of osimertinib as front line therapy is optimal for most patients. Another important aspect in the physician choice of front line therapy is brain penetration, which most TKI therapy is able to achieve, but some are better than others. Importantly, patients will not be treated with novel targeted therapies if they are not tested. Testing can include single gene testing by PCR and FISH, NGS testing and hotspot analysis either on blood or tissue. The utility of liquid biopsies to identify alterations in the metastatic front line setting has been shown,3 and detection has led to actionable therapy.4
Patients expect their physicians to be advocates for their therapy and their lives, and want a reason to hope. Most would like to avoid chemotherapy if possible in the course of treatment. They want the most current, and extensive testing done to determine the right therapy, but also encounter the economic impact of diagnosis and treatment of oncogene-driven NSCLC. Untangling the clinical trial data to provide the therapy most likely to prolong quality of life and survival is essential. Inadequate testing up front can lead to inappropriate treatments, and increased anxiety associated with additional tests and time required to find the right treatment. A NSCLC patient who is also a physician provides valuable insight into the patient perspective, “Everyone with lung cancer needs to have their cancer tissue tested for genetic mutations… That biopsy may lead to identifying mutations that can be successfully targeted. All therapies, whether conventional or targeted, provide bridges to keep you alive for the next therapy, to get to the next bridge. My ultimate goal is not necessarily to cure the disease, but to successfully manage the disease. Very much like the way HIV/AIDS and diabetic patients manage their disease for many, many years….to convert a death sentence to a chronic illness.”5
References
1. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA : the journal of the American Medical Association 2014;311:1998-2006.
2. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:113-25.
3. Leighl NB, Page RD, Raymond VM, et al. Clinical Utility of Comprehensive Cell-free DNA Analysis to Identify Genomic Biomarkers in Patients with Newly Diagnosed Metastatic Non-small Cell Lung Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 2019.
4. Rothwell DG, Ayub M, Cook N, et al. Utility of ctDNA to support patient selection for early phase clinical trials: the TARGET study. Nature medicine 2019;25:738-43.
5. June 7, 2019
Table 1.
Oncogene
Mutation prevalence
Approved drugs
First-line drug of choice
Driver-oncogenes with approved agents
EGFR
Asian 30-40%/ Caucasian 10-20%
Erlotinib
Gefitinib
Afatinib
Osimertinib
Osimertinib
ALK
1-7%
Crizotinib
Ceritinib
Alectinib
Brigatinib
Lorlatinib
Alectinib
ROS1
1.7%
Crizotinib
Ceritinib
Crizotinib
BRAF
2%
Dabrafenib/trametinib
Dabrafenib/trametinib
NTRK
<1%
Larotrectinib
Larotrectinib
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MA13 - Going Back to the Roots! (ID 139)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Maurice Perol, Kaoru Kubota
- Coordinates: 9/09/2019, 14:00 - 15:30, Vancouver (2003)
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MA13.08 - Discussant - MA13.05, MA13.06, MA13.07 (Now Available) (ID 3775)
14:00 - 15:30 | Presenting Author(s): Karen L Reckamp
- Abstract
- Presentation
Abstract not provided
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OA13 - Ideal Approach to Lung Resection and Novel Perioperative Therapy (ID 146)
- Event: WCLC 2019
- Type: Oral Session
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Now Available
- Moderators:Tomasz Grodzki, Kenji Suzuki
- Coordinates: 9/10/2019, 11:30 - 13:00, Toronto (1985)
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OA13.07 - Neoadjuvant Atezolizumab in Resectable NSCLC Patients: Immunophenotyping Results from the Interim Analysis of the Multicenter Trial LCMC3 (Now Available) (ID 1755)
11:30 - 13:00 | Author(s): Karen L Reckamp
- Abstract
- Presentation
Background
The immune mechanisms dictating response and resistance to PD-(L)1 blockade are not well understood in early stage non-small cell lung cancer (NSCLC). Understanding these mechanisms will be key to improve outcomes and identify the next generation of predictive biomarkers of response to these therapies. Here, we present updated immunophenotyping at time of interim analysis of LCMC3, a multicenter trial of neoadjuvant atezolizumab in resectable NSCLC (NCT02927301).
Method
Patients received 2 cycles of atezolizumab before resection. Tumor, LN biopsies and PB were obtained pre-atezolizumab and at surgery. Paired PB, screening and surgical LN were analyzed using IMMUNOME flow cytometry. Plasma-based cytokine arrays were performed on a subset of patients. Immunophenotypic analyses were correlated with treatment effect, major pathologic response (MPR, primary endpoint) and preoperative treatment-related adverse events (preop-TRAE).
Result
We report on 55 patients with paired PB samples (analyzed within 72h after collection) and completed surgery. We observed preop-TRAE in 32/55 patients (18 grade 1, 13 grade 2, 1 grade 3). CD1c+ and CD141+ myeloid cells (MC) were lower at baseline in patients developing preop-TRAEs, while monocytic M-MDSCs were higher in those patients. Senescent T cells decreased in patients with preop-TRAE and increased in patients with non-preop-TRAE. After treatment, the absolute cell counts of late activated CD4+and CD8+T cells decreased in patients achieving MPR. LN IMMUNOME data, cytokine data and 12-month follow-up (DFS, OS) will be reported.
Conclusion
Preliminary immunophenotyping data from the interim analysis showed significantly lower baseline immunosuppressive cell subsets in patients with preop-TRAE and decreased late activated CD4+and CD8+T cells from PB in patients with MPR.These results, together with additional LN IMMUNOME and cytokine analyses, may improve our understanding of immunophenotypic features associated with outcome, and changes induced by neoadjuvant atezolizumab in early stage NSCLC patients.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 3
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-105 - US Real-World Management of EGFR-Mutated Advanced NSCLC: Prescribing and Attrition Data from First-To-Second-Line Treatment (Now Available) (ID 1737)
09:45 - 18:00 | Presenting Author(s): Karen L Reckamp
- Abstract
Background
Following first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy for EGFR mutation-positive (EGFRm) advanced NSCLC, not all patients are able to receive second-line treatment. A significant proportion of patients die before second-line treatment, or are only eligible to receive palliative care. To better understand patient attrition, we investigated temporal trends in treatment patterns among first-line EGFR-TKI treated patients in real-world practice in the US.
Method
We utilised the American Society of Clinical Oncology CancerLinQ Discovery® database to characterise a cohort of patients with EGFRm advanced NSCLC receiving first-line EGFR-TKIs between 2011–2017. CancerLinQ Discovery includes de-identified, demographically, and geographically diverse, longitudinal data. Data were obtained from a network of US cancer centres and community oncology practices participating in CancerLinQ. Patient-level data were derived from electronic health records or underlying data warehouses as structured data, and augmented through technology-assisted human curation of unstructured notes and scanned documents, including diagnosis, anatomic pathology, imaging, surgery, medications, radiotherapy, molecular pathology, etc. Patient data were divided into two cohorts: those who were diagnosed and received first-line treatment pre-2015 versus 2015 onwards.
Result
We identified 426 patients with advanced EGFRm NSCLC who received first-line EGFR-TKI treatment between 2011–2017. Median (interquartile range [IQR]) age at diagnosis was 65.0 years (55.0–75.0); 240 (56%) patients were female; 378 (89%) adenocarcinoma histology; and 165 (39%) former/current smokers. Median (IQR) time between diagnosis of advanced staging and first-line treatment was 31.0 days (18.0–57.8); median (IQR) first-line treatment duration was 7.8 months (2.7–14.3). The table shows first- and second-line treatments received, and patient attrition data. Osimertinib was the most common second-line treatment in the 2015 onwards cohort.
Conclusion
These real-world data confirm that approximately 44% of patients with EGFRm advanced NSCLC receive second-line treatment, and nearly one-third of patients die without receiving second-line treatment.
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P1.01-67 - Ph I/II Carboplatin, Nab-Paclitaxel and Pembrolizumab for Advanced NSCLC (HCRN LUN13-175): Outcomes by Nab-Paclitaxel Dose (ID 530)
09:45 - 18:00 | Author(s): Karen L Reckamp
- Abstract
Background
Combination chemotherapy and immunotherapy have significantly improved survival for patients with treatment-naïve advanced non-small cell lung cancer (NSCLC). We sought to evaluate the safety and efficacy of adding pembrolizumab to a standard regimen at the time of study development, nab-paclitaxel and carboplatin. Safety data from phase I have been reported, and phase II commenced with the same chemotherapy doses and flat dosing of pembrolizumab at 200 mg.
Method
Patients with treatment-naïve, stage IIIB/IV NSCLC AJCC 7 (all histology), any PDL1, no EGFR or ALK, ECOG 0-1, received carboplatin AUC 6 day 1, nab-paclitaxel 100 mg/m2 days 1, 8, 15, and pembrolizumab 200 mg day 1 q21 days for 4 cycles followed by maintenance pembrolizumab q3wks. Co-primary endpoints were progression-free survival (PFS) and response rate (RR). PDL1 was assessed prior to treatment and from biopsies obtained after cycle 4.
Result
46 patients enrolled, 14 on phase I and 32 in phase II, from June 2015–July 2018. Accrual stopped after data was presented from similar phase III trials. 43 were evaluable for the primary endpoints. Median age was 65 years, 48% female, 45% adenocarcinoma, 94% current/former smokers, 9% brain metastases. PDL1 expression (TPS) by <1%, 1-49%, and ≥ 50% cutoffs was 44%, 28%, and 28%, respectively. ORR was 28%. Median PFS was 5.6 months (CI, 4.2-10.5 mo). Median OS was 15.7 mo (CI 11.1-22.3 mo). There was no statistical differences in PFS or OS outcomes by PDL1 status. Paired PDL1 results from pre- and post-treatment biopsies were available in 8 patients. PDL1 status changed categories in 4/8 samples (n=3, 0% to positive; n=1, 99% to 0%). The most common grade 3-4 adverse events (AEs) were neutropenia (64%), anemia (31%), thrombocytopenia (24%), leukopenia (16%) and fatigue (11%). Other notable AEs included rash (58%), diarrhea (47%), neuropathy (22%), arthralgia (18%), transaminitis (13%), and myalgia (11%). 18% discontinued treatment due to AEs. In an exploratory analysis, there was no difference in median PFS for those receiving total nab-paclitaxel dose of 400–799 mg/m2 compared to ≥800 mg/m2 (6.2 mo vs. 8.2 mo, p=0.62).
Conclusion
Although the study did not meet its pre-specified endpoints of PFS 9 months and RR of 50%, results were similar to previously reported phase III Keynote 407 (squamous histology). Despite hematologic toxicity, the combination could safely be administered, and outcomes were similar for those receiving moderate doses of nab-paclitaxel compared to those with an average of at least 200 mg/m2 per cycle.
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P1.01-96 - US Real-World Management of EGFR-Mutated Advanced NSCLC: Survival After First-Line EGFR-Tyrosine Kinase Inhibitor Treatment (ID 703)
09:45 - 18:00 | Author(s): Karen L Reckamp
- Abstract
Background
Outside of the clinical trial setting there are limited data defining clinical outcomes in patients with EGFR mutation-positive (EGFRm) advanced NSCLC treated with first-line EGFR-tyrosine kinase inhibitors (TKIs). To understand the impact of clinical features on outcomes to first-line EGFR-TKI treatment, we investigated overall survival (OS) across a range of variables obtained from real-world clinical practice in the US using the CancerLinQ database.
Method
We utilised the American Society of Clinical Oncology CancerLinQ Discovery® database to characterise a cohort of patients with EGFRm advanced NSCLC receiving first-line EGFR-TKIs. CancerLinQ Discovery includes de-identified, demographically, and geographically diverse, longitudinal data. Data were obtained from a network of US cancer centres and community oncology practices participating in CancerLinQ. Patient-level data were derived from electronic health records or underlying data warehouses as structured data, and augmented through technology-assisted human curation of unstructured notes and scanned documents, and include diagnosis, anatomic pathology, imaging, surgery, medications, radiotherapy, molecular pathology, etc. OS was assessed as the duration between the start date of first-line treatment and last follow-up.
Result
We identified 426 patients with EGFRm advanced NSCLC who had received first-line EGFR-TKI treatment between 2011–2017. Median (interquartile range [IQR]) age at diagnosis was 65.0 years (55.0–75.0); 240 (56%) patients were female; 378 (89%) adenocarcinoma histology; 165 (39%) former/current smoking status. Median (IQR) time between diagnosis of advanced staging and first-line EGFR-TKI treatment was 31.0 days (18.0–57.8). First-line treatments received were erlotinib (n=376, 88%), afatinib (n=48, 11%), and gefitinib (n=2, 0.5%). Median (IQR) duration on first-line treatment was 7.8 months (2.7–14.3). Overall OS was 25 months (95% confidence interval: 21–29). Further OS data are summarised in the table.
Conclusion
OS for patients with EGFRm advanced NSCLC receiving first-line EGFR-TKIs in US clinical practice is in line with expectations based on clinical trials of first- and second-generation EGFR-TKIs.
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-27 - Duration of Targeted Therapy in Advanced NSCLC (aNSCLC) with Drivers Identified by Circulating Tumor DNA (ctDNA) Analysis (ID 953)
09:45 - 18:00 | Author(s): Karen L Reckamp
- Abstract
Background
Identifying targetable genomic drivers is critical for optimal first-line treatment planning in aNSCLC. ctDNA testing can aid treatment selection when tissue specimens are inadequate for complete genotyping or when a rapid turnaround time is advantageous. Targeted therapy (TT) outcomes for ctDNA-detected drivers have not been widely reported in the first-line setting given the relatively recent adoption of this technology into clinical practice.
Method
We conducted a multicenter retrospective review of patients with aNSCLC who received matched TT following identification of a driver on a validated commercial ctDNA assay (Guardant360). Eligible patients were tested per regular clinical care between March 2014-October 2018 and must not have received a TT prior to ctDNA testing (prior chemotherapy or immunotherapy was permitted). Kaplan-Meier analysis was used to estimate median duration of TT (DTT) for both the first and all subsequent sequential targeted therapies where applicable (e.g. osimertinib following erlotinib). Patients still on TT were censored at last follow-up.
Result
76 patients met inclusion criteria. Median age of diagnosis of aNSCLC was 64.5 years (range 31-87y), 67% were female, 74% were never smokers, and 97% had adenocarcinoma histology. 21/76 (28%) patients received chemotherapy (n=17), immunotherapy (5), and/or a biologic (4) prior to receiving TT. 41/76 (54%) patients remain on TT at the time of data analysis, 32 of whom are still on their first TT. 38/41 patients still on TT have at least 6 months follow-up. Treatment outcomes are summarized in Table 1.
Table 1. Duration of Targeted Therapy
Driver
Therapy
n, total patients/discontinued therapy
Median (95% CI) DTT in weeks1
EGFR
Erlotinib
Osimertinib
Afatinib
Gefitinib
Any EGFR TKI2
21 / 19
23 / 6
3 / 2
1 / 1
48 / 20
33 (23-54)
NR
3, 13, 93*
63
86 (48-197)
ALK fusion
Alectinib
Crizotinib
Any ALK TKI3
7 / 2
2 / 2
9 / 2
NR
20, 44
NR
BRAF V600E
Dabrafenib + Trametinib
10 / 7
51 (13-88)
MET exon 14 skipping
Crizotinib
Investigational
3 / 2
1 / 1
4, 77, 63*
14
ROS1 fusion
Investigational
2 / 1
50, 79*
ERBB2 exon 20 insertion
Ado-trastuzumab emtansine
2 / 1
46, 14*
RET fusion
Investigational
1 / 1
47
1 – individual data rather than median provided for counts <5
2 – includes 15 patients receiving sequential EGFR TKIs
3 – includes 3 patients receiving sequential ALK TKIs
* indicates therapy is ongoing for individual data points
Abbreviations: NR – not reached; TKI – tyrosine kinase inhibitor
Conclusion
This study provides interim data on targeted therapy outcomes for aNSCLC patients with Guardant360-detected drivers treated in everyday clinical practice. Outcomes are in line with what is expected for tissue-detected drivers in the TT naïve setting and this cohort will continue to be followed. Identification of NSCLC driver mutation using well-validated ctDNA assays can be used for clinical decision-making.
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P1.14-32 - Rash and Efficacy in Anaplastic Lymphoma Kinase Positive (ALK+) Non-Small Cell Lung Cancer Patients Treated with Ensartinib (ID 2382)
09:45 - 18:00 | Author(s): Karen L Reckamp
- Abstract
Background
Ensartinib is a potent ALK small molecule tyrosine kinase inhibitor (TKI). In a phase 1/2 study, ensartinib was generally well tolerated and demonstrated good clinical activity in pts with ALK+ non-small cell lung cancer (NSCLC). This post hoc analysis sought to determine the relationship between ensartinib-related rash and clinical benefit.
Method
Adverse events (AEs) were coded using MedDRA v15.0; severity was assessed by investigators using NCI CTCAE v4.03. Objective response rate (ORR) and median progression-free survival (mPFS) were explored in the efficacy-evaluable population, which included ALK+ pts receiving ensartinib 225 mg QD who had a postbaseline response assessment.
Result
As of Feb 07, 2019, 80 pts were dosed at the phase 3 dose of 225 mg QD and were efficacy evaluable (13 were ALK TKI naive, 37 had received prior crizotinib only, and 30 had received a prior second-generation ALK TKI). Rash was the most common AE observed in 69% of pts, mostly grade 1/2. The rashes started most frequently (33%) at day 7 or 8. The most common types of rash were general rash, rash maculopapular, and rash erythematous. Rash was primarily managed with topical corticosteroids, with some dose reductions, or no intervention at all and rarely led to discontinuation (2% [n=2]). The median duration of rash was 22 days. The ORR and mPFS were better in pts with rash vs those without (ORR, 53% vs 40%; mPFS, 8.6 vs 5.7 mo; P=.0044) (Table). A multivariate Cox proportional hazards model controlling for baseline factor (eg, age, sex, ECOG PS, and prior ALK TKI) revealed a correlation between rash and PFS (HR=0.556; P=.0755). Pts are still being accrued in this study.
Conclusion
Ensartinib was associated with mild to moderate rash that was easily managed. Preliminary findings suggest that rash is potentially associated with better clinical benefit with ensartinib.
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P1.18 - Treatment of Locoregional Disease - NSCLC (ID 190)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment of Locoregional Disease - NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.18-05 - ChemoXRT W/ Consolidation Pembrolizumab in Unresectable Stage III NSCLC: Long-Term Survival Update and Analysis of Post-Progression Therapy (Now Available) (ID 2765)
09:45 - 18:00 | Author(s): Karen L Reckamp
- Abstract
Background
Consolidation PD-1/PD-L1 inhibition following chemoradiation is a new standard of care for patients with stage III NSCLC. 3-year survival rates in patients receiving consolidation PD-1/PD-L1 have not been previously reported. In addition, the response to subsequent chemotherapy or immunotherapy in patients who experienced disease progression following consolidation PD-1/PD-L1 has also not been previously reported.
Method
This is a phase II, single-arm, multi-center trial of consolidation pembrolizumab 200mg IV every 3 weeks for up to a year following concurrent chemoradiation in patients with unresectable stage III NSCLC. This analysis provides the first-ever report of 3-year overall survival (OS) estimates with consolidation PD-1. In addition, treatment details for patients who experienced progression of disease on or after consolidation pembrolizumab are described.
Result
Median follow is 31.1 months (range 1.2-42.4). Median OS is 35.8 months (95% CI, 24.2 -not estimable). One, two, and three-year OS estimates are 81.1%, 62%, and 49.5%. Of 37 patients reported to have progressive disease (PD), subsequent treatment data were available for 35. Twenty-four received additional systemic therapy, and 11 received no subsequent systemic treatment. Fifteen experienced PD during pembrolizumab, 18 after pembrolizumab (and 4 had missing data). The best response to any systemic therapy (n=24) was 3 partial responses (PR), 9 stable disease (SD), and 12 PD. Chemotherapy was given to 21 patients and 1 patient each received erlotinib, ponatinib, and an investigational agent. Best response to chemo was 2 PR, 6 SD, and 13 PD. 11 patients received pemetrexed with 2 SD and 9 PD; 6 patients received a single agent taxane with 1 SD and 5 PD. 5 patients received combination therapy with 1 PR, 3 SD, and 1 PD. 3 patients received gemcitabine with 1 PR and 2 PD. 6 of 24 patients received subsequent PD-1 or PD-L1 inhibitors; the best response to immunotherapy was 1 PR and 5 PD. The PR was a patient who had completed pembro consolidation 14 months prior to PD and subsequently was retreated with pembro at the time of biopsy-proven recurrence (PD-L1 TPS was 90%). He responded after 3 cycles of pembro and has maintained this response for 13+ cycles.
Conclusion
The 3-year OS estimate indicates that nearly half of all patients treated with consolidation pembrolizumab may be long-term survivors. For patients with disease progression after consolidation pembrolizumab, response rates with chemotherapy are similar to what is expected in the 2nd line setting with 38% experiencing disease control for a period of time. Only 1 of 6 patients re-challenged with a checkpoint inhibitor responded, but this patient has maintained a durable response lasting 13+ cycles.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-88 - Surgical Outcomes of a Multicenter Phase II Trial of Neoadjuvant Atezolizumab in Resectable Stages IB-IIIB NSCLC: Update on LCMC3 Clinical Trial (ID 1817)
10:15 - 18:15 | Author(s): Karen L Reckamp
- Abstract
Background
The role of immune checkpoint inhibitors in resectable NSCLC remains undefined. We report the updated safety results of the first multicenter trial assessing neoadjuvant atezolizumab (a PD-L1 inhibitor) for resectable NSCLC.
Method
Eligible patients with clinical stage IB-IIIB resectable NSCLC received 2 cycles of neoadjuvant atezolizumab (1200 mg, days 1, 22) followed by surgical resection (day 40±10). Pre- and post-treatment PET/CT, pulmonary function tests (PFT), and bio-specimens were obtained. Adverse events (AE) were recorded according to CTCAEv.4.0. Preoperative treatment-related TRAE (preop-TRAE) and postoperative TRAE (postop-TRAE) defined as AE onset on, or after date of surgery, were analyzed.
Result
Follow-up data to post-surgery visit were analyzed for 101 patients out of planned 180: mean age: 64.6 years; male: 47/101(46.5%); current smokers: 23/101(22.8%); non-squamous histology: 66/101(65.3%); and clinical stages IB(10.9%), IIA(15.8%), IIB(27.7%), IIIA(38.6%), and IIIB(6.9%). Two cycles of atezolizumab were not completed in 5/101(5.0%) patients due to grade 1 or 2 AEs. Surgery was not performed in 11/101(10.9%) patients: 5 demonstrated disease progression, and 6 for ‘other’ reasons. 6/101(5.9%) patients were deemed unresectable. Surgery was delayed (outside of 10-day window) in 10/90(11.1%) patients by an average of 11(1-39) days. Two of these delays were due to TRAEs (hypothyroidism and pneumonitis), 3 were patient-elected delays, 2 were surgeon-related, and 3 for ‘other’ reasons. Intraoperative vascular complications occurred in 2/90(2.2%) and extensive hilar fibrosis was noted in 20/90(22.2%) patients. Overall, there was insignificant mean change in the PFTs pre- vs. post-atezolizumab therapy. Only 3/101(3.0%) patients had treatment-related dyspnea, dyspnea on exertion, or pneumonitis.
Table 1
ConclusionTreatment Related Adverse Events
(TRAE)
Preoperative TRAE
(N = 101)
Postoperative TRAE
(N = 90)
All AEs
Any grade
55 (54.5%)
20 (22.2%)
Grade 1
29 (28.7%)
7 (7.8%)
Grade 2
24 (23.8%)
9 (10.0%)
Grade 3
2 (2.0%)
4 (4.4%)
Grade 4
0
0
Grade 5
0
0
Specific AEs
Dyspnea
1 (1.0%; grade 2)
3 (3.3%; grade 1)
Dyspnea on exertion
1 (1.0%; grade 1)
0
Myalgia
4 (4.0%; grade 1 or 2)
0
Hyperthyroidism
3 (3.0%; grade 1 or 2)
1 (1.1%; grade 1)
Hypothyroidism
0
1 (1.1%; grade 2)
Pneumonitis
1 (1.0%; grade 3)
3 (3.3%; grade 2 or 3)
Transaminitis (AST or ALT)
8 (7.9%; grade 1 or 2)
3 (3.3%; grade 1 or 2)
Post-atezolizumab Change in Pulmonary Function Tests
PFT factor
Mean change (95% Confidence Interval)
FEV1 (N = 72)
-0.6% (-2.6% to 1.3%)
FVC (N = 72)
0.0% (-1.8% to 1.8%)
DCLO (N = 64)
-1.2% (-4.1% to 1.7%)
Treatment with neoadjuvant atezolizumab in resectable stage IB-IIIB NSCLC was well tolerated, with minimal delay to surgery, and few treatment associated AEs. This trial continues to accrue and assess MPR, survival, and other long-term endpoints.
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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): Karen L Reckamp
- 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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