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Oscar Juan
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PC05 - Immune Chekpoint Inhibitors in Real World - How Do We Treat NSCLC ''Special Populations'' (ID 87)
- Event: WCLC 2019
- Type: Pro-Con Session
- Track: Advanced NSCLC
- Presentations: 5
- Now Available
- Moderators:Oscar Juan, Fernando José Barata
- Coordinates: 9/10/2019, 14:30 - 16:00, Tokyo (1982)
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PC05.01 - ICIs for Patients with Interstitial Pneumonia (Now Available) (ID 3574)
14:30 - 16:00 | Presenting Author(s): Terufumi Kato
- Abstract
- Presentation
Abstract
Interstitial pneumonia (IP) or pulmonary fibrosis (PF) is one of the most common and poor prognostic comorbidities with lung cancer, and also known as a risk factor of treatment related pneumonitis. Around 10% of patients are diagnosed concomitant IP/PF at the time of cancer diagnosis.
The prognosis of lung cancer patients with IP/PF has been reported to be poor, because 5-20% of those receiving chemotherapy experienced exacerbation of IP/PF, and some of them are mortal. Median overall survival time of these patients with stage IV non-small cell lung cancer is around 10 months, which is 2 months shorter than patients without IP/PF. In spite of risk of acute exacerbation, chemotherapy including platinum doublet or monotherapy are considered as the standard treatment for the patient with IP/PF because of a certain level of efficacy.
Not only chemotherapy, other types of cancer treatment including radiotherapy, surgical resection, and targeted drug also induce acute exacerbation of pre-existing IP/PF occasionally.
Targeted small molecules including EGFR-TKIs are reported to have higher risk of acute exacerbation of pre-existing IP/PF, and some surveillance reports that existence of IP/PF is a most significant risk factor related to emergence of treatment related pneumonitis.
Immuno-checkpoint inhibitors (ICI) now play an important role in lung cancer treatment, and as immune related adverse event, immune mediated pneumonitis is considered that should be paid most attention because of its high frequency and potential lethality. Regarding to ICI, relation between pre-existing IP/PF and treatment related pneumonitis is not clear, so far.
Because of relationship to smoking history, higher level of microsatellite instability (MSI), and tumor mutation burden (TMB), these are associated with favorable efficacy, ICI also may have some role in treatment strategy for the lung cancer patients comorbid with IP/PF.
A phase II trial of nivolumab for pretreated NSCLC patients with IP/PF, in 18 pretreated NSCLC patients with mild idiopathic IP, showed 36% of response rate and a 56% of 6-months progression-free survival rate in mild idiopathic IP. Two grade 2 pneumonitis were observed, and both are improved by corticosteroid treatment.
In this session I will try to review ICI treatment for patients with IP/PF and also discuss about their clinical adaptation for clinical practice.
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PC05.02 - Are ICIs Effective for Poor Performance Status Patients with Advanced NSCLC? (Now Available) (ID 3575)
14:30 - 16:00 | Presenting Author(s): Francesco Grossi | Author(s): Carlo Genova
- Abstract
- Presentation
Abstract
The management of non-small cell lung cancer (NSCLC) in patients with poor performance status (PS) has always been a challenging task. Until the last decade, platinum-based chemotherapy has been the main therapeutic approach to NSCLC, and is retaining a major role in patients without actionable oncogenic drivers and low expression of programmed death protein ligand 1 (PD-L1). However, patients with poor PS are generally excluded from combination-based regimens and from enrollment in novel clinical trials [1]. While immunotherapy with immune checkpoint inhibitors (ICIs) has become a cornerstone in the management of advanced NSCLC, data regarding its role in ECOG PS=2 patients are generally limited; indeed, the most relevant phase III randomized controlled trials involving ICIs in advanced NSCLC have excluded ECOG PS=2 patients, resulting in a general lack of recommendations from international guide-lines [2]. The currently available information on this specific population has been collected from a handful of clinical studies, all of them involving patients receiving ICIs in second or further lines. In the phase II CheckMate 171 trial, 98 ECOG PS= 2 previously treated patients with squamous NSCLC received single-agent nivolumab; in the preliminary data, the safety profile of nivolumab and the objective response rate (ORR) in ECOG PS=2 patients were globally similar to the overall population, while median overall survival (mOS) was lower, as expected due to the prognostic effect of PS [3]. The phase III-IV CheckMate 153 trial, designed to assess safety of nivolumab in pre-treated NSCLC patients, showed similar results, but notably, in patients with ECOG PS=2, a significant improvement in symptom burden was observed [4]. An additional source of data for unfit NSCLC patients treated with ICIs is represented by expanded access programs (EAPs), in which real-life patients received nivolumab before its registration. In the largest EAP (Italian nivolumab non-squamous NSCLC cohort), 108 pre-treated ECOG PS=2 patients received nivolumab; the independent negative prognostic role of ECOG PS on survival was confirmed, while no safety issues were observed [5]. In contrast with the previous studies, the PEPS2 trial was specifically designed to assess the role of pembrolizumab in a population of previously treated NSCLC patients with ECOG PS=2. The study is currently ongoing, although the data reported so far encourage the use of pembrolizumab in this population; moreover, PD-L1 tumor proportion score appeared to be associated with survival [6]. In conclusion, while the well-known prognostic effect of poor performance status is observed during administration of ICIs, the safety profile and the activity of these agents make immunotherapy a feasible strategy for treating unfit NSCLC patients, especially when single-agent ICIs are administered, although limited outcomes in terms of survival are to be taken into account when choosing whether to offer active antineoplastic treatment to unfit patients or not; since ECOG PS=2 represents a wide range of patients, this choice needs to be made on an individual basis. Notably, a limit of the aforementioned data is represented by the lack of comparison with chemotherapy in controlled randomized studies; to fill this gap, some ongoing trials are being conducted: more specifically, the IPSOS trial is designed to enroll patients who are unfit for platinum-based chemotherapy and randomize them to atezolizumab vs. single-agent chemotherapy [7], while another trial (NCT02581943) is designed to compare pembrolizumab alone or in combination with low-dose carboplatin-paclitaxel [8]; finally, the eNERGY trial is designed to compare ipilimumab-nivolumab with a carboplatin-based doublet in ECOG PS=2 patients [9]. The availability of data from these and similar studies will provide additional insights on the role of ICI in unfit NSCLC patients.
Study
Regimen
ECOG PS=2 patients
(% of global population)
Results in ECOG PS=2 (results in global population)
CheckMate 171 (phase II)
Nivolumab
98 (12%)
TRAEs= 46% (50%)
Grade 3-4 TRAEs= 6% (12%)
mOS= 5.4 months (9.9)
ORR= 11% (14%)
CheckMate 153 (phase III-IV)
Nivolumab
128 (9%)
TRAEs= 48% (62%)
Grade 3-4 TRAEs= 11% (12%)
mOS= 4.0 months (9.1)
Italian non-squmous EAP
Nivolumab
108 (7%)
Compared to PS=0-1: increased risk of OS < 3 months (odds ratio at multivariate analysis= 0.29 (0.19-0.44)
PEPS2 (phase II)
Pembrolizumab
60 (100%)
Grade 3-4 TRAEs= 12%
mPFS= 5.4 months
mOS= 11.7 months
ORR= 28%
Table 1. Studies involving ICIs in ECOG PS=2 patients with NSCLC.
REFERENCES
[1] Carmichael JA, Wing-San Mak D, O'Brien M. A Review of Recent Advances in the Treatment of Elderly and Poor Performance NSCLC. Cancers (Basel). 2018;10(7).
[2] Passaro A, Spitaleri G, Gyawali B, et al. Immunotherapy in Non-Small-Cell Lung Cancer Patients With Performance Status 2: Clinical Decision Making With Scant Evidence. J Clin Oncol. 2019:JCO1802118.
[3] Popat S, Ardizzoni A, Ciuleanu TE, et al. 1303PD Nivolumab in previously treated patients with metastatic squamous NSCLC: Results of a European single-arm, phase 2 trial (CheckMate 171) including patients aged ≥70 years and with poor performance status. Annals of Oncology, Volume 28, Issue suppl_5, September 2017, mdx380006, https://doiorg/101093/annonc/mdx380006. 2017.
[4] Spigel DR, McCleod M, Jotte RM, et al. Safety, Efficacy, and Patient-reported Health-related Quality of Life and Symptom Burden with Nivolumab in Patients with Advanced Non-Small Cell Lung Cancer, Including Patients Aged >/=70 Years or with Poor Performance Status (CheckMate 153). J Thorac Oncol. 2019.
[5] Grossi F, Crino L, Delmonte A, et al. 1156P - Italian nivolumab expanded access programme: real-world results in non-squamous non-small cell lung cancer patients. Annals of Oncology (2017) 28 (suppl_5): v403-v427. 2017.
[6] Middleton G, Brock K, Summers Y, et al. Pembrolizumab in performance status 2 patients with non-small-cell lung cancer (NSCLC): results of the PePS2 trial. Annals of Oncology (2018) 29 (suppl_8): viii493-viii547. 2018.
[7] A Study of Atezolizumab Compared With Chemotherapy in Treatment Naïve Participants With Locally Advanced or Recurrent or Metastatic Non-Small Cell Lung Cancer Who Are Deemed Unsuitable For Platinum-Containing Therapy (IPSOS) https://clinicaltrials.gov/ct2/show/NCT03191786.
[8] Effect of Pembrolizumab With or Without Carboplatin and Paclitaxel on Immune Response in Patients With Recurrent or Stage IIIB-IV Non-small Cell Lung Cancer https://clinicaltrials.gov/ct2/show/record/NCT02581943?term=02581943&rank=1.
[9] Randomized Phase III Study Testing Nivolumab and Ipilimumab Versus a Carboplatin Based Doublet in First Line Treatment of PS 2 or Elderly Patients With Advanced Non-small Cell Lung Cancer (eNERGY) https://clinicaltrials.gov/ct2/show/NCT03351361.
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PC05.03 - ICIs for Patients with Immune-Related Comorbidity (Now Available) (ID 3576)
14:30 - 16:00 | Presenting Author(s): Robert Pirker
- Abstract
- Presentation
Abstract
Immune checkpoint inhibitors have recently been established as standard therapy for patients with advanced NSCLC. However, data on immune checkpoint inhibitors are limited for special patient populations such as elderly patients, patients with poor performance status and patients with immune-related comorbidity (1). Major clinical trials excluded patients with active autoimmune diseases requiring systemic steroids, patients with systemic immunosuppressive treatment, patients with interstitial lung disease or history of pneumonitis requiring systemic steroids, and patients with chronic viral infections (e.g. hepatitis, HIV). Patients with immune-related comorbidity include patients with autoimmune diseases, patients with organ transplants, patients with end-stage renal disease and patients with chronic viral infections. Data on the efficacy and safety of immune checkpoint inhibitors are limited for these patients and mainly based on patients with melanomas and only few patients with lung cancers.
Immune checkpoint inhibitors could result in unacceptable immune activation in patients with pre-existing autoimmune diseases (1). Based on a literature report, exacerbations of autoimmune symptoms occurred in about 1/3 of patients who had been treated with these drugs (1). Therefore, great caution with regard to the use of these drugs in patients with autoimmune diseases is mandated.
Patients with organ transplants have been excluded from clinical trials because of the concern of potential organ rejections. Nevertheless, few reports are available on immune checkpoint inhibitors in patients who had undergone prior organ transplantations (2-8). A recent overview (4) reported on 19 patients with the following characteristics: median age 59 (14-77) years, 74% males, melanoma (n=11), cutaneous squamous cell carcinoma (n=3), NSCLC (2) and hepatocellular ca (n=2), and duodenal cancer (n=1). Median time to start of checkpoint inhibitors after organ transplantation was 11 (range 1-25) years. Patients were treated with nivolumab (53%), ipilimumab (26%) or pembrolizumab (21%). Most patients received low dose prednisone. Graft rejections occurred in ten patients (7/12 kidney, 2/5 liver, and 1/2 heart transplants), particularly among patients who had been treated with anti PD-1 antibodies. Median time to rejection was 21 (range 5-60) days. Among nine patients without rejections, four had immune-related adverse events (hepatitis, colitis, pneumonitis, and dermatitis). A clinical benefit was seen in 57% of patients. This overview indicated that treatment with immune checkpoint inhibitors is associated with a high rate of transplant rejections. A high rejection rate was also reported by others (5). A retrospective analysis of patients with liver transplants indicated transplant rejections in two out of seven patients undergoing treatment with PD-1 inhibitors for hepatocellular carcinomas (n=5) and melanomas (n=2) (8). Taken together, patients with solid organ transplants have a clinically relevant risk of transplant rejection when treated with immune checkpoint inhibitors.
Little information is available for patients with impaired renal function including end-stage renal disease (1, 9). In a report on three patients undergoing hemodialysis, immune checkpoint inhibitors resulted in a partial response in one patient and in stable disease in two patients (9). The toxicity was acceptable except grade 2 pneumonitis in one patient. Based on a literature review, 10 out of 13 patients undergoing hemodialysis responded to immune checkpoint inhibitors. Grade 3-4 immune-related adverse events occurred in three patients. The authors concluded that immune checkpoint inhibitors may not be contra-indicated in patients undergoing hemodialysis but may result in significant toxicity (9).
Patients with chronic viral infections, especially hepatitis C, appear to have little risk of treatment-related increases in adverse events and, therefore, may be treated with immune chekpoint inhibitors under careful monitoring (1).
Although our knowledge on immune checkpoint inhibitors in patients with cancers is rapidly expanding, we still need more information on the efficacy and safety of these drugs in patients with immune-mediated diseases. Data in the real-world setting would be of particular interest. The gathering of these data could be facilitated by establishing registries on national and international levels. Until further information on the safety of these drugs will become available, immune checkpoint inhibitors should be administered with great caution and only after a careful risk benefit assessment in patients with immune-related comorbidity.
References
1. Johnson DB, Sullivan RJ, Menzies AM. Immune checkpoint inhibitors in challenging populations. Cancer 2017; 123: 1904-1911.
2. Kittai AS, Oldham H, Cetnar J, Taylor M. Immune checkpoint inhibitors in organ transplant patients. J Immunother 2017; 40: 277-281.
3. Chae YK, Galvez C, Anker JF, et al. Cancer immunotherapy in a neglected population: The current use and future of T-cell-mediated checkpoint inhibitors in organ transplant patients. Cancer Treat Rev 2018; 63: 116-121.
4. Hassan NA, Abudayyeh A, Shah M, et al. The outcome of checkpoint inhibitor therapy in patients with cancer and solid organ transplant: A systematic review of the literature. J Clin Oncol 2018; 36: 5 suppl, 41.
5. Abdel-Wahab N, Safa H, Abudayyeh A, et al. Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature. J ImmunoTher Cancer 2019; 7: 106.
6. Owonikoko TK, Kumar M, Yang S, et al. Cardiac allograft rejection as a complication of PD-1 checkpoint blockade for cancer immunotherapy: a case report. Cancer Immunol Immunother 2017; 66: 45-50.
7. Charles J, Giovannini D, Terzi N, et al. Multi-organ failure induced by nivolumab in the context of allo-stem cell transplantation. Exp Hematol Oncol 2019; 8: 8.
8. DeLeon TT, Salomao MA, Aqel BA, et al. Pilot evaluation of PD-1 inhibition in metastatic cancer patients with a history of liver transplantation: the Mayo Clinic experience. J Gastrointest Oncol 2018; 9: 1054-1062.
9. Cheun H, Kim M, Lee H, et al. Safety and efficacy of immune checkpoint inhibitors for end-stage renal disease patients undergoing dialysis: a retrospective case series and literature review. Invest New Drugs 2019; 37: 579-583.
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PC05.04 - ICIs for Elderly Patients with Advanced NSCLC (Now Available) (ID 3577)
14:30 - 16:00 | Presenting Author(s): Hossein Borghaei
- Abstract
- Presentation
Abstract
Immunotherapy with checkpoint inhibitors has changed the treatment landscape of many cancers. In the management of patients with non-small cell lung cancer the introduction of immunotherapy as a single agent or in combination with chemotherapy has led to significant improvement in survival and response rates in many patients but not all. I will discuss the role of this approach in the treatment of the elderly patient population with non-small cell lung cancer. I will examine the available data related to clinical efficacy and toxicity of these treatments and hope to delineate a potential role for the continued use of checkpoint inhibitors in the elderly patient population.
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PC05.05 - ICIs in Patients with HIV Infection (Now Available) (ID 3578)
14:30 - 16:00 | Presenting Author(s): Mark Awad
- Abstract
- Presentation
Abstract not provided
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Author of
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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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MA13.05 - Nab-Paclitaxel Maintenance in Squamous Non-Small Cell Lung Cancer (NSCLC): Updated Results of the Phase III ABOUND.sqm Study (Now Available) (ID 294)
14:00 - 15:30 | Author(s): Oscar Juan
- Abstract
- Presentation
Background
Background: nab-Paclitaxel maintenance therapy after nab-paclitaxel/carboplatin induction in patients with advanced squamous NSCLC was evaluated in the phase III, randomized, controlled, open-label, multicenter ABOUND.sqm trial. At the 12-month follow-up, there was no statistically significant difference in progression-free survival (PFS) between patients randomized to maintenance nab-paclitaxel + best supportive care (BSC) vs BSC alone. However, a trend of an overall survival (OS) advantage was observed with nab-paclitaxel + BSC vs BSC alone. Here we report the 18-month follow-up of OS.
Method
Methods: Patients (aged ≥ 18 years) with histologically or cytologically confirmed stage IIIB/IV squamous NSCLC and no prior chemotherapy were eligible. Patients received four 21-day cycles of nab-paclitaxel 100 mg/m2 (days 1, 8, and 15) plus carboplatin AUC 6 (day 1) as induction. Patients with radiologically assessed complete or partial response or stable disease without clinical progression after 4 cycles were randomized 2:1 to maintenance nab-paclitaxel 100 mg/m2 (days 1 and 8 of each 21-day cycle) plus BSC or BSC alone until disease progression. The primary efficacy analysis was performed on the ITT population. PFS from randomization into the maintenance part of the study was the primary endpoint. Secondary endpoints included safety, OS (from randomization), and response.
Result
Results: 420 patients received induction therapy; 202 were randomized to maintenance nab-paclitaxel + BSC (n = 136) or BSC alone (n = 66). The median PFS in patients in the nab-paclitaxel + BSC arm vs those in the BSC-alone arm was 3.1 vs 2.6 months (HR, 0.85; P = 0.349), respectively; the median OS was 17.8 vs 12.2 months (HR, 0.71; P = 0.058), respectively. The overall response rate was 69.1% vs 57.6% (RRR, 1.20; P = 0.087). Following the maintenance part, 73.5% (nab-paclitaxel + BSC) and 68.2% (BSC alone) of patients received subsequent anti-cancer treatment. Over the entire study, the most frequent grade 3/4 TEAEs were neutropenia (53.1% vs 50.0%) and anemia (33.1% vs 32.3%); only peripheral neuropathy occurred in ≥ 5% of patients during maintenance (13.1% in the nab-paclitaxel + BSC arm).
Conclusion
Conclusion: Although PFS and OS differences were not statistically significant in the ITT population, the 18-month follow-up of OS demonstrated the feasibility of nab-paclitaxel maintenance therapy for patients with anced squamous NSCLC.
ClinicalTrials.gov identifier: NCT02027428
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MA22 - Partnering with Patients to Understand Stigma, Disparities and Values Leading to Improved Lung Cancer Care (ID 154)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advocacy
- Presentations: 1
- Now Available
- Moderators:Diego Villalón, Christina Sit
- Coordinates: 9/09/2019, 15:45 - 17:15, Amsterdam (2011)
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MA22.05 - Assessment of Gender Differences in the Psychosocial and Economic Impact on Patients with Stage IV Non-Small Cell Lung Cancer (Now Available) (ID 718)
15:45 - 17:15 | Author(s): Oscar Juan
- Abstract
- Presentation
Background
Incidence of lung cancer in women is rising overtime reporting evident gender-based differences in epidemiology, biology, and treatment outcome. However, little is known about gender-differences regarding psychological, economic and social aspects. The objectives of this prospective study are to evaluate the psychosocial and economic impact of metastatic non-small cell lung cancer (NSCLC), according to gender. Additionally, to assess the emotional burden and the economic impact of the disease on the primary caregiver from a gender perspective
Method
Multicenter, prospective, observational, study of two cohorts of patients with metastatic NSCLC (male and female) in Oncology departments of 20 Spanish hospitals. The following measurement tools were used: the APGAR questionnaire (family functionality: adaptability, partnership, growth, affection, and resolve), the Relationship impact scale, the DUKE-UNC scale (perceived socio-affective support), the patient and the caregiver economic impact scale and the Zarit scale (caregiver burden). All questionnaires were performed at the first visit, repeated 4 months later and following the first and second disease progression.
Result
Of the 333 pts included, 104 were females and 229 male, of whom 63% and 97%, respectively, were smokers/ex-smokers (p=0.0001). More women than men (85% vs 70%) had adenocarcinomas . The median overall survival was longer in women but did not reach statistical significance [17.1 vs 11.0 months, HR 0.732 (95% CI 0.534 to 1.005), p=0.0524]. Most families considered themselves functional (high score in APGAR questionnaire) with no changes in their partner relationship and social support was evaluated as optimal for majority of patients. Around a quarter of interviewed patients said their economic situation was a little worse after the lung cancer diagnosis, without remarkable differences by gender. Statistically significant differences were found between both groups regarding the caregiver´s relationship to the patient (more parents were the caregiver in females than in males) (p <0.0001) and the caregiver’s employment situation (more employed caregivers in females) (p<0.0001). Most caregivers of both sexes considered that taking care of their relative did not pose a significant burden. No remarkable differences by gender were found between the different variables across the study.
Conclusion
This study provides a preliminary insight into gender-related characteristics in the management of advanced NSCLC and its impact on the emotional, social and economic burden of patients and their caregivers, and recall the high priority of researching in cancer from a gender perspective
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OA03 - Systemic Therapies for SCLC: Novel Targets and Patients' Selection (ID 121)
- Event: WCLC 2019
- Type: Oral Session
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Now Available
- Moderators:Christine Lee Hann, Makoto Nishio
- Coordinates: 9/08/2019, 13:30 - 15:00, Hilton Head (1978)
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OA03.03 - Initial Efficacy and Safety Results of Irinotecan Liposome Injection (nal-IRI) in Patients with Small Cell Lung Cancer (Now Available) (ID 1985)
13:30 - 15:00 | Author(s): Oscar Juan
- Abstract
- Presentation
Background
SCLC accounts for ~15% of lung cancers, with 5-year survival <10%. 50-90% of patients with extensive disease respond to initial treatment; many rapidly relapse due to acquired resistance to front-line platinum-based chemotherapy. Limited treatment options are available for second-line patients. nal-IRI is a liposomal formulation of irinotecan (topoisomerase-1 inhibitor), utilizing intraliposomal stabilization technology to enable high drug load and in-vivo stability.
Method
RESILIENT (NCT03088813) is a two-part Phase 2/3 study assessing the safety, tolerability, and efficacy of monotherapy nal-IRI in SCLC patients who progressed on/after a front-line platinum regimen: Part 1 includes dose-finding then dose-expansion. Key eligibility criteria included ECOG PS 0-1 and adequate organ function, with prior exposure to immunotherapy allowed. Eligible patients received nal-IRI 70mg/m2 or 85mg/m2 (free-base equivalent) q2w. Primary endpoints were safety and tolerability. Efficacy assessments included objective response rate (ORR), best overall response (BOR), progression-free survival (PFS), and overall survival (OS).
Result
30 patients were treated for >12 weeks in Part 1 (male, 43%; median age, 60.4y; platinum-resistant, 40%) with tumor assessments q6w. During dose-finding, 5 patients received nal-IRI 85mg/m2 (deemed not tolerable: dose-limiting toxicity) and 12 patients received nal-IRI 70mg/m2 (deemed tolerable: selected for dose expansion). At data cut-off** (median follow-up, 4.4mo), 25 patients had received nal-IRI 70mg/m2. Diarrhea was the most common gastrointestinal adverse events (AEs) (Gr3, 20%). Hematologic AEs included neutropenia (Gr3, 8%; Gr4, 8%), anemia (Gr3, 8%), febrile neutropenia (Gr3, 4%), thrombocytopenia (Gr3, 4%; Gr4, 4%). Preliminary efficacy identified 11 patients with partial responses (ORR 44%), BOR (PR+SD) of 72%, and 12-week disease control rate (DCR12wks PR+SD) of 48%. PFS and OS are not yet mature.
Conclusion
Part 1 demonstrated encouraging anti-tumor activity for nal-IRI 70mg/m2 in patients with SCLC (ORR: 44%, BOR: 72%). nal-IRI 70mg/m2 was generally well tolerated. Future research is warranted to assess nal-IRI in second-line SCLC.
Table 1. Baseline Demographic, Patient Disposition, Safety & Tolerability, and Clinical Efficacy for Part 1 of the RESILIENT studyDose-Finding /
Dose-Exploration PhaseIrinotecan
Liposome
Injection
85mg/m2
(N=5)Irinotecan
Liposome
Injection
70mg/m2
(N=25)Baseline Characteristics Gender, Male, n (%) 3 (60.0) 10 (40.0) Age (Years, median) 62.0 59.0 Baseline ECOG 0 1 (20.0) 3 (12.0) 1 4 (80.0) 22 (88.0) Time Since Most Recent Progression (Weeks, median) 3.4 3.2 Disease Location, n (%) Locally Advanced 0 2 (8.0) Metastatic 5 (100.0) 23 (92.0) Disposition, n (%) Patient Completed Study 4 (80.0) 12 (48.0) Patient Currently Ongoing* – 7 (28.0) Deaths 2 (40.0) 6 (24.0) Disease Related 1 3 Adverse Event Not Related to Study Drug 1 1 Cardiac Arrest 1 - Hepatic Failure - 1 Adverse Event Related to Study Drug 0 2 Abdominal Sepsis - 2 Patient Discontinued Treatment 5 (100.0) 18 (72.0) Safety & Tolerability, n (%) Any Treatment-Emergent Adverse Event (TEAE) 5 (100.0) 25 (100.0) Grade 3 or Higher TEAE (≥ 2 patients) 5 (100.0) 15 (60.0) Neutropenia 1 (20.0) 4 (16.0) Anemia – 2 (8.0) Thrombocytopenia – 2 (8.0) Diarrhea 3 (60.0) 5 (20.0) Asthenia – 2 (8.0) General Physical Health Deterioration – 2 (8.0) Pneumonia 2 (40.0) 1 (4.0) Abdominal Sepsis – 2 (8.0) Hypokalemia 1 (20.0) 2 (8.0) Renal Failure – 2 (8.0) Best Overall Response Complete Response (CR) – – Partial Response (PR) 2 (40.0) 11 (44.0) Stable Disease 1 (20.0) 7 (28.0) Progressive Disease 1 (20.0) 5 (20.0) Non-evaluable 1 (20.0) 2 (8.0) Objective Response Rate CR + PR 2 (40.0) 11 (44.0) Non-responder 3 (60.0) 14 (56.0) ** Data Cut-off: May 8, 2019. * Per RECIST v1.1 or RANO criteria. 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.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-111 - ATEZO-BRAIN, A Single-Arm Phase II Study of Atezolizumab Combined with Chemotherapy in Stage IV NSCLC Patients with Untreated Brain Metastases (ID 733)
09:45 - 18:00 | Author(s): Oscar Juan
- Abstract
Background
Brain metastases (BM) are a frequent complication in non-small cell lung cancer (NSCLC), have significant impact on quality of life and are associated with poor prognosis. Systemic therapies might be an alternative approach to whole brain radiotherapy (WBRT) to avoid cognitive-related adverse events. Immune checkpoint inhibitors (ICI) showed intracranial activity in advanced NSCLC patients with BM. However clinical data about efficacy and safety of immune checkpoint inhibitors in combination with chemotherapy in patients with untreated BM are limited and further research in this setting is needed. We hypothesize that addition of ICI to conventional platinum-based chemotherapy may increase intracranial tumor response and provide clinically relevant benefit in terms of PFS, OS and quality of life to the patients with asymptomatic and non-previously treated BM.
Method
This is an ongoing multicenter, open-label, single-arm phase 2 study (EUDRACT: 2017-005154-11) to evaluate the efficacy and safety of atezolizumab 1200 mg combined with 4-6 cycles of carboplatin AUC 5 and pemetrexed 500mg/m2 every 3 weeks followed by maintenance with atezolizumab 1200 mg plus pemetrexed 500mg/m2 every 3 weeks in stage IV non-squamous NSCLC patients with untreated synchronous BM. Patients should have multiple and measurable BM, adequate performance status and organic function, do not harbor EGFR or ALK genomic alterations, be treatment naïve and do not have any contraindication to receive immunotherapy. Exclusion criteria consist of active neurological symptoms, dexamethasone dose ≥ 4 mg QD, prior treatment with brain radiotherapy, presence of leptomeningeal carcinomatosis, spinal or hemorrhagic metastases in the central nervous system. Primary endpoints are progression-free survival (PFS) at 12 weeks according to RANO-BM and RECIST v1.1 criteria and safety based on CTCAE v4. Both primary endpoints will be assessed in 40 patients in 15 sites using a Bayesian approach. Patients will undergo tumor assessments by body CT scan and brain MRI at baseline every 6 weeks for the first 12 weeks and thereafter tumor assessments will be performed every 9 weeks until disease progression or loss of clinical benefit. Secondary endpoints: intracranial and systemic objective response rate and duration of response. Exploratory endpoints: to assess neurocognitive function and quality of life; to determine time to neurological deterioration and time to need of salvage brain radiotherapy. Enrollment started on August 2018 and currently 12 patients have been included in the study.
Result
Clinical trial in progress
Conclusion
Clinical trial in progress
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P1.01-93 - Metastases Sites as a Prognostic Factor in a Real-World Multicenter Cohort Study of Spanish ALK-Positive NSCLC Patients (p) (ID 1377)
09:45 - 18:00 | Author(s): Oscar Juan
- Abstract
Background
ALK gene rearrangements are detected in 3-7% of Non-Small-Cell-Lung-Cancer (NSCLC) p. EML4-ALK translocation was first identified as an oncogene in NSCLC p in 2007. To date, published real-world data on the prognostic factors of patients with ALK-positive advanced NSCLC in Spain are limited. We aim to evaluate the effect of number of metastases (M1) organs on overall survival (OS) in a multicenter cohort of Spanish ALK-positive NSCLC p diagnosed between 2008 and 2017.
Method
We included p with stage IV at diagnosis since 2011 to April 2018. OS (months [m]) was estimated with the Kaplan-Meier method. Survival curves were compared between groups of p using the log-rank test. Hazard risk (HR) to death was estimated with multivariable Cox model, adjusted by site of metastases, gender, age and first line type of treatment.
Result
Out of the 163 p in the cohort a total of 98 p were included, with a median follow-up of 28.6 m and 45 deaths reported. Characteristics at diagnosis were median age 58 years, female 46.9%, never-smokers 59.2%, 50% with comorbidities, PS by ECOG 0-1 93%, 58.2% lung M1, 45.9% central nervous system M1, 42.9% bone M1, 22.4% liver M1 and 29.6% pleural M1.
54.3% p and 89.4% p were treated with ALK inhibitors as first line and second line respectively. The median OS was 34.4 months, being 46.9 months in p treated with ALK inhibitors and 38.8 months in p treated with chemotherapy as first line (p= 0.9).
There were 72 p who presented M1 in more than one organ and 26 p in a single organ. The risk of death increased with greater number of organs involved at diagnosis (HR= 3.0, p=.016), and presenting liver M1 at diagnosis (HR=2.2, p=.046, with OS of 19.1 m), compared to p single site involvement (OS: 45.4 m).
Conclusion
OS was worse with increased metastatic sites involved at diagnosis in p with ALK positive NSCLC, being liver M1 associated with the highest risk of mortality. Brain metastases at diagnosis were not a prognostic factor for OS in our series.
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P1.03 - Biology (ID 161)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.03-26 - Genetic and Molecular Profiling of Non-Smoking Related Lung Adenocarcinomas (ID 1701)
09:45 - 18:00 | Author(s): Oscar Juan
- Abstract
Background
The etiology and many details of the genomic profile and molecular basis of lung adenocarcinomas (LuADs) in nonsmoker patients remain elusive. Further, the scarcity of primary cultures available from non-smoking related lung adenocarcinomas (NSK-LuADs) contributes to hamper our biological understanding of these tumors.
Method
We established patient-derived cancer cell (PDCs) cultures from NSK-LuADs, and performed whole exome sequencing (WES) and RNA sequencing (RNA-seq) analysis to delineate their genomic architecture. For validations, we analyzed independent cohorts of LuADs.
Result
The analysis revealed non-smoker related alterations such as those at the growth factor receptors RET, ALK, EGFR and ERBB2. There were also mutations affecting signal transduction molecules such as AKT1, BRAF and KRAS, and mutations in tumor suppressor genes, including TP53, CDKN2A, RB1, ARID1A, ATM and STK11. We also identified new fusions and recurrent mutations in some genes, one of them, a possible regulator of gene expression, affecting ten percent of the LuADs, thus constituting a potentially relevant tumor suppressor gene. We also report a predominance of RB1-inactivation, mostly complex intragenic rearrangements (homozygous deletions or duplications) in EGFR-mutant tumors. Three EGFR-/RB1-mutant tumors, treated with EGFR-TKIs, and one EGFR-wild type tumor, treated with standard chemotherapy, developed small cell lung cancer and/or squamous cell carcinoma transformation, evident in the re-biopsies and/or PDCs. Finally, we found pathogenic germ-line mutations at genes associated to familiar-cancer syndromes, especially the TP53-associated Li Fraumeni syndrome, affecting ten percent of EGFR-mutant LuADs patients, underscoring a genetic predisposition origin for a subset of NSK-LuADs.
Conclusion
The recurrent gene inactivation found in candidate gene in LuADs heralds a tumor suppressor role which deserves further exploration. The pre-existent inactivation of RB1 predominates in EGFR-mutant tumors and may underlie an extremely ductile nature, albeit additional gene alterations are required to overcome sensitivity to the TKIs. Given their potential clinical and therapeutic implications, testing for RB1-alterations and for the Li-Fraumeni syndrome in EGFR-mutant LuADs patients may need to be incorporated in the clinical settings.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-10 - Real Clinical Practice Study to Evaluate 2 Line Treatment Based on Comprenhensive Genomic Profiling in NSCLC. LungONE Study (Now Available) (ID 1558)
10:15 - 18:15 | Author(s): Oscar Juan
- Abstract
Background
Cancer is a genomic disease and molecular-targeted therapy plays an increasingly important role in the treatment of advanced NSCLC. The current standard of care (SoC) indication for NSCLC is defined by genomic biomarkers to classify the tumor as a carrier of a therapeutic approved target. However, the current standard of practice for molecular testing in NSCLC in Spain is highly heterogeneous, depending on several factors such as hospital size, resources, laboratory equipment and experience. In addition, there are several other markers and/or genomic signatures which are not determined due to the current lack of scientific evidence, i.e. MSI, TMB, KRAS, BRAF, RET, MET, HER2 and NTKR, which could guide physician second line treatment choice, including clinical trial options. The aim of this study is to evaluate the impact on decision making in the 2nd line treatment using a comprehensive genomic profiling (CGP) in advanced/metastatic NSCLC with adenocarcinoma histology.
Method
Section not applicable
Result
Section not applicable
Conclusion
This is a multicenter, prospective, single-cohort study to describe the clinical management of the 2nd line SoC treatment in patients with locally advanced/metastatic NSCLC with adenocarcinoma histology, when a comprehensive genomic profile based on FoundationOne®CDx or FoundationOne® Liquid test, is provided. 12 academic institutions in Spain were selected and 180 patients were planned to be recruited. The principal objective is to evaluate if there is any change in planned 2nd line treatment decisions after receiving the CGP report. Secondary objectives for this study are:1) to identify non-previously detected actionable molecular aberrations by conventional molecular assays; 2) to evaluate the economic impact in terms of use of healthcare resources of the CGP vs. standard diagnostic panels; and 3) to describe each patient’s status 2 years after the inclusion of the last patient in the study. Patients will follow usual clinical pathways for biomarker analysis and a comprehensive genomic profiling in the remaining tissue through FoundationOne® CDx, will be conducted or liquid biopsy with FoundationOne® Liquid, if exhausted. To be enrolled in the study, patients must have an ECOG between 0 and 2 and biomarkers ALK, EGFR, ROS1 must have been assayed (negative or unknown results). Enrolment begun on October 2018 and, to date, a total of 110 patients have been included.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-16 - Agreement Between Different Methodologies for Non-Invasive p.T790M and EGFR Sensitizing Mutation Testing (ID 1965)
10:15 - 18:15 | Author(s): Oscar Juan
- Abstract
Background
Tyrosine kinase inhibitors (TKIs) are the current standard of care for patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, most patients progressed within 1 to 2 years. The EGFR p.T790M mutation is the most common resistance mechanism to first and second generation EGFR TKIs. The identification of p.T790M mutation is of considerable clinical relevance as osimertinib has demonstrated clinical efficacy in this setting. Guidelines recommend testing for the p.T790M mutation in blood at relapse to TKIs, and re-biopsy only in case of a negative result. Several blood based methodologies for detection of EGFR mutations have been developed in the recent years. However, the number of comparison studies between platforms is very limited.
Method
This is a multicenter, cross-sectional study (ClinicalTrials.gov Identifier: NCT03363139) performed by the Spanish Lung Cancer Group. Samples from 75 consecutive EGFR mutant NSCLC patients were collected at disease progression to first line TKI treatment. The presence of EGFR mutations in the cfDNA was evaluated in 39 samples by 7 methodologies, namely: Cobas® EGFR Mutation Test v2 (Roche Diagnostics), Therascreen EGFR Plasma RGQ PCR Kit (Qiagen), QuantStudio® 3D Digital PCR System (Thermofisher), a 5′-nuclease real-time PCR (TaqMan®) assay in presence of PNA, OncoBEAM EGFR (Sysmex Inostics), NGS with two different gene panels: Oncomine® (Thermofisher) and Lung Cancer Panel (Qiagen). The agreement between methodologies was assessed using the kappa coefficient (K) and its corresponding 95% confidence intervals (95% CI). For quantitative variables the concordance correlation coefficient (ccc) was used.
Result
Complete results are available for 39 patients. Overall, the agreement between all methodologies for the detection of p.T790M mutation as well as the original EGFR sensitizing mutation was good (K=0.669; 95CI: 0.504-0.835 and K=0.750 95CI: 0.599-0.899 respectively). Remarkably, the agreement between FDA-approved methodologies for p.T790M detection was almost perfect (K=0.926; 95CI: 0.712-1) and good for the EGFR sensitizing mutations (K=0.657; 95CI: 0.417-0.902). Similarly, the agreement between NGS-based methodologies for the detection of p.T790M and the EGFR activating mutations was very high (K=0.843; 95CI: 0.567-1 and K=0.872 95CI: 0.595-1 respectively). Moreover, concordance between both technologies for p.T790M and EGFR sensitizing mutation mutant allele frequency was excellent (ccc=0.956; 95CI: 0.906-1 and ccc=0.980 95CI: 0.950-1 respectively). The proportion of samples that were positive for p.T790M detection varied from 28% (PCR based technologies) to 37% depending on the methodology.
Conclusion
NGS and PCR-based methodologies show a good to excellent agreement for the detection of EGFR mutations, including the p.T790M. Our results support the use of liquid biopsies for non-invasive testing of clinically relevant mutations (Data from the whole cohort will be presented at the meeting).
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P2.03-31 - Chemokine Receptor CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC (ID 2817)
10:15 - 18:15 | Author(s): Oscar Juan
- Abstract
Background
Activating EGFR mutations in NSCLC confer sensitivity to reversible EGFR TKIs, including gefitinib and erlotinib. Despite promising initial response, acquired resistance develops mediated by the emergence of the secondary T790M mutation or by focal amplification of MET. An epithelialtomesenchymal transition (EMT) is clinically linked to NSCLCs with acquired EGFR TKI resistance. The exact mechanisms of EGFR TKI resistance with EMT phenotype remain elusive.
Method
We have engineered EGFRmutated NSCLC cell lines with a mesenchymal phenotype by stably depleting ECadherin, overexpressing Snail, or chronically exposing the cells to TGFβ1. The resulting mesenchymal cells are resistant to EGFR TKIs. We employed genomic analyses to identify commonly activated oncogenic drivers that maintain signaling pathways upon EGFR inhibition. We also used EGFRmutated HCC4006 NSCLC cells grown resistant to gefitinib that developed a mesenchymal phenotype (HCC4006GeR). To extend our findings to in vivo, we have utilized matched pre- and post-EGFR TKI treatment samples from NSCLC patient and mouse models of acquired EGFR TKI resistance to test if our approach using these cell lines is instructive.
Result
We discovered that an atypical GPCR, CXC chemokine receptor type 7 (CXCR7), is commonly overexpressed in the cell line models of EGFR TKI resistance with a mesenchymal phenotype. The murine tumors driven by human EGFR exon19 deletion/T790M (TD) with acquired resistance to WZ4002 present mesenchymal phenotype and overexpress CXCR7. 50% of NSCLC patients harboring an EGFR kinase domain mutation who progressed on EGFR inhibitors showed an increase in CXCR7 expression. Using the cell line model of EGFR TKI acquired resistance with a mesenchymal phenotype, we find that CXCR7 activates the MAPK-ERK pathway via b-arrestin. Depletion of CXCR7 abrogates the MAPK pathway and significantly attenuated EGFR TKI resistance in the cells with a mesenchymal phenotype. In the long term, the depletion of CXCR7 resulted in mesenchymal to epithelial transition. Ectopic overexpression of CXCR7 in HCC4006 cells was sufficient in activation of ERK1/2 for the generation of EGFR TKI resistant cells. Furthermore, CXCL12 stimulation resulted in an increase in ERK phosphorylation while EGFR was inhibited in HCC4006Ge-R cells. Similarly, we found we found CXCL12 expression is elevated in patient samples with increased CXCR7 expression.
Conclusion
Taken together, we discovered that the CXCR7-CXCL12 signaling axis is necessary and sufficient for the maintenance of EGFR TKI resistance with mesenchymal phenotype and CXCR7 inhibition could significantly delay and prevent the emergence of acquired EGFR TKI resistance in EGFR mutant NSCLC.
