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Fernando José Barata
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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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