Immune checkpoint inhibitors in advanced non–small cell lung cancer: A metacentric experience from India

Immune checkpoint inhibitors in advanced non–small cell lung cancer: A metacentric experience from India

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Current Problems in Cancer xxx (xxxx) xxx

Contents lists available at ScienceDirect

Current Problems in Cancer journal homepage: www.elsevier.com/locate/cpcancer

Immune checkpoint inhibitors in advanced non–small cell lung cancer: A metacentric experience from India Q1

Santosh Kumar a, Srujana Joga b, Bivas Biswas c, Deepak Dabkara c, Kuruswamy Thurai Prasad d, Navneet Singh d, Prabhat Singh Malik a, Sachin Khurana a, Sandip Ganguly e, Valliappan Muthu d, Ullas Batra f,∗ a

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Department of Medical Oncology, Dr B.R.A. Institute-Rotary Cancer Hospital., All India Institute of Medical Sciences, New Delhi, India b DNB General Medicine, DNB resident, Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India c Department of Medical Oncology, Tata Medical Center, Kolkata, India d Department of Pulmonary Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India e Department of Medical Oncology, Tata Medical Center, Kolkata, India f Medical Oncology, Chief of Thoracic Medical Services, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India

a b s t r a c t Background: Immune check point inhibitors (ICIs) have changed the treatment paradigm of driver mutation negative non–small cell lung cancer (NSCLC) and they are increasingly incorporated in first-line treatment. Real-world experience of use of these drugs is limited. We aim to evaluate the real-world experience of use of ICIs in patients with advanced NSCLC. Patients and methods: Medical records of patients with NSCLC treated with ICIs at 4 major academic cancer centers in India between January 2016 and December 2018 were analyzed. The type of ICI taken, response rates, survival, and toxicity profiles were analyzed. Results: The median age at presentation was 60 years (range: 27-79 years). Nivolumab was the most commonly used ICI drug [80%, n = 70] followed by pembrolizumab [10%, n = 9], and atezolizumab [10%, n = 9]. The median number of ICIs cycles received were 4 (range 2-65). Among the evaluable responses in



Funding: No funding was received for this study. Conflicts of Interest: Each of the authors declares that there is no conflict of interest ∗ Correspondence to: Ullas Batra MD, DM, ECMO, Medical Oncology, Chief of Thoracic Medical Services, Rajiv Gandhi Cancer Institute and Research Centre, Sector-5, Rohini, New Delhi 110085. E-mail address: [email protected] (U. Batra). ✩✩

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https://doi.org/10.1016/j.currproblcancer.2020.100549 0147-0272/© 2020 Published by Elsevier Inc.

Please cite this article as: S. Kumar, S. Joga and B. Biswas et al., Immune checkpoint inhibitors in advanced non– small cell lung cancer: A metacentric experience from India, Current Problems in Cancer, https://doi.org/10.1016/j. currproblcancer.2020.100549

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74 patients, the objective response rates was 25.6% and clinical benefit rate was 46%. Immune related toxicity occurred in 39.9% of patients but, severe toxicity of Grade III and Grade IV occurred in 5 (5.6%) patients. After a median follow-up time of 8.86 months (95%CI 5.2-11.1) the progression-free survival was 4.73 months (95%CI 3.7-8.9), and overall survival was 11.6 months (95%CI 7.33-NR). ECOG PS at the time of start of ICIs was found to be significant determinant of Progression-free survival and overall survival. Conclusion: Our study demonstrates the feasibility of usage of ICIs in advanced NSCLC in Indian setting with acceptable safety profile and comparable responses with the published studies.

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© 2020 Published by Elsevier Inc.

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Keywords: Immune check point inhibitors; Advanced non–small cell lung cancer; India

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Introduction

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Evasion of host immunity is identified as one of the hallmarks of cancer.1 Harnessing host immunity against cancer by blocking checkpoints like PD1-PDL1 (programmed death receptorprogrammed death ligand-1) axis and CTLA-4 (cytotoxic T lymphocyte associated protein-4) is the premise of treatment with immune check point inhibitor (ICIs).2 Check point inhibitors have been shown to be effective in multiple cancers. Treatment responses were observed in melanoma, lung, renal, head, and neck malignancies.3-6 At present the whole treatment paradigm of non–small cell lung cancer has changed and ICIs have moved to even first-line treatment in driver mutation negative patient population either alone or in combination.7 , 8 Longterm data from early trials of ICIs have demonstrated the survival improvement even at 5 years in a proportion of patients of metastatic disease.3 , 9 Immunohistochemistry of PD-L1 serves as a predictive biomarker for selecting patients for ICIs however variations of antibody clones, staining platforms and reporting cut offs used in various trials of ICIs make its clinical use more complex.10 Tumor mutation burden is another potential biomarker however technical complexities, cost, and variations in the results make its use limited to few centers where technical expertise are available.11 Much of the experience of the immune checkpoint inhibitors (ICIs) is from the randomized controlled trials, where stringent inclusion criteria are used and very close follow-up is present. Also, the clinical studies were conducted mostly on western population. However, the real-world experience of these drugs is limited especially in India owing to their high cost, limited expertise, and limited infrastructure for standard companion diagnostics.12-14 The data regarding immune related adverse events in Indian patients is also sparse. In this study we aim to evaluate the real-world experience of use of ICIs in patients with advanced NSCLC at 4 major academic centers in India.

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Methods

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We retrospectively analyzed the medical records of patients with NSCLC treated with ICIs at 4 major academic cancer centers in India between January 2016 and December 2018. Ethical approval was obtained from the individual institutional ethical review committees and consent waiver was granted in view of retrospective nature of evaluation. Patient’s confidentiality was maintained by coding the patient’s identifiers. Demographic, clinic-pathologic, treatment, treatment outcome, and toxicity details were entered in a predesigned proforma. Patients who received more than 1 cycle of ICIs drugs either PD-1 inhibitors (nivolumab/pembrolizumab) or PD-L1 inhibitors (atezolizumab) were included in the study. The dosages were according to the standard international recommendations. The drugs were continued until intolerable toxicities

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or disease progression. Clinical evaluation was done after each cycle. Radiological evaluation was performed by computed tomography or positron emission tomography/computed tomography scans as per institutional policies after 3-4 cycles and as and when clinically indicated subsequently. RECIST v1.1 was used for recording responses and CTCAE (ver 4.0) was used for toxicities. Toxicity management was done as per standard guidelines including immune related adverse event management. Progression-free survival (PFS) was calculated from date of start of ICIs to date of progression or death. Overall survival (OS) was calculated from date of initiation of ICIs till date of death due to any cause. Data was censored on May 31, 2019 or when the patient was last known to alive (alive without disease progression for PFS).

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Statistical methods

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Descriptive statistics was used to describe baseline characteristics of the patients. χ 2 or Fisher’s exact test was used to detect an association between categoric variables. Survival was estimated by the Kaplan-Meier method. Various subgroups were compared using the log-rank test. Cox regression analysis was used to assess factors predicting survival. STATA v 13(Stata Corp. 2013. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP) was used for statistical analysis.

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Results

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Baseline characteristics

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A total of 88 patients from 4 major academic cancer centers from India were included for the analysis. The median age at presentation was 60 years (range: 27-79 years) (Table 1). Majority of the patients (88%) were male. About 35 % of the patients had 2 or more comorbidities and 70% were current or former smokers. An Eastern Cooperative Oncology Group performance status (PS) of 2 or more at start of ICIs was found in 38.6% of patients. A single patient had diagnosis based on fluid cytology, remainder of the patients were diagnosed based on biopsy. Adenocarcinoma was the most common histologic subtype (53%) followed by squamous cell carcinoma (43%). Three patients were EGFR mutated adenocarcinoma and none had ALK gene rearrangement. PDL1 status was known in only 39 patients and 11 of them (28%) had a Tumor proportionate score (TPS) of ≥50. Most of the PDL1 testing were done by Ventana SP263 antibody (70%) and DAKO 22C3 was used in only in 5 cases.

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Treatment and response

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Nivolumab was the most commonly used ICI drug [80%, n = 70] followed by pembrolizumab [10%, n = 9], and atezolizumab [10%, n = 9] (Table 2). ICIs were used in first line of therapy only in 4 patients. Most patients (67%) received as second-line therapy and remaining patients received in third or subsequent lines of therapy. Out of the patients who received ICIs beyond first line of treatment, all but 1 patients had received chemotherapy as their first-line treatment. One patient with sensitizing EGFR mutation had EGFR TKI before starting ICI. Among patients who received ICIs beyond first line, duration of prior treatment was available in 53. Duration of prior treatment ≥6 months was there in 15 (28.3%) cases. The median number of ICIs cycles received were 4 (range 2-65). Among all the patients, radiological response was evaluable in 74 patients. Complete response was observed in 1 patient, partial response in 24% of patients giving an objective response rates of 25.6% (Table 3). Stable disease was the best response achieved in 15 cases suggesting a clinical benefit rate of 46%. Patients with high PD-L1 TPS (≥50) had significantly higher objective response rates compared to patients with TPS of 1-49 or 0 (53.85% vs 15.4% vs 30.7%; P = 0.032).

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66 Q5 67 68 69 70 71 72 73 74 75 76 77 78

Please cite this article as: S. Kumar, S. Joga and B. Biswas et al., Immune checkpoint inhibitors in advanced non– small cell lung cancer: A metacentric experience from India, Current Problems in Cancer, https://doi.org/10.1016/j. currproblcancer.2020.100549

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Table 1 Baseline characteristics of patients. Baseline characteristics

N (%) (N = 88)

Age (median-range) Sex • Male • Female

60 y (27-79) 78 (88%) 10 (12%)

Smoking • Smokers • Nonsmokers

62 (70%) 26 (30%)

Comorbidities • No comorbidity • Single • ≥2 • Unknown

18 (20.45%) 25 (28.40%) 30 (35.1%) 15 (17.04%)

PS • • • •

15 (17%) 39 (44%) 31 (35%) 3 (3%)

0 1 2 3

Stage: • 3A • 4

6 (6.8%) 82 (93.2%)

Histology • Adenocarcinoma • Squamous cell carcinoma • Adenosquamous • Others

47 (53.4%) 38 (43.2) 2 (2.27%) 1 (1.14%)

PD • • •

39 16 (41%) 12 (30.7%) 11 (28.3%)

L1 status known 0 1-49% ≥50%

EGFR (available in 48) • Positive • Negative ALK (available in 47) • Negative

3 (6.25%) 45 (93.75%) 47 (100%)

Table 2 Treatment given. N = 88 Check point inhibitor • Nivolumab • Pembrolizumab • Atezolizumab

70 (79%) 9 (10%) 9 (10%)

Line of therapy • First line • Second line • >2 lines Number of cycles

4 (4%) 59 (67%) 25 (28%) 4 (2-65) median

Please cite this article as: S. Kumar, S. Joga and B. Biswas et al., Immune checkpoint inhibitors in advanced non– small cell lung cancer: A metacentric experience from India, Current Problems in Cancer, https://doi.org/10.1016/j. currproblcancer.2020.100549

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Table 3 Response to therapy. Evaluable patients: 74 CR PR SD PD ORR (objective response rates) CBR (clinical benefit rates)

1 (1.35 %) 18 (24.32%) 15 (20.27)% 41 (55.4%) 25.6% 45.9%

CR, complete response; PR, partial response.

Fig. 1. Kaplan-Meier survival curves; (A) progression-free survival; (B) overall survival.

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Toxicity

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Some form of immune related toxicity was observed in 39.9% of patients. Grade III and Grade IV toxicities occurred only in 5 (5.6%) patients. Endocrine abnormalities were found in 8 (9%) patients, skin toxicity in 6 patients, pneumonitis in 5 patients, diarrhea in 3 patients, and hematological toxicities were seen in 3 patients. Auto immune meningoencephalitis, myocardial infarction, and Addison’s disease each were observed in 1 patient. There were 2 treatment related deaths. One patient died due to autoimmune meningoencephalitis and another one due to acute myocardial infarction. Hyperprogression of disease was seen in 4 patients. All of these patients were males, smoker, and had adenocarcinoma histology. PD-L1 TPS was 0 in 3 of them and all of these patients received ICI as second-line treatment.

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Survival analysis

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After a median follow-up time 8.86 months (95%CI 5.2-11.1) the PFS was 4.73 months (95%CI 3.7-8.9) and OS was 11.6 months (95%CI 7.33-NR; Fig 1A and B). At the time of data analysis, 50 PFS events (disease progression/death) and 33 deaths had occurred. ECOG PS at the time of start of ICIs was found to be significant determinant of PFS and OS. The median PFS in patients with PS 0/1 was 10 months (95% CI 14.43-14.56), whereas in patients with PS ≥ 2, it was 3.2 months (95%CI 2.23-4.9), hazard ratio 2.01 (95%CI 1.14-3.50) P = 0.012 . Similarly median OS of patients with PS 0/1 was not reached (95%CI 10.9-NR), whereas in patients with PS > 2 it was 5.9 months (4.7-11.63) hazard ratio 2.06 (95%CI 1.03-4.11) P = 0.03 (Fig 2A and B). PD-L1 TPS was not found significantly associated with PFS or OS however

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Please cite this article as: S. Kumar, S. Joga and B. Biswas et al., Immune checkpoint inhibitors in advanced non– small cell lung cancer: A metacentric experience from India, Current Problems in Cancer, https://doi.org/10.1016/j. currproblcancer.2020.100549

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Fig. 2. Kaplan-Meier survival curves according to ECOG PS; (A) progression-free survival; (B) overall survival.

Fig. 3. Progression-free survival according to PD-L1 TPS.

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in patients with TPS ≥50% PFS was numerically higher than patients with TPS 0% or 1-49% (2.2 months, 3.9 months, and 14.56 months, respectively) (Fig 3).

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Discussion

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ICIs are a novel class of drugs showing efficacy in advanced NSCLC. Initially showed efficacy in later lines of therapy.15-17 Now they are approved in frontline setting, especially in driver mutation negative metastatic NSCLC.18-19 They are also being used in curative settings especially post chemo-radiotherapy as consolidation treatment.20 Now combinations of ICIs with chemotherapy are also approved in first-line treatment.6 Most ICIs regulatory trials were conducted outside India leading to lack of data on safety and efficacy of ICIs in Indian patients. Furthermore availability and regulatory approvals of these agents were delayed making real-world experience limited. Our study provides a glimpse into the real-world use of immunotherapy drugs outside clinical trial setting in Indian patients.

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The objective response rate of 25.6% and clinical benefit rate of 46% were observed in our study. In large prospective randomized clinical studies, the objective response rate for single agent immunotherapy in second-line setting with pembrolizumab was 18%, with nivolumab it was 19%, and with atezolizumab it was 14%.15-16 The possible reasons for slightly higher response rate might be limited number of patients, retrospective nature of the study. Those patients who have received only single cycle and no further follow-up were excluded from the study. The ideal yard stick for measurements of responses to immunotherapy is under development. In our study RECIST 1.1 criteria was used for response assessment.21 There is an unique pattern of pseudo-progression with ICIs for which immune RECISE(i-RECIST) is suggested for response assessment.22 In view of these differences clinical benefit rate is used as an indicator for disease stabilization and response. Clinical benefit rate in our series is 46%. It is similar to other published reports.17 In a small series of retrospective study of 8 patients of metastatic NSCLC among Indian patients showed a clinical benefit rate of 50%.23 The median PFS was 4.73 months and median OS was 11.6 months in our study. These are also similar with the published prospective trial results and real-world data.24 The median progression-free survival and OS reported with use of nivolumab was 3.5 months and 9.2 months respectively.15 Few long-term durable responses are seen in our patients. One patient received 65 cycles of ICI in our cohort. These long-term durable responders were reported in other studies also.9 There is no ideal predictive biomarker for usage of ICIs. Most commonly recommended is the use PD-L1 testing by immunohistochemistry.10 In our study cohort it could be done in only 44% of the patients since most patients received ICIs in second or subsequent lines. Significantly higher responses were observed in patients with PD-L1 TPS ≥50% as compared to those with TPS 1%-49% or 0%.However objective responses were observed in cases with TPS of 0% as well (30.7%). There were numerically higher PFS and OS in those patients with higher TPS scores (≥50%), although this was not statistically significant possibly due to small number of patients with PD-L1 information. PD-L1 testing was not done in all our patients. On univariate cox regression analysis, of the various parameters analyzed only ECOG PS was found to be significant for PFS and OS. ECOG PS of ≥ 2 was associated with significantly inferior outcomes compared with PS of 0/1. In large prospective randomized clinical studies for approval of ICIs included patients with ECOG PS of 0/1 only.15-17 Data of use of ICIs in patients with poor PS is limited. Although our analysis suggest that patients with poor PS do badly even with ICIs, it has to be prospectively validated. In the real-world usage the ICIs toxicity is manageable. Treatment-related adverse events of any grade were observed in 39.9% of patients; of these 5.6% had grade 3-4 toxicities. The most common treatment-related select AEs were of the endocrine related followed by skin. Pneumonitis occurred in 5 patients. This toxicity profile is similar to various prospective clinical trials published.16-18 As compared with cytotoxic chemotherapy the most adverse events were modest and manageable. There was 1 acute coronary syndrome resulting in death. Myocardial infarctions are reported post usage of ICIs in other studies.25 , 23 There was a second mortality due to autoimmune meningoencephalitis not responding to steroids. Endocrine adverse events were manageable with hormone replacement without any requirement of steroids. Our study also showed that ICIs can be used safely with manageable toxicity profile even in patients with poor ECOG PS and patients with comorbidities and in later lines of therapies. About 35% of our patients had ≥2 comorbidities and ECOG PS of ≥2 was present in 38% of our patients. In 28% of patients ICIs were used as ≥3 lines of therapy. These 3 subsets of patient groups are underrepresented in large prospective multicenter randomized clinical trials. Our study is the first multicenter study from 4 academic centers from India reporting the experience of use of ICIs. Till date there is only 1 small single center study of 20 patients, of which lung cancer constituted of 8 patients reporting the use of ICIs in India.12 , 23 Our analysis confirms that ICIs are equally efficacious and safe in Indian patients with advanced NSCLC. Apart from being a retrospective in nature our study has several limitations. Response assessment was available only in 74 patients of total 88 patients and periodic assessments have

Please cite this article as: S. Kumar, S. Joga and B. Biswas et al., Immune checkpoint inhibitors in advanced non– small cell lung cancer: A metacentric experience from India, Current Problems in Cancer, https://doi.org/10.1016/j. currproblcancer.2020.100549

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been done at variable intervals as per individual institutional practices, making PFS assessment a little difficult. Further PD-L1 status was not available in all patients.

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Conclusions

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This multicentric real-world data analysis demonstrates the feasibility of usage of ICIs in advanced NSCLC in Indian setting with acceptable safety profile. The responses and survival are 169 comparable to international prospective randomized clinical trials despite having more patients 170 with multiple comorbidities, poorer ECOG PS and use of ICIs in later lines of therapy in our 171 study. ECOG PS of ≥2 is associated with poorer outcomes. 167

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References

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