|Year : 2019 | Volume
| Issue : 4 | Page : 315-319
An observational single-center study of nivolumab in Indian patients with recurrent advanced non-small cell lung cancer
Naresh Somani1, Pawan Agarwal1, Harish Singhal1, Abhishek K Singh1, Abhilasha Sinha1, Rajshri Somani2, Jia Agarwal3, Shaurya Dugar1
1 Department of Medical Oncology, Bhagwan Mahaveer Cancer Hospital and Research Centre, Jaipur, Rajasthan, India
2 Mahatma Gandhi National Institute of Medical Sciences, Jaipur, Rajasthan, India
3 Somex Healthcare Ltd, Jaipur, Rajasthan, India
|Date of Web Publication||11-Oct-2019|
Department of Medical Oncology, Bhagwan Mahaveer Cancer Hospital and Research Centre, Jaipur, Rajasthan
Source of Support: None, Conflict of Interest: None
Purpose: Limited treatment options are available for patients with advanced non-small cell lung cancer (NSCLC) after failure of first-line platinum-based chemotherapy. The treatment of recurrent advanced NSCLC progressed with the arrival of nivolumab and other immunotherapeutic agents. Our single-center prospective study aimed to present the effectiveness and safety of nivolumab in second-line setting after first-line platinum doublet in Indian patients with advanced NSCLC.
Patients and Methods: Twenty-nine adult patients with stage IV NSCLC treated with nivolumab after failure of first-line platinum-based chemotherapy at Bhagwan Mahaveer Cancer Hospital and Research Centre, Jaipur, India, between October 2016 and January 2018, were included in the study. Overall survival (OS), hematological, and nonhematological toxicities were evaluated.
Results: A total of 29 patients (mean age of 59.6 years at enrollment) were evaluated. Histological evaluation revealed adenocarcinoma (44.8%) and squamous (55.2%) type of cancer. The Eastern Cooperative Oncology Group performance score was II in 7 patients (24.1%) and I in 22 (75.9%) patients. Patients received an average of four cycles of nivolumab. The median survival duration was 101 days, and OS rate in the study was 51.7%. Six patients (20.7%) had stable disease response, five patients (17.2%) had partial response, and three patients (10.3%) were lost to follow-up. Asthenia and cough were the most common nonhematological toxicities. Only three patients developed hematological toxicities (anemia and thrombocytopenia).
Conclusion: Data from our study suggest nivolumab is well-tolerated and effective in Indian patients with recurrent advanced NSCLC after failure of the multiple first lines of platinum-based combination chemotherapy.
Keywords: Hematotoxicity, India, lung cancer, overall survival, platinum-based therapy
|How to cite this article:|
Somani N, Agarwal P, Singhal H, Singh AK, Sinha A, Somani R, Agarwal J, Dugar S. An observational single-center study of nivolumab in Indian patients with recurrent advanced non-small cell lung cancer. Indian J Cancer 2019;56:315-9
|How to cite this URL:|
Somani N, Agarwal P, Singhal H, Singh AK, Sinha A, Somani R, Agarwal J, Dugar S. An observational single-center study of nivolumab in Indian patients with recurrent advanced non-small cell lung cancer. Indian J Cancer [serial online] 2019 [cited 2020 Feb 20];56:315-9. Available from: http://www.indianjcancer.com/text.asp?2019/56/4/315/268957
| » Introduction|| |
According to the World Health Organization report, lung cancer is a commonly diagnosed cancer accounting for approximately more than 1 million cancer deaths worldwide., On a global scenario, it is the second most prevalent cancer after prostate cancer in men. In India, lung cancer accounts for 5.9% of all the newly diagnosed cancer cases and contributes to 8.8% of the cancer-related mortality in both men and women.
According to the data from the GLOBOCAN 2018 report for India, the estimated incidence of lung cancer was 67,795 across all age groups of men and women. Considering the incidence rate, lung cancer ranks fourth among various types of cancer. In addition, it is the second most common cancer in men and the fourth most common cause of cancer-related death after breast, oral cavity, and cervical cancers in both men and women.
Lung cancer can be broadly classified into two types: non-small cell lung cancer (NSCLC), which accounts for a majority (80%) of all the lung cancer cases, and small cell lung cancer. NSCLC can further be subclassified into squamous cell carcinoma and adenocarcinoma.,,
According to a pathological review conducted in more than 400 confirmed lung cancer cases at All India Institute of Medical Sciences, New Delhi, over a duration of 3 years, squamous cell carcinoma emerged as the common histopathological lung cancer during the independent histopathological review. The same data, when analyzed by expert pathological review team revealed that adenocarcinoma instead of squamous cell carcinoma emerged as the most common lung cancer subtype. Hence, accurate histopathological, immunohistological, and molecular analysis is an important step toward designing a personalized treatment regimen for lung cancer.,
Cancer staging or the extent of disease forms the basis of NSCLC treatment, and surgical intervention is the preferred choice in early stage (stage I) of the disease. Stage II and stage III patients are treated with multidisciplinary approach. Stage II patients not considered fit for surgical treatment are managed with chemoradiotherapy approach. Postoperative radiotherapy is given to stage III cases to reduce the local relapse.,, Various guidelines recommend cytotoxic platinum-based combination chemotherapy as the first-line therapy for stage IV NSCLC except for definite therapy-amenable oligometastatic disease. Second-line therapy includes docetaxel in combination with ramucirumab, pemetrexed, and targeted immunotherapeutic agents.,, However, despite the advancement in cancer treatment modalities, a significant improvement needs to be made for tackling the toxicities of current therapies and improving the long-term survival benefits in patients with advanced NSCLC.,
The highly selective programmed cell death 1 (PD-1) inhibitors, which function as immune checkpoint inhibitors, are becoming a promising immunotherapeutic approach. They increase the antitumor activity of the immune system, significantly improving the therapeutic outcomes in patients with cancer., Nivolumab, one of the immunotherapeutic agents, is a recently approved immune checkpoint inhibitor that improves the overall survival (OS) rate in patients with advanced recurrent NSCLC previously treated with platinum-based chemotherapy. Data from various international, randomized controlled trials have revealed that nivolumab provides an improved median and OS in patients with NSCLC when compared with docetaxel. In addition, data show that nivolumab has a better safety profile than docetaxel.,
However, there is dearth of data from clinical studies regarding the nivolumab immunotherapy in the Indian population. Hence, we aim to provide effectiveness and safety data of nivolumab unique to Indian patients with recurrent advanced NSCLC after failure of first-line platinum-based combination chemotherapy.
| » Patients and Methods|| |
This was a single-center, nonrandomized, observational study wherein the data were collated in a prospective manner.
The study included 29 adult men and women patients diagnosed with recurrent stage IV NSCLC cancer and treated with nivolumab monotherapy at Bhagwan Mahaveer Cancer Hospital and Research Centre, Jaipur, India, between October 2016 and January 2018. Inclusion criteria included histopathologic diagnosis of recurrent NSCLC, age between 18 and 75 years, Eastern Cooperative Oncology Group (ECOG) performance status between 0 and II, and failure of platinum-based doublet chemotherapy and currently receiving nivolumab. Exclusion criteria included prior malignancy or deemed inappropriate by the treating physician for enrolment in the study.
The primary objective of the study was to evaluate nivolumab's effectiveness through OS and safety through incidences of hematological and nonhematological toxicities in patients with stage IV lung cancer after failure of first-line platinum-based combination chemotherapy.
Histopathological staging (stage IV NSCLC) was performed for all the patients based on TNM classification of the Union for International Cancer Control and the American Joint Committee on Cancer. All the enrolled patients were epidermal growth factor receptor gene (EGFR)- and anaplastic lymphoma kinase (ALK) mutation-negative. Patients in whom previously first-line platinum-based doublet for NSCLC had failed were administered nivolumab by the investigator.
The efficacy of nivolumab was assessed by OS of the patients. OS was defined as the time from randomization until death from any cause. Patients' survival was followed throughout the study duration. In addition, response assessment of the tumor was performed using response evaluation criteria in solid tumors (RECIST) criteria, and complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) data were evaluated. Safety assessment was performed by evaluating the incidence of hematological and nonhematological toxicities, which were graded with the use of the National Cancer Institute -Common Terminology Criteria for Adverse Events (CTCAE version 4.03).
Demographic characteristics were summarized using descriptive statistics (mean and standard deviation for continuous variables, and frequency and percentages for categorical variables). Chi-square test was used to test the statistical significance of the efficacy variables. P- value <0.05 was considered statistically significant. As this observational study had no hypothesis testing, formal calculation of sample size and statistical power was not performed.
| » Results|| |
Patient and treatment
A total of 29 patients with a mean age of 59.6 (30–77) years were enrolled in the study, and most of them were men (86.2%). More than half (55.2%) of the patients were in the age group of 60–69 years. Histological evaluation revealed squamous cell carcinoma in 55.2% of patients and adenocarcinoma type in 44.8% of patients. Most patients (75.9%) had an ECOG score of I, and 24.1% (n = 7) of patients had an ECOG score of II. Diabetes (n = 1, 3.4%), hypertension (n = 2, 6.9%), and hypothyroidism (n = 1, 3.4%) were the comorbidities [Table 1].
All patients in whom the first-line platinum-based therapy had failed received an average of four cycles (range 1–15 cycles) of nivolumab. Only one patient (3.4%) received 15 cycles of nivolumab and 27.6% of patients received 1 cycle of nivolumab. Nivolumab was the second-line therapy for most patients (51.7%). The drug was administered at a dose of 3 mg/kg, and the total dose administered in the study was 162.34 mg [Table 2]. The details for the start and end of cycles of nivolumab for the patients are presented in [Figure 1].
|Figure 1: Time chart for nivolumab cycle details in patients with advanced lung cancer|
Click here to view
The median duration of survival in the study was 101 days. OS was defined as percentage of patients who survived 3, 6, and 12 months after the time from randomization and was found to be 41.4%, 58.6%, and 62.1% respectively. The OS rate of the study was 51.7%. The overall response rates as assessed by CR, PR, SD, and PD were found to be 3.4%, 17.2%, 20.7%, and 44.8%, respectively. Three patients (10.3%) were lost to follow-up. PR, SD, and PD were assessed using chi-square test (P = 0.0875) [Table 3]. The cumulative survival for the patients is presented in [Figure 2].
Only 3 patients in the study developed hematological toxicities (anemia and thrombocytopenia) [Table 4], and 27 patients (93.1%) developed some grade of nonhematological and immune-related toxicities [Table 5]. Asthenia (50%) and cough (25%) were the most common nonhematological toxicities. Hyperglycemia (13.7%) hypothyroidism (10.3%), and hypophysitis (3.4%) were the main immune-related toxicities [Table 5].
| » Discussion|| |
The American Society of Clinical Oncology and European Society for Medical Oncology guidelines consider platinum-based combination chemotherapy to be an acceptable option for first-line treatment of advanced NSCLC.
Patients with advanced NSCLC with disease progression represent a challenge and reveal the wide gap present in the current treatment regimen for achieving long-term survival goals. The current 5-year OS in patients with advanced NSCLC ranges between 4% and 5%.,
However, with enhanced understanding of the underlying interaction between the immune system cells and cancer, new agents targeting the immune system have surfaced in the NSCLC treatment landscape. PD-1 checkpoint pathway, which is overexpressed in some cancers, is one such target., Nivolumab along with other targeted immunotherapeutic agents is a PD-1 receptor inhibitor approved for the treatment of metastatic NSCLC with progression on or after platinum-based combination therapy., Key trials such as CheckMate 063 and CheckMate 057 have established the safety and tolerability of nivolumab. CheckMate 063 and CheckMate 057 reported 1-year OS rates of 39% and 51% (95% confidence interval, 45–56), respectively, with nivolumab in comparison to docetaxel.,
Although our study population was small compared with that in the above-mentioned key trials, the OS rate was similar to that in CheckMate 057. The result for CR, PR, SD, and PD parameters (3.4%, 17.2%, 20.7%, and 44.8%, respectively) obtained in our study was similar to that obtained in a German multicenter observational study conducted by Misch et al. Patients with NSCLC in the German study (N = 148) received nivolumab as second-line or greater treatment, and their CR, PR, SD, and PD rates were 0%, 18.8%, 36.7%, and 44.5%, respectively. The results from our study were also consistent with those obtained from an observational study by Jennifer et al., which reported PR, SD, and PD rates of 16%, 18%, and 49%, respectively.
In an observational study conducted by Carmen et al. in 34 patients with advanced NSCLC from Spain, most patients (n = 22) had grade I–II adverse events (AEs), with the most common AEs being fatigue and rash/pruritus. The toxicities were manageable and there was no grade 3–4 AEs or treatment-related deaths. Most patients in our study developed nonhematological toxicities of ungraded and grade II type, and only three patients developed hematological toxicities. Asthenia and cough were the most common nonhematological toxicities and only three patients developed hematological toxicities of anemia and thrombocytopenia.
The safety profile of nivolumab in our study was also found to be consistent with the expectations of AEs based on previously published data from key trials with respect to the type, percentage, and graded severity of reported events. In addition, no new safety concerns were observed in our study with the use of nivolumab in Indian patients.
This study has a few limitations. First, it was observational in nature for a small group of patients, although the obtained data can serve as a catalyst for future development of randomized controlled trials specific to the Indian population. Second, the nivolumab cycles were variable among the included patients, which might have introduced a bias. Our study contributes robust data of real-world efficacy and safety for nivolumab in the Indian context, which can be taken forward for suggestive changes in the Indian guidelines/recommendations for advanced recurrent NSCLC treatment.
| » Conclusion|| |
The study revealed safe and efficacious profile of nivolumab in the treatment of patients with recurrent advanced NSCLC in whom first-line platinum-based combination chemotherapy had failed. The study provides valuable data unique to the Indian population. The data revealed an impressive OS rate of 51.7% along with a good safety profile, as only three patients developed hematological toxicities. Large randomized prospective studies are warranted to further appreciate the efficacy and safety benefits offered by nivolumab.
We would like to extend our thanks to BioQuest Solutions for providing support in analysis and editorial services of the article and Natco pharmaceuticals for providing unrestricted educational grant.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Noronha V, Pinninti R, Patil V, Joshi A, Prabhash K. Lung cancer in the Indian subcontinent. South Asian J Cancer 2016;5:95.
] [Full text]
Zarogoulidis K, Zarogoulidis P, Darwiche K, Boutsikou E, Machairiotis N, Tsakiridis K, et al
. Treatment of non-small cell lung cancer (NSCLC). J Thorac Dis 2013;5(Suppl 4):2-9.
Kazandjian D, Suzman DL, Blumenthal G, Mushti S, He K, Libeg M, et al
. FDA approval summary: Nivolumab for the treatment of metastatic non-small cell lung cancer with progression on or after platinum-based chemotherapy. Oncologist 2016;21:634-42.
Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al
. The 2015 World Health Organization classification of lung tumors: Impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol 2015;10:1243-60.
Malik PS, Sharma MC, Mohanti BK, Shukla NK, Deo S, Mohan A, et al
. Clinico-pathological profile of lung cancer at AIIMS: A changing paradigm in India. Asian Pacific J Cancer Prev 2013;14:489-94.
Inumura K. Update on immunohistochemistry for the diagnosis of lung cancer. Cancers (Basel) 2018;10:E72.
Walraven I, Damhuis RA, ten Berge MG, Rosskamp M, van Eycken L, de Ruysscher D, et al
. Treatment variation of sequential versus concurrent chemoradiotherapy in stage III non-small cell lung cancer patients in the Netherlands and Belgium. Clin Oncol 2017;29:e177-85.
Novello S, Barlesi F, Califano R, Cufer T, Ekman S, Levra MG, et al
. Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016;27(Suppl 4):V1-27.
Pratishtha BC. Nivolumab - Pearls of evidence. Indian J Med Paediatr Oncol 2017;38:520-5.
Guo L, Zhang H, Chen B. Nivolumab as programmed death-1 (PD-1) inhibitor for targeted immunotherapy in tumor. J Cancer 2017;8:410-6.
Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, et al
. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 2017;376:2415-26.
Sundar R, Cho BC, Brahmer JR, Soo RA. Nivolumab in NSCLC: Latest evidence and clinical potential. Ther Adv Med Oncol 2015;7:85-96.
Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al
. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123-35.
Le AD, Alzghari SK, Jean GW, La-Beck NM. Update on targeted therapies for advanced non-small cell lung cancer: Nivolumab in context. Ther Clin Risk Manag 2017;13:223-36.
Rizvi NA, Planchard D, Dy GK, Stinchcombe TE, Dy GK, Antonia SJ, et al
. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer. Lancet Oncol 2015;16:257-65.
ClinicalTrials.gov: Study of BMS-936558 (nivolumab) compared to docetaxel in previously treated metastatic non-squamous NSCLC. Available from: http://clinicaltrials.gov/show/NCT01673867
. [Last accessed on 2018 Mar 11].
Misch D, Wit M, Grah C, Grohé C, Kollmeier J, Blum T, et al
. Efficacy and safety of nivolumab in routine NSCLC treatment-an observational study in 5 lung cancer centers in Berlin, Germany. Lung Cancer 2017;50:OA1477.
Jennifer C, Adrien C, Sophie R, Fallet V, Jouveshomme S, Leprieur EG, et al
. Real-life use of nivolumab in non-small cell lung cancer: A multicentric cohort to determine its clinical efficacy and predictive factors of early progression. J Clin Oncol 2017;35(Suppl 15):e20543.
Areses MC, Afonso AFJ, Vazquez RF, Rivera FV, Quintela ML, Vazquez-Estevez S, et al
. An observational study of the efficacy and safety of nivolumab in pretreated patients with advanced non-small cell lung cancer (NSCLC): A Galician lung cancer group clinical practice. ASCO Meet Abstr 2016;34(Suppl 15):e20612.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]