Abstract
Background
Immune checkpoint inhibitors (ICIs) are now considered revolutionary agents in the treatment of various cancers. Prospective data are limited on the patterns of usage and toxicity profile of these drugs. We planned this study for addressing the same in Indian patients.
Methods
This prospective study was conducted over a period of 2 years. All patients who were treated with Nivolumab, pembrolizumab, atezolizumab, and durvalumab were included. Immune-related adverse events were recorded. Toxicities were graded and number of patients experiencing dose limiting toxicities was recorded.
Results
A total of 53 patients received one of the above four agents. Majority of patients were less than 60 years of age. Carcinoma lung was the most frequent malignancy followed by renal cell carcinoma, Hodgkin's Lymphoma, Urinary Bladder cancers, Malignant Melanoma, and Recurrent/Metastatic Head and neck cancer. Nivolumab was used in most of the study population followed by pembrolizumab. Majority of agents were used in second line. The frequency of all grade adverse events for fatigue, anemia, pneumonitis, skin rash, dyspnea, diarrhea, and hypothyroidism were (in %) 73.58, 62.26, 16.9, 11.32, 9.43, 9.43, and 7.55, respectively. No grade 5 toxicity was observed. None of the grade 3 or 4 toxicities led to treatment discontinuation. Statistically, no difference was found for all grade toxicities among ICI drugs and among the various lines of use.
Conclusion
Nivolumab was the commonest drug used in our cohort. Most of ICIs were used in second-line setting. Toxicities are in line with the published literature.
Keywords: Malignancy, Immunotherapy, Immune Chekpoint Inhibitors, Immune related adverse events
Introduction
Cancer ranks among the primary causes of death in our country. While surgery, chemotherapy, and radiation therapy have been established as conventional treatments, they still have limitations. Despite significant advancements in these treatments over the past decade, radiation and chemotherapy are only able to eliminate a portion of the cancerous cells, often with the negative consequence of cytotoxicity against healthy cells.1 Additionally, these cancer therapies fall short of meeting the requirements for an ideal, safe, and highly effective treatment, especially when treating metastatic cancer types.
In recent years, immune checkpoint inhibitors (ICIs) have been recognized as ground-breaking agents for treating metastatic solid cancers, leading to significant advancements in this area.2 The identification of the programmed cell death protein 1 (PD-1) pathway has paved the way for the clinical development of PD-1 inhibitors, such as nivolumab and pembrolizumab. These drugs have demonstrated their effectiveness in managing solid cancers in both the upfront and metastatic settings. The introduction of these novel agents has been a game-changer in the management of advanced lung cancer,3 urothelial cancer,4 head-and-neck cancer,5 and gastrointestinal cancer.6 Major international guidelines now endorse their use. One key benefit of these agents is their lower toxicity and better overall quality of life, which sets them apart from traditional chemotherapy treatments.
There is a lacuna in literature when it comes to the usage, tolerability, and toxicities of these agents. Despite their availability in India over the past 5 years, the high cost of these drugs has been a significant barrier to their widespread adoption.7 Moreover, the current usage of these drugs is primarily based on Western data, and there is a lack of published real-world experiences in the Indian population.8 Published data on the toxicity profile of these agents in India are limited to isolated case reports.9 Therefore, we designed this study to investigate the patterns of usage and toxicity profiles of various immunotherapy agents among Indian patients.
Material and methods
This was a single center prospective observational study conducted in a Tertiary Healthcare Center at Delhi from Sep 2019 to Oct 2021. The approval of institutional ethics committee was obtained before starting the study. Patients informed consent was obtained for inclusion in this study.
The study enrolled individuals who were over 18 years of age, having confirmed cases of cancer, any performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG), and any stage or metastatic cancer that had progressed despite chemotherapy, as well as any PD L1 expression. Those with concurrent severe or uncontrolled medical conditions, serious active infections, recent cancer therapy within 4 weeks, chronic systemic steroid therapy, active central nervous system metastases or carcinomatous meningitis, active autoimmune disease requiring systemic steroids or immunosuppressive agents, positive status for Human Immunodeficiency Virus, Hepatitis B or Hepatitis C virus, or those who were pregnant or breastfeeding, were excluded from the study.
All demographic information was collected along with detailed history. Basic laboratory investigations and imaging done at the start of therapy was recorded and immunotherapy was administered as per protocol. Response assessment was done clinically after each cycle and radiologically after 3 months of therapy and thereafter every 2–3 months of therapy. Immune-related response criteria (irRC) were used to document progression.10 Immune-related adverse events (IRAEs) were recorded for individual immunotherapeutic agents. Dose modifications was done as per guidelines for severe toxicity and recorded when done. Number of patients experiencing dose-limiting Toxicities According to National Cancer Institute, Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4.0) in participants was recorded.11
The sample size was calculated based on the study of Borghaei et al12 which observed that five-year pooled overall survival (OS) rate was 13.4%. Taking this value as reference, the minimum required sample size with 10% margin of error and 5% level of significance is 45 patients. Taking lost to follow-up as 15%, total sample size was taken as 53.
The data entry was done in the Microsoft Excel, and the final analysis was done with the use of Statistical Package for Social Sciences software, IBM manufacturer, Chicago, USA, ver 21.0.
For statistical significance, p value of less than 0.05 was considered statistically significant.
Good clinical care guidelines as per declaration of Helsinki were followed.
Results
A total of 53 patients of various malignancies received immunotherapies (nivolumab, pembrolizumab, atezolizumab, and durvalumab) over a period of 2 years. The baseline characteristics of study patients were as depicted in Table 1. Carcinoma lung (comprising non-small-cell and small cell) was the most common malignancy followed by renal cell carcinoma, relapsed/refractory Hodgkin's lymphoma, carcinoma urinary bladder, malignant melanoma, recurrent/metastatic head and neck cancer, hepatocellular carcinoma, carcinoma esophagus, stomach, endometrium and rectum.
Table 1.
Distribution of baseline characteristics of study subjects.
| Baseline characteristics | Frequency | Percentage |
|---|---|---|
| Age(years) | ||
| ≤60 | 34 | 64.15% |
| >60 | 19 | 35.85% |
| Mean ± SD | 53.57 ± 16.3 | |
| Median(25th–75th percentile) | 56(45–67) | |
| Range | 18–78 | |
| Gender | ||
| Female | 11 | 20.75% |
| Male | 42 | 79.25% |
| Performance status | ||
| 1 | 35 | 66.04% |
| 2 | 17 | 32.08% |
| 3 | 1 | 1.89% |
| Smokers/non smokers | ||
| Non-smoker | 29 | 54.72% |
| Smoker | 24 | 45.28% |
Overall majority of study subjects were of metastatic disease i.e., Stage IV (98.11%) with only one patient of non-metastatic disease being a case Stage III non small cell lung cancer (NSCLC) (Squamous).
Regarding the immunotherapeutic agents used in study subjects across various malignancies, nivolumab was used in most of the study population followed by pembrolizumab, atezolizumab, and durvalumab. Majority of immunotherapeutic agents were used in second-line across various malignancies. They were used in combination with chemotherapy in 4 out of 53 patients and in remaining 49 as a single agent. Only one patient with Stage III NSCLC received durvalumab as maintenance therapy after undergoing concurrent chemoradiotherapy. This patient took durvalumab for four months but had to stop further treatment due to COVID. At the time of the data cut-off, which was at a two-year follow-up, this patient was still alive and had stable disease.
Nivolumab being the major immunotherapeutic agent used in this study, its usage was distributed across various malignancies like carcinoma lung being the major one followed by Hodgkin's lymphoma, malignant melanoma, head and neck cancer, renal cell carcinoma, carcinoma urinary bladder, hepatocellular carcinoma, and carcinoma esophagus with majority of its usage in second-line settings and with weight-based dosing used in 50% of subjects and rest fixed dosage usage as depicted in Table 2.
Table 2.
Distribution Of Nivolumab and Pembrolizumab usage in study subjects.
| Nivolumab details |
Pembrolizumab details |
||||
|---|---|---|---|---|---|
| Frequency | Percentage | Frequency | Percentage | ||
| Malignancy distribution | Malignancy distribution | ||||
| Carcinoma Lung | 6 | 23.08% | Carcinoma Lung | 8 | 40.00% |
| Renal cell carcinoma | 2 | 7.69% | Renal cell carcinoma | 6 | 30.00% |
| Hodgkin's Lymphoma | 7 | 26.92% | Hodgkin's Lymphoma | 1 | 5.00% |
| Carcinoma urinary bladder | 2 | 7.69% | Carcinoma urinary bladder | 1 | 5.00% |
| Malignant melanoma | 4 | 15.38% | Head and neck cancer | 1 | 5.00% |
| Hepatocellular carcinoma | 1 | 3.85% | Carcinoma stomach | 1 | 5.00% |
| Head and neck cancer | 3 | 11.54% | Carcinoma endometrium | 1 | 5.00% |
| Carcinoma esophagus | 1 | 3.85% | Carcinoma rectum | 1 | 5.00% |
| Carcinoma lung | Carcinoma lung | ||||
| Non small cell lung cancer | 6 | 100.00% | Non small cell lung cancer | 8 | 100.00% |
| Hodgkin's lymphoma | Hodgkin's lymphoma | ||||
| Post ASCT | 3 | 42.86% | Post ASCT | 1 | 100.00% |
| Relapsed/refractory | 4 | 57.14% | |||
| Line of therapy | Line of therapy | ||||
| First-line | 3 | 11.54% | First-line | 6 | 30.00% |
| Second-line | 16 | 61.54% | Second-line | 9 | 45.00% |
| Third-line | 2 | 7.69% | Third-line | 3 | 15.00% |
| Fourth-line | 3 | 11.54% | Fourth-line | 1 | 5.00% |
| Fifth-line | 2 | 7.69% | Fifth-line | 1 | 5.00% |
| Dose | Dose | ||||
| 3 mg/kg | 13 | 50.00% | 200 mg | 20 | 100.00% |
| 240 mg | 9 | 34.62% | |||
| 360 mg | 1 | 3.85% | |||
| 480 mg | 3 | 11.54% | |||
| Schedule | Schedule | ||||
| Q2 weekly | 21 | 80.77% | Q3 weekly | 20 | 100.00% |
| Q4 weekly | 5 | 19.23% | |||
Pembrolizumab was used in 20 patients in this study across various malignancies like carcinoma lung, renal cell carcinoma, hodgkin's lymphoma, carcinoma urinary bladder, head and neck cancer, carcinoma stomach, esophagus and endometrium with majority used in second-line setting and used in its standard dosing of 200 mg once in three week in all 20 patients as depicted in Table 2.
Atezolizumab was used in 5 patients in study population with carcinoma lung (SCLC:ES) and carcinoma urinary bladder with first-line setting in SCLC ES followed by second- and third-line in carcinoma urinary bladder in its standard dosing format as depicted in Table 3.
Table 3.
Distribution of Atezolizumab and Durvalumab usage in study subjects.
| Atezolizumab details |
Durvalumab details |
||||
|---|---|---|---|---|---|
| Frequency | Percentage | Frequency | Percentage | ||
| Malignancy distribution | Malignancy distribution | ||||
| Carcinoma lung | 3 | 60.00% | Carcinoma lung | 1 | 50.00% |
| Carcinoma urinary bladder | 2 | 40.00% | Carcinoma urinary bladder | 1 | 50.00% |
| Carcinoma lung | Carcinoma lung | ||||
| Small cell lung cancer | 3 | 100.00% | Non-small cell lung cancer | 1 | 100.00% |
| Line of therapy | Line of therapy | ||||
| First-line | 3 | 60.00% | |||
| Second-line | 1 | 20.00% | Second-line | 2 | 100.00% |
| Third-Line | 1 | 20.00% | |||
| Dose | Dose | ||||
| 1200 mg | 5 | 100.00% | 10 mg/kg | 2 | 100.00% |
| Schedule | Schedule | ||||
| Q3 weekly | 5 | 100.00% | Q2 weekly | 2 | 100.00% |
Durvalumab was used in only 2 patients of study population, one each in case of carcinoma lung and carcinoma urinary bladder in its standard dosing as depicted in Table 3.
All grade adverse events were fatigue (73.58%) in most of them followed by anemia (62.26%), pneumonitis (16.98%), rash (11.32%), dyspnea (9.43%), diarrhea (9.43%), and hypothyroidism (7.55%) in majority of patients with hyperglycemia, pleural effusion, arthritis, arthralgia, and infusion reaction comprising 1.89% each as depicted in Table 4. Severe Grade 3 anemia was seen in 1 patient (1.89%). None of these led to treatment discontinuation.
Table 4.
Distribution of adverse events in total and for each drug.
| Variables | Frequency | Percentage | Atezolizumab | Durvalumab | Nivolumab | Pembrolizumab | |
|---|---|---|---|---|---|---|---|
| Dermatologic | Rash | 6 | 11.32 | 0 | 0 | 3 | 3 |
| Grade 1 | 4 | 7.55 | 0 | 0 | 2 | 2 | |
| Grade 2 | 2 | 3.77 | 0 | 0 | 1 | 1 | |
| Gastroenterology | Diarrhea | 5 | 9.43 | 1 | 0 | 2 | 2 |
| Grade 1 | 4 | 7.55 | 1 | 0 | 1 | 2 | |
| Grade 3 | 1 | 1.89 | 0 | 0 | 1 | 0 | |
| Endocrine | Hyperglycaemia | 1 | 1.89 | 0 | 1 | 0 | 0 |
| Grade 2 | 1 | 1.89 | 0 | 1 | 0 | 0 | |
| Hypothyroidism | 4 | 7.55 | 1 | 0 | 1 | 2 | |
| Grade 2 | 4 | 7.55 | 1 | 0 | 1 | 2 | |
| Respiratory | Dyspnea | 5 | 9.43 | 1 | 0 | 2 | 2 |
| Grade 1 | 5 | 9.43 | 1 | 0 | 2 | 2 | |
| Pneumonitis | 9 | 16.98 | 0 | 0 | 4 | 5 | |
| Grade 1 | 8 | 15.09 | 0 | 0 | 4 | 4 | |
| Grade 2 | 1 | 1.89 | 0 | 0 | 0 | 1 | |
| Pleural effusion | 1 | 1.89 | 0 | 0 | 0 | 1 | |
| Grade 2 | 1 | 1.89 | 0 | 0 | 0 | 1 | |
| Rheumatic | Arthritis | 1 | 1.89 | 0 | 0 | 1 | 0 |
| Grade 2 | 1 | 1.89 | 0 | 0 | 1 | 0 | |
| Arthralgia | 1 | 1.89 | 0 | 0 | 0 | 1 | |
| Grade 2 | 1 | 1.89 | 0 | 0 | 0 | 1 | |
| Hematologic | Anemia | 33 | 62.26 | 3 | 1 | 17 | 12 |
| Grade 1 | 31 | 58.49 | 3 | 1 | 17 | 10 | |
| Grade 2 | 1 | 1.89 | 0 | 0 | 0 | 1 | |
| Grade 3 | 1 | 1.89 | 0 | 0 | 0 | 1 | |
| Infusion related | Infusion reaction | 1 | 1.89 | 0 | 0 | 0 | 1 |
| Grade 2 | 1 | 1.89 | 0 | 0 | 0 | 1 | |
| General | Fatigue | 39 | 73.58 | 5 | 1 | 17 | 16 |
| Grade 1 | 37 | 69.81 | 5 | 1 | 16 | 15 | |
| Grade 2 | 2 | 3.77 | 0 | 0 | 1 | 1 | |
Discussion
We conducted a prospective observational study of 53 patients with various malignancies who were treated with ICIs evaluating their spectrum of usage and toxicity profile. The median age of the patients was 56 years, and the majority being male.
Patients PS was assessed using the ECOG scale, with the majority falling into PS 1 followed by PS 2. The usage of immunotherapy in relation to patients PS was consistent with the results of a meta-analysis by Melissa et al.13 The meta-analysis, which included eighteen studies with 11,354 patients, showed that the pooled hazard ratio (HR) for OS was 0.78 in PS 0 patients. In PS 1–2 patients, the pooled OS HR was also 0.78, indicating that the OS difference between PS 0 and PS 1–2 patients treated with ICIs was not significant. These findings suggest that ICI treatment improves survival irrespective of patients PS, indicating that PS should not guide treatment choice for anticancer immunotherapy.
Nivolumab, pembrolizumab, atezolizumab, and durvalumab were the immunotherapeutic agents used in the study, in accordance with recommendations from major international guidelines issued by professional societies such as national comprehensive cancer network (NCCN), European Society of Medical Oncology (ESMO), and American Society of Medical Oncology (ASCO).
Nivolumab was the most used ICI, particularly in the second-line setting after progression from initial cytotoxic chemotherapy. It was administered using both standard weight-based dosing and fixed-dose schedules, with a few dose and schedule adjustments made for the convenience of patients during the COVID-19 pandemic. Phase I clinical trials with ICIs have shown that there is no correlation between dose and efficacy, and no dose–toxicity relationship has been evident. The maximal tolerated dose for nivolumab has not been identified, and a similar safety profile has been demonstrated across tumor types and dose levels (0.1–10 mg/kg).14 However, in low- and middle-income countries like India, financial toxicity hampers the usage of ICIs, so further research is needed to compare the approved dose and schedule with less-intensive treatment, with a greater emphasis on pharmacoeconomic strategies for the benefit of a broader population.
Pembrolizumab was the next most used ICI, with maximum usage seen in patients with metastatic NSCLC. This pattern of usage was largely based on evidence from the KEYNOTE 407 study, which showed that the addition of pembrolizumab to chemotherapy improved OS and progression-free survival (PFS).15 Its usage in subsequent lines was based on data from the KEYNOTE 010 study, which demonstrated prolonged OS and a favorable benefit-to-risk profile in patients with previously treated, PD-L1-positive, advanced NSCLC.16
Pembrolizumab was also used in a small number of patients with advanced renal cell carcinoma (RCC), relapsed/refractory Hodgkin lymphoma post-ASCT, metastatic urothelial carcinoma, relapsed head and neck cancer post-progression on platinum-based therapy, metastatic carcinoma of the endometrium in the Microsatellite Instability-High phenotype, and metastatic carcinoma of the rectum. The usage in these cases was based on available data from relevant studies, demonstrating improved objective response rates, durable antitumor activity, and longer OS.4,17, 18, 19, 20
It was administered in its standard fixed dose schedule as approved by the Food and Drug Administration (FDA). As mentioned earlier for nivolumab, its antitumor activity was observed across all doses (1–10 mg/kg) and schedules (every 2 or 3 weeks).21 In the KEYNOTE-010 study, there was no difference in efficacy between the 10 mg/kg and 2 mg/kg doses. Based on this study, the FDA determined that the higher dose was unnecessary and approved a pembrolizumab dose of 2 mg/kg. More recently, a fixed dose of 200 mg was approved, further highlighting the importance of pharmacoeconomic strategies for the benefit of all.
Atezolizumab usage was primarily seen in patients with small cell lung cancer in combination with chemotherapy in the first-line setting. This usage was based on evidence from the IMpower 133 study, which demonstrated a significantly longer OS and PFS than chemotherapy alone.22 It was administered at a standard dose of 1200 mg every three weeks.
Durvalumab was used in patients with stage III squamous NSCLC who had a partial response following concurrent platinum-based chemotherapy, based on data from the PACIFIC trial, which showed significantly longer PFS and OS.23 Its usage in the second-line setting for advanced or metastatic urothelial carcinoma was withdrawn based on the results of the DANUBE trial which failed to demonstrate OS benefit over platinum-based chemotherapy.24 Durvalumab was administered at a standard dose of 10 mg/kg every two weeks.
Previous trials of ICIs have generally demonstrated favorable safety profiles, although there is a risk of IRAEs that can be serious or even life-threatening in some cases. Gathering real-world data on IRAEs is crucial for effectively assessing the risk-benefit ratio of these drugs in our specific population. In our study, which involved 53 patients receiving ICIs, we found that the treatment was generally well-tolerated, with only two patients experiencing Grade III toxicity, specifically anemia and diarrhea. Numerous publications have highlighted the relatively low risk of severe toxicity associated with ICIs, with figures ranging from 7% to 20% across various studies.25
Fatigue is the most reported adverse event associated with anti-PD-1/PD-L1 therapy. In studies focusing on individual drugs, the incidence of fatigue ranged from 16% to 37% for anti-PD-1 and 12%–24% for anti-PD-L1.26 In comparison to the CTLA4 blocking agent ipilimumab, high-grade toxicities from anti-PD-1 were less frequent. For instance, in patients with metastatic melanoma receiving nivolumab, any treatment-related adverse event was observed in 74%–85% of cases, with 12%–20% being grade 3 or 4.27 Similarly, in patients with advanced cisplatin-refractory squamous NSCLC, the incidence of adverse events was 58% and 7%, respectively, for any grade and grade 3 or 4. For those with metastatic cisplatin-refractory non-squamous NSCLC, it was 69% and 10%, respectively,3 while in patients with tyrosine kinase inhibitor refractory metastatic renal cell carcinoma, it was 79% and 19%, respectively.28
In the Keynote-002 study, which compared pembrolizumab at doses of 2 and 10 mg/kg to chemotherapy in ipilimumab pre-treated metastatic melanoma patients, grade 1 to 2 IRAEs were observed in 57%–60% of patients, while grade 3 to 4 toxicity was seen in 14% of patients.29 The Keynote-010 study, which focused on cisplatin-refractory NSCLC patients, reported treatment-related adverse events in 63% and 66% of cases for pembrolizumab at doses of 2 mg/kg and 10 mg/kg, respectively, compared to docetaxel. Among these patients, 13% and 16% experienced grade 3 to 4 toxicities, respectively. In the Keynote-024 study, which compared pembrolizumab at a fixed dose of 200 mg every 3 weeks to cisplatin-based chemotherapy in metastatic NSCLC patients, treatment-related toxicity was observed in 73.4% of patients for any adverse event, with 26.6% experiencing a grade 3 or higher adverse event.30
In our study, fatigue was also the most common IRAE reported, with fatigue of any grade reported in 73.58% of patients, followed by anemia of any grade in 62.26% of patients. The incidence of grade 3 toxicity was very low at 3.77%, indicating a good tolerance of ICIs in our population with no significant safety concerns.
Our study had certain limitations, including a relatively small sample size and the unavailability of immunohistochemistry data for PD-L1 expression.
Conclusions
Overall, our study provides valuable real-world insights into the usage and toxicity profile of immunotherapy drugs in Indian patients with various malignancies. The findings align with international experiences, suggesting that oncologists can feel reassured when using these agents in similar clinical settings.
Patients/ Guardians/ Participants consent
Patients informed consent was obtained.
Ethical clearance
Institute/hospital ethical clearance certificate was obtained.
Source of support
Nil.
Disclosure of competing interest
The authors have none to declare.
Acknowledgment
None.
References
- 1.Urruticoechea A., Alemany R., Balart J., Villanueva A., Viñals F., Capellá G. Recent advances in cancer therapy: an overview. Curr Pharmaceut Des. 2010 Jan;16(1):3–10. doi: 10.2174/138161210789941847. [DOI] [PubMed] [Google Scholar]
- 2.Postow M.A., Callahan M.K., Wolchok J.D. Immune checkpoint blockade in cancer therapy. J Clin Oncol Off J Am Soc Clin Oncol. 2015 Jun 10;33(17):1974–1982. doi: 10.1200/JCO.2014.59.4358. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Horn L., Spigel D.R., Vokes E.E., et al. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057) J Clin Oncol Off J Am Soc Clin Oncol. 2017 Dec 10;35(35):3924–3933. doi: 10.1200/JCO.2017.74.3062. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Bellmunt J., de Wit R., Vaughn D.J., et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015–1026. doi: 10.1056/NEJMoa1613683. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Ferris R.L., Blumenschein G., Fayette J., et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016 Nov 10;375(19):1856–1867. doi: 10.1056/NEJMoa1602252. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Kang Y.K., Boku N., Satoh T., et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Lond Engl. 2017 Dec 2;390(10111):2461–2471. doi: 10.1016/S0140-6736(17)31827-5. [DOI] [PubMed] [Google Scholar]
- 7.For Indian Cancer Patients, Immunotherapy is Way Pricey. 2017. Available from: https://www.deccanchronicle.com/;https://www.deccanchronicle.com/lifestyle/health-and-wellbeing/280717/for-indian-cancer-patients-immunotherapy-is-way-pricey.html. [Google Scholar]
- 8.Postow M.A., Sidlow R., Hellmann M.D. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018 Jan 11;378(2):158–168. doi: 10.1056/NEJMra1703481. [DOI] [PubMed] [Google Scholar]
- 9.Chandrakanth M.V., Noronha V., Joshi A., Patil V., Mahajan A., Prabhash K. Nivolumab instills hope in a hopeless situation in advanced nonsmall cell lung cancer with poor performance status. Indian J Cancer. 2017;54(1):55–56. doi: 10.4103/ijc.IJC_10_17. [DOI] [PubMed] [Google Scholar]
- 10.Wolchok J.D., Hoos A., O'Day S., et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res Off J Am Assoc Cancer Res. 2009 Dec 1;15(23):7412–7420. doi: 10.1158/1078-0432.CCR-09-1624. [DOI] [PubMed] [Google Scholar]
- 11.Common Terminology Criteria for Adverse Events (CTCAE)Version 4.0 Published: May 28, 2009 U.S. Department Of Health And Human Services.
- 12.Borghaei H., Paz-Ares L., Horn L., et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015 Oct 22;373(17):1627–1639. doi: 10.1056/NEJMoa1507643. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Bersanelli M., Brighenti M., Buti S., Barni S., Petrelli F. Patient performance status and cancer immunotherapy efficacy: a meta-analysis. Med Oncol Northwood Lond Engl. 2018 Aug 20;35(10):132. doi: 10.1007/s12032-018-1194-4. [DOI] [PubMed] [Google Scholar]
- 14.Yamamoto N., Nokihara H., Yamada Y., et al. Phase I study of Nivolumab, an anti-PD-1 antibody, in patients with malignant solid tumors. Invest N Drugs. 2017 Apr;35(2):207–216. doi: 10.1007/s10637-016-0411-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Novello S., Kowalski D.M., Luft A., et al. Pembrolizumab plus chemotherapy in squamous non-small-cell lung cancer: 5-year update of the phase III KEYNOTE-407 study. J Clin Oncol Off J Am Soc Clin Oncol. 2023 Apr 10;41(11):1999–2006. doi: 10.1200/JCO.22.01990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Herbst R.S., Baas P., Kim D.W., et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet Lond Engl. 2016 Apr 9;387(10027):1540–1550. doi: 10.1016/S0140-6736(15)01281-7. [DOI] [PubMed] [Google Scholar]
- 17.Powles T., Plimack E.R., Soulières D., et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1563–1573. doi: 10.1016/S1470-2045(20)30436-8. [DOI] [PubMed] [Google Scholar]
- 18.Chen R., Zinzani P.L., Fanale M.A., et al. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol Off J Am Soc Clin Oncol. 2017 Jul 1;35(19):2125–2132. doi: 10.1200/JCO.2016.72.1316. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Cohen E.E.W., Soulières D., Le Tourneau C., et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet Lond Engl. 2019 Jan 12;393(10167):156–167. doi: 10.1016/S0140-6736(18)31999-8. [DOI] [PubMed] [Google Scholar]
- 20.Le D.T., Uram J.N., Wang H., et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015 Jun 25;372(26):2509–2520. doi: 10.1056/NEJMoa1500596. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Chatterjee M., Turner D.C., Felip E., et al. Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer. Ann Oncol Off J Eur Soc Med Oncol. 2016 Jul;27(7):1291–1298. doi: 10.1093/annonc/mdw174. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Liu S.V., Reck M., Mansfield A.S., et al. Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with Atezolizumab, carboplatin, and etoposide (IMpower133) J Clin Oncol Off J Am Soc Clin Oncol. 2021 Feb 20;39(6):619–630. doi: 10.1200/JCO.20.01055. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Spigel D.R., Faivre-Finn C., Gray J.E., et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2022 Apr 20;40(12):1301–1311. doi: 10.1200/JCO.21.01308. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Powles T., van der Heijden M.S., Castellano D., et al. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1574–1588. doi: 10.1016/S1470-2045(20)30541-6. [DOI] [PubMed] [Google Scholar]
- 25.Haanen JB.a.G., Carbonnel F., Robert C., et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol Off J Eur Soc Med Oncol. 2017 Jul 1;28(suppl l_4):iv119–i142. doi: 10.1093/annonc/mdx225. [DOI] [PubMed] [Google Scholar]
- 26.Naidoo J., Page D.B., Li B.T., et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol Off J Eur Soc Med Oncol. 2015 Dec;26(12):2375–2391. doi: 10.1093/annonc/mdv383. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Weber J.S., Hodi F.S., Wolchok J.D., et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol Off J Am Soc Clin Oncol. 2017 Mar;35(7):785–792. doi: 10.1200/JCO.2015.66.1389. [DOI] [PubMed] [Google Scholar]
- 28.Motzer R.J., Escudier B., McDermott D.F., et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015 Nov 5;373(19):1803–1813. doi: 10.1056/NEJMoa1510665. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Hodi F.S., Hwu W.J., Kefford R., et al. Evaluation of immune-related response criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab. J Clin Oncol Off J Am Soc Clin Oncol. 2016 May 1;34(13):1510–1517. doi: 10.1200/JCO.2015.64.0391. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Reck M., Rodríguez-Abreu D., Robinson A.G., et al. Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ≥ 50. J Clin Oncol Off J Am Soc Clin Oncol. 2021 Jul 20;39(21):2339–2349. doi: 10.1200/JCO.21.00174. [DOI] [PMC free article] [PubMed] [Google Scholar]