Efficacy and Safety of Low-Dose Nivolumab in Treatment of Advanced Solid Tumors: A Retrospective Audit from Resource-Constrained Settings

Abstract

Background

Immunotherapy has improved outcomes in many advanced solid tumors. In resource-constrained settings, less than 2% of patients can afford standard dose immunotherapy. A recent phase II study showed the efficacy of low-dose immunotherapy in this setting. We used low-dose immunotherapy on a compassionate basis in patients who had progressed on available standard treatment options and standard dose immunotherapy was not feasible.

Patients and Methods

We retrospectively collected data from the medical oncology department for consecutive patients who had initially received standard lines of therapy followed by low-dose immunotherapy (nivolumab 40 mg) on a compassionate basis. The demographic details, histology, prior treatment, clinical and radiological response, date of disease progression, date of death, and toxicity data were collected.

Results

A total of 54 consecutive patients, who received low-dose immunotherapy with nivolumab from January 1, 2018 to February 14, 2020, were included in this analysis; 4 patients were not radiologically evaluable. The median age was 50.4 years (range 35–74 years), male:female ratio was 6:1. The most common comorbidities were hypertension and diabetes seen in 12 (22.2%) and 6 (11.1%) patients, respectively. The majority of the patients (70.4%) were of head and neck cancer. The median follow-up was 4.5 months (range 0.5–11.7). Clinical benefit was observed in 18 (33.3%) patients. Partial response and stable disease were achieved in 9 (16.7%) and 5 (9.3%) patients, respectively. Median survival was not reached for these patients. Six months progression-free survival and overall survival were 100 versus 8.7% (hazard ratio [HR] 0.05, 95% confidence interval [CI]: 0.01–0.36; p = 0.003) and 100 versus 29.7% (HR 0.03, 95% CI: 0.00–0.95; p = 0.047), respectively, for responders and nonresponders. The side effects were manageable.

Conclusion

In resource-constrained settings, low-dose immunotherapy with nivolumab seems to be an effective treatment option. Further studies are warranted to evaluate this approach.

Keywords

low-dose immunotherapy - nivolumab - resource-constrained settings - solid tumor

• References

• 1 Yoo SH, Keam B, Kim M. et al. Low-dose nivolumab can be effective in non-small cell lung cancer: alternative option for financial toxicity. ESMO Open 2018; 3 (05) e000332
• 2 Ferris RL, Blumenschein Jr G, Fayette J. et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016; 375 (19) 1856-1867
• 3 Cohen EEW, Soulières D, Le Tourneau C. et al; KEYNOTE-040 investigators. 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 2019; 393 (10167): 156-167
• 4 Keam B, Jung H, Nam BH. Optimal design and endpoint of clinical trials using immune checkpoint blocking agents. Expert Rev Anticancer Ther 2016; 16 (12) 1217-1218
• 5 Topalian SL, Hodi FS, Brahmer JR. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366 (26) 2443-2454
• 6 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 New Drugs 2017; 35 (02) 207-216
• 7 Chatterjee M, Turner DC, Felip E. et al. Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer. Ann Oncol 2016; 27 (07) 1291-1298
• 8 Patnaik A, Kang SP, Rasco D. et al. Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res 2015; 21 (19) 4286-4293
• 9 Freshwater T, Kondic A, Ahamadi M. et al. Evaluation of dosing strategy for pembrolizumab for oncology indications. J Immunother Cancer 2017; 5: 43
• 10 Patil VM, Noronha V, Joshi A. et al. Low doses in immunotherapy: are they effective?. Cancer Res Stat Treat 2019; 2: 54-60
• 11 Sachs JR, Mayawala K, Gadamsetty S, Kang SP, de Alwis DP. Optimal dosing for targeted therapies in oncology: drug development cases leading by example. Clin Cancer Res 2016; 22 (06) 1318-1324
• 12 Eisenhauer EA, Therasse P, Bogaerts J. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45 (02) 228-247
• 13 Jadhav SB, Khaowroongrueng V, Fueth M, Otteneder MB, Richter W, Derendorf H. Tissue distribution of a therapeutic monoclonal antibody determined by large pore microdialysis. J Pharm Sci 2017; 106 (09) 2853-2859
• 14 Nivolumab (Opdivo), highlights of prescribing information. EMA report 2019; 2855: 90
• 15 Brahmer JR, Drake CG, Wollner I. et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010; 28 (19) 3167-3175
• 16 Agrawal S, Feng Y, Roy A, Kollia G, Lestini B. Nivolumab dose selection: challenges, opportunities, and lessons learned for cancer immunotherapy. J Immunother Cancer 2016; 4: 72
• 17 Renner A, Burotto M, Rojas C. Immune checkpoint inhibitor dosing: can we go lower without compromising clinical efficacy?. J Glob Oncol 2019; 5: 1-5
• 18 Long GV, Tykodi SS, Schneider JG. et al. Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer. Ann Oncol 2018; 29 (11) 2208-2213
• 19 Zhao X, Suryawanshi S, Hruska M. et al. Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a 3-mg/kg dosing regimen in patients with advanced tumors. Ann Oncol 2017; 28 (08) 2002-2008
• 20 Bajaj G, Wang X, Agrawal S, Gupta M, Roy A, Feng Y. Model-based population pharmacokinetic analysis of nivolumab in patients with solid tumors. CPT Pharmacometrics Syst Pharmacol 2017; 6 (01) 58-66
• 21 Hurkmans DP, Basak EA, van Dijk T. et al. A prospective cohort study on the pharmacokinetics of nivolumab in metastatic non-small cell lung cancer, melanoma, and renal cell cancer patients. J Immunother Cancer 2019; 7 (01) 192
• 22 Gettinger SN, Horn L, Gandhi L. et al. Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 2015; 33 (18) 2004-2012
• 23 Sharma P, Retz M, Siefker-Radtke A. et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2017; 18 (03) 312-322
• 24 Motzer RJ, Escudier B, McDermott DF. et al; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015; 373 (19) 1803-1813
• 25 Seiwert TY, Burtness B, Mehra R. et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 2016; 17 (07) 956-965
• 26 Patil VM, Noronha V, Menon N. et al. Low-dose immunotherapy in head and neck cancer: a randomized study. J Clin Oncol 2023; 41 (02) 222-232
• 27 Gillison ML, Blumenschein GR, Fayette J. et al. Nivolumab (Nivo) vs investigator's choice (IC) for platinum-refractory (PR) re- [15] current or metastatic (R/M) squamous cell carcinoma of the head and neck(SCCHN; CheckMate 141): outcomes in first-line (1L) R/M patients and updated safety and efficacy. [abstract] J Clin Oncol 2017; 35 (Suppl. 15) 6019
• 28 Patil V, Abraham G, Ravikrishna M. et al. Retrospective analysis: checkpoint inhibitor accessibility for thoracic and head and neck cancers and factors influencing it in a tertiary centre in India. Ecancermedicalscience 2022; 16: 1464