The optimal duration of therapy in patients receiving immune-checkpoint inhibitors (ICIs) is a new but crucial question that has arisen owing to the observation of durable remissions in >85% of patients with metastatic melanoma who stop receiving an anti-PD-1 antibody after a complete response (CR). Long-term treatment-free remissions have also been seen, albeit much less frequently, in patients receiving ICIs for other forms of cancer who have a CR. Despite these promising observations, the optimal duration of treatment with ICIs remains unknown and requires further investigation in randomized controlled trials. In the absence of prospective data, some general criteria to guide the safe cessation of ICIs can be proposed, at least for patients with melanoma, in whom ICI cessation after a confirmed CR and at least 6 months of treatment is generally deemed safe. In this Perspective, we describe the available data on ICI interruption in patients with melanoma and in those with various other cancers. We also address the patient management implications of stopping ICI therapy.
Subscribe to Journal
Get full journal access for 1 year
only $17.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Nishino, M., Ramaiya, N. H., Hatabu, H. & Hodi, F. S. Monitoring immune-checkpoint blockade: response evaluation and biomarker development. Nat. Rev. Clin. Oncol. 14, 655–668 (2017).
Nishino, M., Hatabu, H. & Hodi, F. S. Imaging of cancer immunotherapy: current approaches and future directions. Radiology 290, 9–22 (2019).
Nishino, M. et al. Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements. Clin. Cancer Res. 19, 3936–3943 (2013).
Seymour, L. et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 18, e143–e152 (2017).
Haanen, J. et al. Management of toxicities from immunotherapy: ESMO clinical practice guidelines. Ann. Oncol. 28, iv119–iv142 (2017).
Robert, C. et al. Durable complete response after discontinuation of pembrolizumab in patients with metastatic melanoma. J. Clin. Oncol. 36, 1668–1674 (2018).
Hoos, A. et al. Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy. Semin. Oncol. 37, 533–546 (2010).
Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Robert, C., Schadendorf, D., Messina, M., Hodi, F. S. & O’Day, S. Efficacy and safety of retreatment with ipilimumab in patients with pretreated advanced melanoma who progressed after initially achieving disease control. Clin. Cancer Res. 19, 2232–2239 (2013).
US Food and Drug Administration. Ipilimumab. http://wayback.archive-it.org/7993/20170113081138/http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm248478.htm (2015).
European Medicines Agency. Yervoy (ipilimumab). An overview of Yervoy and why it is authorised in the EU. https://www.ema.europa.eu/en/documents/overview/yervoy-epar-medicine-overview_en.pdf (2011).
Cabel, L. et al. Long-term complete remission with ipilimumab in metastatic castrate-resistant prostate cancer: case report of two patients. J. Immunother. Cancer 5, 31 (2017).
Graff, J. N., Puri, S., Bifulco, C. B., Fox, B. A. & Beer, T. M. Sustained complete response to CTLA-4 blockade in a patient with metastatic, castration-resistant prostate cancer. Cancer Immunol. Res. 2, 399–403 (2014).
US Food and Drug Administration. Pembrolizumab. http://wayback.archive-it.org/7993/20170111231652/http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm412861.htm (2015).
Hamid, O. et al. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann. Oncol. 30, 582–588 (2019).
Jansen, Y. J. L. et al. Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity: clinical outcomes in advanced melanoma. Ann. Oncol. 30, 1154–1161 (2019).
Betof Warner, A. et al. Long-term outcomes and responses to retreatment in patients with melanoma treated with PD-1 blockade. J. Clin. Oncol. 38, 1655–1663 (2020).
Gauci, M.-L. et al. Long-term survival in patients responding to anti-PD-1/PD-L1 therapy and disease outcome upon treatment discontinuation. Clin. Cancer Res. 25, 946–956 (2019).
McCoach, C. E. et al. Exploratory analysis of the association of depth of response and survival in patients with metastatic non-small-cell lung cancer treated with a targeted therapy or immunotherapy. Ann. Oncol. 30, 492 (2019).
Robert, C. et al. Pembrolizumab versus Ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).
Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 20, 1239–1251 (2019).
Nishino, M. et al. Tumor response dynamics of advanced non-small cell lung cancer patients treated with PD-1 inhibitors: imaging markers for treatment outcome. Clin. Cancer Res. 23, 5737–5744 (2017).
Spigel, D. R. et al. Randomized results of fixed-duration (1-yr) vs continuous nivolumab in patients (PTS) with advanced non-small cell lung cancer (NSCLC) [abstract 1297O]. Ann. Oncol. 28 (Suppl. 5), v461 (2017).
Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).
Larkin, J. et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 381, 1535–1546 (2019).
Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 1990 45, 228–247 (2009).
Provencio, M. et al. Neoadjuvant chemo-immunotherapy for the treatment of stage IIIA non-small-cell lung cancer (NSCLC): a phase II multicenter exploratory study — final data of patients who underwent surgical assessment [abstract]. J. Clin. Oncol. 37 (Suppl. 15), 8509 (2019).
Tan, A. C. et al. FDG-PET response and outcome from anti-PD-1 therapy in metastatic melanoma. Ann. Oncol. 29, 2115–2120 (2018).
Seremet, T. et al. Undetectable circulating tumor DNA (ctDNA) levels correlate with favorable outcome in metastatic melanoma patients treated with anti-PD1 therapy. J. Transl Med. 17, 303 (2019).
Tan, L. et al. Prediction and monitoring of relapse in stage III melanoma using circulating tumor DNA. Ann. Oncol. 30, 804–814 (2019).
Sheth, S., Gao, C., Mueller, N., Martinez, P. & Soria, J.-C. Durvalumab activity in previously treated patients who stopped durvalumab without disease progression [abstract 1175O]. Ann. Oncol. 30 (Suppl. 5), v475–v476 (2019).
Herbst, R. S. et al. Long-term outcomes and retreatment among patients with previously treated, programmed death-ligand 1-positive, advanced non-small-cell lung cancer in the KEYNOTE-010 study. J. Clin. Oncol. 38, 1580–1590 (2020).
Brahmer, J. R. 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. 28, 3167–3175 (2010).
US Food and Drug Administration. FDA approves new dosing regimen for pembrolizumab. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-new-dosing-regimen-pembrolizumab (2020).
The ASCO post. KEYNOTE-555 supports 6-week pembrolizumab dosing schedule in melanoma. https://www.ascopost.com/issues/june-10-2020/keynote-555-supports-6-week-pembrolizumab-dosing-schedule-in-melanoma/ (2020).
Ascierto, P. A. et al. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 18, 611–622 (2017).
Sharma, P. et al. Nivolumab alone and with ipilimumab in previously treated metastatic urothelial carcinoma: CheckMate 032 nivolumab 1 mg/kg plus ipilimumab 3 mg/kg expansion cohort results. J. Clin. Oncol. 37, 1608–1616 (2019).
Lebbé, C. et al. Evaluation of two dosing regimens for nivolumab in combination with ipilimumab in patients with advanced melanoma: results from the phase IIIb/IV CheckMate 511 trial. J. Clin. Oncol. 37, 867–875 (2019).
Eggermont, A. M. M. et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 16, 522–530 (2015).
Eggermont, A. M. M. et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N. Engl. J. Med. 378, 1789–1801 (2018).
Weber, J. et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N. Engl. J. Med. 377, 1824–1835 (2017).
US Food & Drug Administration. FDA approves pembrolizumab for adjuvant treatment of melanoma.https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adjuvant-treatment-melanoma (2019).
US Food & Drug Administration. FDA grants regular approval to nivolumab for adjuvant treatment of melanoma. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-nivolumab-adjuvant-treatment-melanoma (2017).
Long, G. V. et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N. Engl. J. Med. 377, 1813–1823 (2017).
Antonia, S. J. et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N. Engl. J. Med. 379, 2342–2350 (2018).
Robert, C. Is earlier better for melanoma checkpoint blockade? Nat. Med. 24, 1645–1648 (2018).
Miller, K., Abraham, J. H., Rhodes, L. & Roberts, R. Use of the word “cure” in oncology. J. Oncol. Pract. 9, e136–e140 (2013).
Mathews, J. D. et al. Cancer risk in 680,000 people exposed to computed tomography scans in childhood or adolescence: data linkage study of 11 million Australians. BMJ 346, f2360 (2013).
Westeel, V. et al. Results of the phase III IFCT-0302 trial assessing minimal versus CT-scan-based follow-up for completely resected non-small cell lung cancer (NSCLC) [abstract 1273O]. Ann. Oncol. 28 (Suppl. 5), v452 (2017).
Dellestable, P. et al. Impact of whole body magnetic resonance imaging (MRI) in the management of melanoma patients, in comparison with positron emission tomography/computed tomography (TEP/CT) and CT [French]. Ann. Dermatol. Venereol. 138, 377–383 (2011).
Pfluger, T. et al. PET/CT in malignant melanoma: contrast-enhanced CT versus plain low-dose CT. Eur. J. Nucl. Med. Mol. Imaging 38, 822–831 (2011).
Sznol, M. et al. Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. Cancer Treat. Rev. 58, 70–76 (2017).
Brunet-Possenti, F., Opsomer, M. A., Gomez, L., Ouzaid, I. & Descamps, V. Immune checkpoint inhibitors-related orchitis. Ann. Oncol. 28, 906–907 (2017).
Quach, H. T. et al. Severe epididymo-orchitis and encephalitis complicating anti-PD-1 therapy. Oncologist 24, 872–876 (2019).
Laidsaar-Powell, R. et al. A meta-review of qualitative research on adult cancer survivors: current strengths and evidence gaps. J. Cancer Surviv. 13, 852–889 (2019).
Butow, P., Laidsaar-Powell, R., Konings, S., Lim, C. Y. S. & Koczwara, B. Return to work after a cancer diagnosis: a meta-review of reviews and a meta-synthesis of recent qualitative studies. J. Cancer Surviv. 14, 114–134 (2020).
Holland, J. C. et al. Distress management. J. Natl. Compr. Canc. Netw. 11, 190–209 (2013).
Yi, J. C. & Syrjala, K. L. Anxiety and depression in cancer survivors. Med. Clin. North. Am. 101, 1099–1113 (2017).
Snyder, C. R. et al. The will and the ways: development and validation of an individual-differences measure of hope. J. Pers. Soc. Psychol. 60, 570–585 (1991).
Libert, Y. et al. Communication about uncertainty and hope: a randomized controlled trial assessing the efficacy of a communication skills training program for physicians caring for cancer patients. BMC Cancer 17, 476 (2017).
Berendes, D. et al. Hope in the context of lung cancer: relationships of hope to symptoms and psychological distress. J. Pain. Symptom Manage. 40, 174–182 (2010).
Rajandram, R. K. et al. Interaction of hope and optimism with anxiety and depression in a specific group of cancer survivors: a preliminary study. BMC Res. Notes 4, 519 (2011).
Stiefel, F. et al. Training in communication of oncology clinicians: a position paper based on the third consensus meeting among European experts in 2018. Ann. Oncol. 29, 2033–2036 (2018).
Hellmann, M. D. et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N. Engl. J. Med. 381, 2020–2031 (2019).
Motzer, R. J. et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015).
Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 20, 1370–1385 (2019).
Ferris, R. L. et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 375, 1856–1867 (2016).
Bellmunt, J. et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N. Engl. J. Med. 376, 1015–1026 (2017).
C.R. has acted as a consultant of Amgen, Biothera, BMS, MSD, Novartis, Pierre Fabre, Roche, Sanofi and Ultimovacs. A.M. has acted as a consultant of Bayer, BPI, Daichii Sankyo, EISAI, Faron, Genticel, Imaxio, Molecular partners, Onxeo, Pierre Fabre, Pilar partners, Rigontec, Roche and Sanofi/BioNTech. K.F. has served on the advisory boards of AAA, Amgen, Astellas, AstraZeneca, Bayer, Clovis, Curevac, ESSA, Genentech, Janssen, MSD, Orion and Sanofi. C.C. has acted as a consultant of AstraZeneca, BMS, MSD, and Roche. B.B. has conducted research funded by Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, Ipsen, Merck, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda and Tiziana Pharm. H.H. and P.R. declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Robert, C., Marabelle, A., Herrscher, H. et al. Immunotherapy discontinuation — how, and when? Data from melanoma as a paradigm. Nat Rev Clin Oncol (2020). https://doi.org/10.1038/s41571-020-0399-6