Anti-PD-1 antibodies offer potentially life-saving treatment for some cancer patients, but their chronic administration generates high and ever-increasing costs. Despite licensing for long-term use, optimal treatment duration is unknown. We challenge the need for long-term treatment duration, using evidence from melanoma research, both published and in process

AC Tan

Alexandra Smith

C Robert

CRP da Veiga

Helen Marshall

J Schachter

Jane Hook

JD Wolchok

NI Khushalani

O Hamid

Pippa Corrie

Sarah Danson

Simon Rodwell

Sue Bell

YJL Jansen

English

Crossref

Are we over-treating with checkpoint inhibitors?

Danson, S.

Hook, J.

Marshall, H.

Smith, A.

Bell, S.

Rodwell, S.

Corrie, P.

White Rose Research Online

This is a repository copy of Are we over-treating with checkpoint inhibitors?.White Rose Research Online URL for this paper:http://eprints.whiterose.ac.uk/152515/Version: Published VersionArticle:Danson, S. orcid.org/0000-0002-3593-2890, Hook, J., Marshall, H. et al. (4 more authors) (2019) Are we over-treating with checkpoint inhibitors? British Journal of Cancer, 121 (8). pp. 629-630. ISSN 0007-0920 https://doi.org/10.1038/s41416-019-0570-yeprints@whiterose.ac.ukhttps://eprints.whiterose.ac.uk/Reuse This article is distributed under the terms of the Creative Commons Attribution (CC BY) licence. This licence allows you to distribute, remix, tweak, and build upon the work, even commercially, as long as you credit the authors for the original work. More information and the full terms of the licence here: https://creativecommons.org/licenses/ Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request. COMMENTAre we over-treating with checkpoint inhibitors?Anti-PD-1 antibodies offer potentially life-saving treatment for some cancer patients, but their chronic administration generateshigh and ever-increasing costs. Despite licensing for long-term use, optimal treatment duration is unknown. We challenge the needfor long-term treatment duration, using evidence from melanoma research, both published and in process.British Journal of Cancer (2019) 121:629–630; https://doi.org/10.1038/s41416-019-0570-yMAINAnti-PD-1 antibodies (pembrolizumab and nivolumab) arelicensed to be administered to metastatic melanoma patientsuntil disease progression. Multiple anti-PD(L)-1 antibodies arebeing licensed to treat various different cancer types, all withprolonged durations of treatment to 2 years or more forresponding patients. The question of whether anti-PD(L)-1 therapyneeds administering continuously to generate an immuneresponse is taxing the global oncology community. Chronicadministration generates a significant burden for patients andhealthcare systems, entailing multiple clinic visits and the risk ofchronic, life changing and sometimes life-threatening immune-mediated toxicities. The health-economic impact is substantial,which not all healthcare systems can absorb.1The first checkpoint inhibitor to enter the clinic was the anti-CTLA-4 antibody ipilimumab. In contrast to anti-PD(L)-1 anti-bodies, ipilimumab is administered over 12 weeks only, andaround 20% of patients will sustain durable remissions in theabsence of ongoing infusions. CTLA-4 and PD-1 differ in their T-cell receptor role and function, yet there is no biological evidencejustifying continuous therapy with anti-PD(L)-1 antibodies.2Indeed, contrary evidence is now accumulating.Long-term follow-up of metastatic melanoma patients treatedin the first prospective trials evaluating anti-PD-1 suggeststreatment to progression may not be justified.2–4 In theKeynote-001 pembrolizumab trial, 105 of 655 (17%) recruitedpatients had a complete response and 67 of 105 stoppedpembrolizumab while still in complete response, mostly due topatient choice. The 2-year disease-free survival rate from the timeof complete response was 90% for all, whether or not theystopped treatment.5 In the Keynote-006 trial comparing pembro-lizumab with ipilimumab as first line immunotherapy for meta-static melanoma, the planned treatment with pembrolizumab was2 years.6 A total of 104 of 556 (19%) patients completed theplanned course. After following the 104 patients for a median of9 months, their progression-free survival (PFS) was 91%: 95% forcomplete responders, 91% for partial responders, and 83% forthose with stable disease. A total of 17% of patients experiencedsevere (grade 3/4) toxicity during treatment. Based on these data,many clinicians and patients are electing to stop treatment at 2years.3,6For metastatic melanoma, 40% of patients can expect torespond to anti-PD-1 antibodies and therefore are likely to beeligible to continue treatment to 2 years or more.3,4 Mostresponses to anti-PD-1 antibodies occur within 6 months ofstarting treatment and there is growing motivation to stoptreatment before 2 years.7 A recent retrospective study deter-mined that ‘real-life’ duration of treatment is shorter than thatreported in clinical trials; patients with a complete response (CR)compared with a partial response (PR) or stable disease may havea lower risk of relapse off therapy. In those with CR, the risk ofprogression was significantly higher in those treated for<6 months compared with those treated for >6 months.8 Anotherretrospective review of 104 progression-free metastatic mela-noma patients undergoing FDG-PET/CT after 1 year of anti-PD-1antibodies reported that complete metabolic response (CMR) wasassociated with 2-year PFS of 96%, compared with 49% in thosepatients whose scans did not show CMR (HR [hazard ratio] 0.06,95% CI [confidence interval] 0.02–0.23), so other tools may offervalue in tailoring treatment in the future.9 Even so, nationalreimbursement models are generally licence-driven and neitherstopping early, nor treatment re-challenge, may actually bepermitted. There is clearly a need to generate high-qualityevidence to define early stopping rules.The CheckMate153 study is the only randomised studypublished to date specifically evaluating duration of anti-PD-1therapy. CheckMate153 compared treatment until progressionwith 12 months of nivolumab in patients with advanced non-smallcell lung cancer (NSCLC). In this study, 220 patients receivingnivolumab who were progression-free at 12 months wererandomised to continue until progression, or to stop treatment;patients in the discontinuation arm were allowed to re-startnivolumab at progression. Initial results10 reported better PFS withcontinuous versus 12-months treatment: median PFS was notreached in the continuous arm compared with 10.3 months (95%CI 6.4–15.2) in the discontinuation arm (HR 0.42, 95% CI 0.25–0.71).Despite PFS differences, overall survival did not show astatistically significant difference between the two treatmentarms (HR 0.63, 95% CI 0.33–1.20), although the data are immature.Whether these results are generalisable to other tumourtypes needs to be determined and two key prospective clinicaltrials are now under way in metastatic melanoma. Bothare pragmatic and use standard of care, government-fundedanti-PD-1 therapy.The Canadian STOP-GAP study (NCT02821013) is currentlyassessing intermittent versus continuous treatment with anti-PD-1inhibitors, with a primary endpoint of overall survival. In this trial,614 patients are being randomised in the first 16 weeks of anti-www.nature.com/bjcReceived: 13 August 2019 Revised: 20 August 2019 Accepted: 23 August 2019Published online: 17 September 2019© The Author(s) 2019 Published by Springer Nature on behalf of Cancer Research UKPD-1 treatment to either standard 2 years of treatmentor treatment to maximal tumour response with retreatmentat the time of progression. Maximal tumour response isdetermined by at least two radiological measurements 3 monthsapart. STOP-GAP therefore is primarily evaluating the role of re-challenge rather than the specific question of optimal treatmentduration.The UK National Institute for Health Research (NIHR) portfolioDANTE trial (ISRCTN15837212) is randomising metastatic melanomapatients receiving anti-PD-1 therapy who are progression-free at12 months to either stop (with re-challenge allowed on progression)or continue treatment as per standard use. This non-inferiority trialhas a primary endpoint of PFS. Patients are being registered in thefirst year of treatment, with a plan to randomise 1208 patients at12 months. Opportunities are being explored to utilise this uniquetrial to evaluate biomarkers of treatment response as well as toxicity,including genetic signatures, circulating tumour DNA, gut microbiotaand 18F-FDG PET/CT.We encourage patients and investigators alike to supportprospective randomised controlled trials like DANTE andSTOP-GAP, generating the evidence needed to ensure safe,effective and affordable treatment for our patients now and in thefuture.AUTHOR CONTRIBUTIONSSD and PC were responsible for the concept of the comment and wrote the first draft.JH, HM, AS, SB and SR commented on the manuscript. All authors approved the finalversion and agreed with submission to the British Journal of Cancer.ADDITIONAL INFORMATIONCompeting interests: The authors are co-applicants on the DANTE trial. S.D. hasreceived conference and travel support from MSD, Pierre Fabre and BMS; and sat onadvisory boards for MSD and BMS. P.C. has received speaker fees and sat on advisoryboards for MSD, BMS, Novartis and Pierre Fabre. S.R. is CEO of the charity MelanomaFocus. The remaining authors declare no competing interests.Ethics approval and consent to participate: Not applicableFunding: The DANTE study is funded by the National Institute for Health ResearchHealth Technology Assessment (HTA) Programme (project number 15/57/66). Theviews expressed are those of the author(s) and not necessarily those of the NHS, theNIHR or the Department of Health and Social Care. The funder has not been involvedin the writing of this article.Consent to publish: Not applicableData availability: Not applicablePublisher’s note: Springer Nature remains neutral with regard to jurisdictional claimsin published maps and institutional affiliations.Sarah Danson1, Jane Hook2, Helen Marshall2, Alexandra Smith2,Sue Bell2, Simon Rodwell3 and Pippa Corrie41University of Sheffield and Sheffield Teaching Hospitals NHSFoundation Trust, Sheffield, UK; 2Leeds CTRU, University of Leeds,Leeds, UK; 3Melanoma Focus, Cambridge, UK and 4CambridgeUniversity Hospitals NHS Foundation Trust and University ofCambridge, Cambridge, UKCorrespondence: Sarah Danson (s.danson@sheffield.ac.uk)REFERENCES1. da Veiga, C. R. P., da Veiga, C. P. & Drummond-Lage, A. P. Concern over cost ofand access to cancer treatments: a meta-narrative review of nivolumab andpembrolizumab studies. Crit. Rev. Oncol. Hematol. 129, 133–145 (2018).2. Hamid, O., Robert, C., Daud, A., Hodi, F. S., Hwu, W. J., Kefford, R. et al. Five-yearsurvival outcomes for patients with advanced melanoma treated with pem-brolizumab in KEYNOTE-001. Ann. Oncol. 30, 582–588 (2019).3. Robert, C., Schachter, J., Long, G. V., Arance, A., Grob, J. J., Mortier, L. et al.Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372,2521–2532 (2015).4. Wolchok, J. D., Chiarion-Sileni, V., Gonzalez, R., Rutkowski, P., Grob, J. J., Cowey, C.L. et al. Overall survival with combined nivolumab and ipilimumab in advancedmelanoma. N. Engl. J. Med. 377, 1345–1356 (2017).5. Robert, C., Ribas, A., Hamid, O., Daud, A., Wolchok, J. D., Joshua, A. M. et al.Durable complete response after discontinuation of pembrolizumab in patientswith metastatic melanoma. J. Clin. Oncol. 36, 1668–1674 (2018).6. Schachter, J., Ribas, A., Long, G. V., Arance, A., Grob, J. J., Mortier, L. et al. Pem-brolizumab versus ipilimumab for advanced melanoma: final overall survivalresults of a multicenter, randomised, open-label phase 3 study (KEYNOTE-006).Lancet 390, 1853–1862 (2017).7. Khushalani, N. I. Duration of anti-programmed death-1 therapy in advanced mel-anoma: how much of a good thing is enough? J. Clin. Oncol. 36, 1649–1653 (2018).8. Jansen, Y. J. L., Rozeman, E. A., Mason, R., Goldringer, S. M., Geukes Foppen, M. H.,Hoejbergs, L. et al. Discontinuation of anti-PD-1 antibody therapy in the absenceof disease progression or treatment limiting toxicity: clinical outcomes inadvanced melanoma. Ann. Oncol. 30, 1154–1161 (2019).9. Tan, A. C., Emmett, L., Lo, S., Liu, V., Kapoor, R., Carlino, M. S. et al. FDG-PETresponse and outcome from anti-PD-1 therapy in metastatic melanoma. Ann.Oncol. 29, 2115–2120 (2018).10. Spigel D., McCleod M., Hussein M., Waterhouse D. M., Einhorn L., Horn L., et al.Randomized results of fixed-duration (1-yr) vs continuous nivolumab in patients(pts) with advanced non-small cell lung cancer (NSCLC). Ann. Oncol. 2017; 28, 461(Suppl 5), abstract 12970 (2017).Open Access This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in anymedium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is not included in thearticle’s Creative Commons license and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directlyfrom the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.© The Author(s) 2019Comment6301234567890();,:

Danson, Sarah

Hook, Jane

Marshall, Helen

Smith, Alexandra

Bell, Sue

Rodwell, Simon

Corrie, Pippa

Apollo (Cambridge)

COMMENTAre we over-treating with checkpoint inhibitors?Anti-PD-1 antibodies offer potentially life-saving treatment for some cancer patients, but their chronic administration generateshigh and ever-increasing costs. Despite licensing for long-term use, optimal treatment duration is unknown. We challenge the needfor long-term treatment duration, using evidence from melanoma research, both published and in process.British Journal of Cancer (2019) 121:629–630; https://doi.org/10.1038/s41416-019-0570-yMAINAnti-PD-1 antibodies (pembrolizumab and nivolumab) arelicensed to be administered to metastatic melanoma patientsuntil disease progression. Multiple anti-PD(L)-1 antibodies arebeing licensed to treat various different cancer types, all withprolonged durations of treatment to 2 years or more forresponding patients. The question of whether anti-PD(L)-1 therapyneeds administering continuously to generate an immuneresponse is taxing the global oncology community. Chronicadministration generates a significant burden for patients andhealthcare systems, entailing multiple clinic visits and the risk ofchronic, life changing and sometimes life-threatening immune-mediated toxicities. The health-economic impact is substantial,which not all healthcare systems can absorb.1The first checkpoint inhibitor to enter the clinic was the anti-CTLA-4 antibody ipilimumab. In contrast to anti-PD(L)-1 anti-bodies, ipilimumab is administered over 12 weeks only, andaround 20% of patients will sustain durable remissions in theabsence of ongoing infusions. CTLA-4 and PD-1 differ in their T-cell receptor role and function, yet there is no biological evidencejustifying continuous therapy with anti-PD(L)-1 antibodies.2Indeed, contrary evidence is now accumulating.Long-term follow-up of metastatic melanoma patients treatedin the first prospective trials evaluating anti-PD-1 suggeststreatment to progression may not be justified.2–4 In theKeynote-001 pembrolizumab trial, 105 of 655 (17%) recruitedpatients had a complete response and 67 of 105 stoppedpembrolizumab while still in complete response, mostly due topatient choice. The 2-year disease-free survival rate from the timeof complete response was 90% for all, whether or not theystopped treatment.5 In the Keynote-006 trial comparing pembro-lizumab with ipilimumab as first line immunotherapy for meta-static melanoma, the planned treatment with pembrolizumab was2 years.6 A total of 104 of 556 (19%) patients completed theplanned course. After following the 104 patients for a median of9 months, their progression-free survival (PFS) was 91%: 95% forcomplete responders, 91% for partial responders, and 83% forthose with stable disease. A total of 17% of patients experiencedsevere (grade 3/4) toxicity during treatment. Based on these data,many clinicians and patients are electing to stop treatment at 2years.3,6For metastatic melanoma, 40% of patients can expect torespond to anti-PD-1 antibodies and therefore are likely to beeligible to continue treatment to 2 years or more.3,4 Mostresponses to anti-PD-1 antibodies occur within 6 months ofstarting treatment and there is growing motivation to stoptreatment before 2 years.7 A recent retrospective study deter-mined that ‘real-life’ duration of treatment is shorter than thatreported in clinical trials; patients with a complete response (CR)compared with a partial response (PR) or stable disease may havea lower risk of relapse off therapy. In those with CR, the risk ofprogression was significantly higher in those treated for<6 months compared with those treated for >6 months.8 Anotherretrospective review of 104 progression-free metastatic mela-noma patients undergoing FDG-PET/CT after 1 year of anti-PD-1antibodies reported that complete metabolic response (CMR) wasassociated with 2-year PFS of 96%, compared with 49% in thosepatients whose scans did not show CMR (HR [hazard ratio] 0.06,95% CI [confidence interval] 0.02–0.23), so other tools may offervalue in tailoring treatment in the future.9 Even so, nationalreimbursement models are generally licence-driven and neitherstopping early, nor treatment re-challenge, may actually bepermitted. There is clearly a need to generate high-qualityevidence to define early stopping rules.The CheckMate153 study is the only randomised studypublished to date specifically evaluating duration of anti-PD-1therapy. CheckMate153 compared treatment until progressionwith 12 months of nivolumab in patients with advanced non-smallcell lung cancer (NSCLC). In this study, 220 patients receivingnivolumab who were progression-free at 12 months wererandomised to continue until progression, or to stop treatment;patients in the discontinuation arm were allowed to re-startnivolumab at progression. Initial results10 reported better PFS withcontinuous versus 12-months treatment: median PFS was notreached in the continuous arm compared with 10.3 months (95%CI 6.4–15.2) in the discontinuation arm (HR 0.42, 95% CI 0.25–0.71).Despite PFS differences, overall survival did not show astatistically significant difference between the two treatmentarms (HR 0.63, 95% CI 0.33–1.20), although the data are immature.Whether these results are generalisable to other tumourtypes needs to be determined and two key prospective clinicaltrials are now under way in metastatic melanoma. Bothare pragmatic and use standard of care, government-fundedanti-PD-1 therapy.The Canadian STOP-GAP study (NCT02821013) is currentlyassessing intermittent versus continuous treatment with anti-PD-1inhibitors, with a primary endpoint of overall survival. In this trial,614 patients are being randomised in the first 16 weeks of anti-www.nature.com/bjcReceived: 13 August 2019 Revised: 20 August 2019 Accepted: 23 August 2019Published online: 17 September 2019© The Author(s) 2019 Published by Springer Nature on behalf of Cancer Research UKPD-1 treatment to either standard 2 years of treatmentor treatment to maximal tumour response with retreatmentat the time of progression. Maximal tumour response isdetermined by at least two radiological measurements 3 monthsapart. STOP-GAP therefore is primarily evaluating the role of re-challenge rather than the specific question of optimal treatmentduration.The UK National Institute for Health Research (NIHR) portfolioDANTE trial (ISRCTN15837212) is randomising metastatic melanomapatients receiving anti-PD-1 therapy who are progression-free at12 months to either stop (with re-challenge allowed on progression)or continue treatment as per standard use. This non-inferiority trialhas a primary endpoint of PFS. Patients are being registered in thefirst year of treatment, with a plan to randomise 1208 patients at12 months. Opportunities are being explored to utilise this uniquetrial to evaluate biomarkers of treatment response as well as toxicity,including genetic signatures, circulating tumour DNA, gut microbiotaand 18F-FDG PET/CT.We encourage patients and investigators alike to supportprospective randomised controlled trials like DANTE andSTOP-GAP, generating the evidence needed to ensure safe,effective and affordable treatment for our patients now and in thefuture.AUTHOR CONTRIBUTIONSSD and PC were responsible for the concept of the comment and wrote the first draft.JH, HM, AS, SB and SR commented on the manuscript. All authors approved the finalversion and agreed with submission to the British Journal of Cancer.ADDITIONAL INFORMATIONCompeting interests: The authors are co-applicants on the DANTE trial. S.D. hasreceived conference and travel support from MSD, Pierre Fabre and BMS; and sat onadvisory boards for MSD and BMS. P.C. has received speaker fees and sat on advisoryboards for MSD, BMS, Novartis and Pierre Fabre. S.R. is CEO of the charity MelanomaFocus. The remaining authors declare no competing interests.Ethics approval and consent to participate: Not applicableFunding: The DANTE study is funded by the National Institute for Health ResearchHealth Technology Assessment (HTA) Programme (project number 15/57/66). Theviews expressed are those of the author(s) and not necessarily those of the NHS, theNIHR or the Department of Health and Social Care. The funder has not been involvedin the writing of this article.Consent to publish: Not applicableData availability: Not applicablePublisher’s note: Springer Nature remains neutral with regard to jurisdictional claimsin published maps and institutional affiliations.Sarah Danson1, Jane Hook2, Helen Marshall2, Alexandra Smith2,Sue Bell2, Simon Rodwell3 and Pippa Corrie41University of Sheffield and Sheffield Teaching Hospitals NHSFoundation Trust, Sheffield, UK; 2Leeds CTRU, University of Leeds,Leeds, UK; 3Melanoma Focus, Cambridge, UK and 4CambridgeUniversity Hospitals NHS Foundation Trust and University ofCambridge, Cambridge, UKCorrespondence: Sarah Danson (s.danson@sheffield.ac.uk)REFERENCES1. da Veiga, C. R. P., da Veiga, C. P. & Drummond-Lage, A. P. Concern over cost ofand access to cancer treatments: a meta-narrative review of nivolumab andpembrolizumab studies. Crit. Rev. Oncol. Hematol. 129, 133–145 (2018).2. Hamid, O., Robert, C., Daud, A., Hodi, F. S., Hwu, W. J., Kefford, R. et al. Five-yearsurvival outcomes for patients with advanced melanoma treated with pem-brolizumab in KEYNOTE-001. Ann. Oncol. 30, 582–588 (2019).3. Robert, C., Schachter, J., Long, G. V., Arance, A., Grob, J. J., Mortier, L. et al.Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372,2521–2532 (2015).4. Wolchok, J. D., Chiarion-Sileni, V., Gonzalez, R., Rutkowski, P., Grob, J. J., Cowey, C.L. et al. Overall survival with combined nivolumab and ipilimumab in advancedmelanoma. N. Engl. J. Med. 377, 1345–1356 (2017).5. Robert, C., Ribas, A., Hamid, O., Daud, A., Wolchok, J. D., Joshua, A. M. et al.Durable complete response after discontinuation of pembrolizumab in patientswith metastatic melanoma. J. Clin. Oncol. 36, 1668–1674 (2018).6. Schachter, J., Ribas, A., Long, G. V., Arance, A., Grob, J. J., Mortier, L. et al. Pem-brolizumab versus ipilimumab for advanced melanoma: final overall survivalresults of a multicenter, randomised, open-label phase 3 study (KEYNOTE-006).Lancet 390, 1853–1862 (2017).7. Khushalani, N. I. Duration of anti-programmed death-1 therapy in advanced mel-anoma: how much of a good thing is enough? J. Clin. Oncol. 36, 1649–1653 (2018).8. Jansen, Y. J. L., Rozeman, E. A., Mason, R., Goldringer, S. M., Geukes Foppen, M. H.,Hoejbergs, L. et al. Discontinuation of anti-PD-1 antibody therapy in the absenceof disease progression or treatment limiting toxicity: clinical outcomes inadvanced melanoma. Ann. Oncol. 30, 1154–1161 (2019).9. Tan, A. C., Emmett, L., Lo, S., Liu, V., Kapoor, R., Carlino, M. S. et al. FDG-PETresponse and outcome from anti-PD-1 therapy in metastatic melanoma. Ann.Oncol. 29, 2115–2120 (2018).10. Spigel D., McCleod M., Hussein M., Waterhouse D. M., Einhorn L., Horn L., et al.Randomized results of fixed-duration (1-yr) vs continuous nivolumab in patients(pts) with advanced non-small cell lung cancer (NSCLC). Ann. Oncol. 2017; 28, 461(Suppl 5), abstract 12970 (2017).Open Access This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in anymedium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is not included in thearticle’s Creative Commons license and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directlyfrom the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.© The Author(s) 2019Comment6301234567890();,:

Danson, S

Hook, J

Marshall, H

Smith, A

Bell, S

Rodwell, S

Corrie, P

COMMENTAre we over-treating with checkpoint inhibitors?Anti-PD-1 antibodies offer potentially life-saving treatment for some cancer patients, but their chronic administration generateshigh and ever-increasing costs. Despite licensing for long-term use, optimal treatment duration is unknown. We challenge the needfor long-term treatment duration, using evidence from melanoma research, both published and in process.British Journal of Cancer https://doi.org/10.1038/s41416-019-0570-yMAINAnti-PD-1 antibodies (pembrolizumab and nivolumab) arelicensed to be administered to metastatic melanoma patientsuntil disease progression. Multiple anti-PD(L)-1 antibodies arebeing licensed to treat various different cancer types, all withprolonged durations of treatment to 2 years or more forresponding patients. The question of whether anti-PD(L)-1 therapyneeds administering continuously to generate an immuneresponse is taxing the global oncology community. Chronicadministration generates a signiﬁcant burden for patients andhealthcare systems, entailing multiple clinic visits and the risk ofchronic, life changing and sometimes life-threatening immune-mediated toxicities. The health-economic impact is substantial,which not all healthcare systems can absorb.1The ﬁrst checkpoint inhibitor to enter the clinic was the anti-CTLA-4 antibody ipilimumab. In contrast to anti-PD(L)-1 anti-bodies, ipilimumab is administered over 12 weeks only, andaround 20% of patients will sustain durable remissions in theabsence of ongoing infusions. CTLA-4 and PD-1 differ in their T-cell receptor role and function, yet there is no biological evidencejustifying continuous therapy with anti-PD(L)-1 antibodies.2Indeed, contrary evidence is now accumulating.Long-term follow-up of metastatic melanoma patients treatedin the ﬁrst prospective trials evaluating anti-PD-1 suggeststreatment to progression may not be justiﬁed.2–4 In theKeynote-001 pembrolizumab trial, 105 of 655 (17%) recruitedpatients had a complete response and 67 of 105 stoppedpembrolizumab while still in complete response, mostly due topatient choice. The 2-year disease-free survival rate from the timeof complete response was 90% for all, whether or not theystopped treatment.5 In the Keynote-006 trial comparing pembro-lizumab with ipilimumab as ﬁrst line immunotherapy for meta-static melanoma, the planned treatment with pembrolizumab was2 years.6 A total of 104 of 556 (19%) patients completed theplanned course. After following the 104 patients for a median of9 months, their progression-free survival (PFS) was 91%: 95% forcomplete responders, 91% for partial responders, and 83% forthose with stable disease. A total of 17% of patients experiencedsevere (grade 3/4) toxicity during treatment. Based on these data,many clinicians and patients are electing to stop treatment at 2years.3,6For metastatic melanoma, 40% of patients can expect torespond to anti-PD-1 antibodies and therefore are likely to beeligible to continue treatment to 2 years or more.3,4 Mostresponses to anti-PD-1 antibodies occur within 6 months ofstarting treatment and there is growing motivation to stoptreatment before 2 years.7 A recent retrospective study deter-mined that ‘real-life’ duration of treatment is shorter than thatreported in clinical trials; patients with a complete response (CR)compared with a partial response (PR) or stable disease may havea lower risk of relapse off therapy. In those with CR, the risk ofprogression was signiﬁcantly higher in those treated for<6 months compared with those treated for >6 months.8 Anotherretrospective review of 104 progression-free metastatic mela-noma patients undergoing FDG-PET/CT after 1 year of anti-PD-1antibodies reported that complete metabolic response (CMR) wasassociated with 2-year PFS of 96%, compared with 49% in thosepatients whose scans did not show CMR (HR [hazard ratio] 0.06,95% CI [conﬁdence interval] 0.02–0.23), so other tools may offervalue in tailoring treatment in the future.9 Even so, nationalreimbursement models are generally licence-driven and neitherstopping early, nor treatment re-challenge, may actually bepermitted. There is clearly a need to generate high-qualityevidence to deﬁne early stopping rules.The CheckMate153 study is the only randomised studypublished to date speciﬁcally evaluating duration of anti-PD-1therapy. CheckMate153 compared treatment until progressionwith 12 months of nivolumab in patients with advanced non-smallcell lung cancer (NSCLC). In this study, 220 patients receivingnivolumab who were progression-free at 12 months wererandomised to continue until progression, or to stop treatment;patients in the discontinuation arm were allowed to re-startnivolumab at progression. Initial results10 reported better PFS withcontinuous versus 12-months treatment: median PFS was notreached in the continuous arm compared with 10.3 months (95%CI 6.4–15.2) in the discontinuation arm (HR 0.42, 95% CI 0.25–0.71).Despite PFS differences, overall survival did not show astatistically signiﬁcant difference between the two treatmentarms (HR 0.63, 95% CI 0.33–1.20), although the data are immature.Whether these results are generalisable to other tumourtypes needs to be determined and two key prospective clinicaltrials are now under way in metastatic melanoma. Bothare pragmatic and use standard of care, government-fundedanti-PD-1 therapy.The Canadian STOP-GAP study (NCT02821013) is currentlyassessing intermittent versus continuous treatment with anti-PD-1inhibitors, with a primary endpoint of overall survival. In this trial,614 patients are being randomised in the ﬁrst 16 weeks of anti-www.nature.com/bjcReceived: 13 August 2019 Revised: 20 August 2019 Accepted: 23 August 2019© The Author(s) 2019 Published by Springer Nature on behalf of Cancer Research UKPD-1 treatment to either standard 2 years of treatmentor treatment to maximal tumour response with retreatmentat the time of progression. Maximal tumour response isdetermined by at least two radiological measurements 3 monthsapart. STOP-GAP therefore is primarily evaluating the role of re-challenge rather than the speciﬁc question of optimal treatmentduration.The UK National Institute for Health Research (NIHR) portfolioDANTE trial (ISRCTN15837212) is randomising metastatic melanomapatients receiving anti-PD-1 therapy who are progression-free at12 months to either stop (with re-challenge allowed on progression)or continue treatment as per standard use. This non-inferiority trialhas a primary endpoint of PFS. Patients are being registered in theﬁrst year of treatment, with a plan to randomise 1208 patients at12 months. Opportunities are being explored to utilise this uniquetrial to evaluate biomarkers of treatment response as well as toxicity,including genetic signatures, circulating tumour DNA, gut microbiotaand 18F-FDG PET/CT.We encourage patients and investigators alike to supportprospective randomised controlled trials like DANTE andSTOP-GAP, generating the evidence needed to ensure safe,effective and affordable treatment for our patients now and in thefuture.AUTHOR CONTRIBUTIONSSD and PC were responsible for the concept of the comment and wrote the ﬁrst draft.JH, HM, AS, SB and SR commented on the manuscript. All authors approved the ﬁnalversion and agreed with submission to the British Journal of Cancer.ADDITIONAL INFORMATIONCompeting interests: The authors are co-applicants on the DANTE trial. S.D. hasreceived conference and travel support from MSD, Pierre Fabre and BMS; and sat onadvisory boards for MSD and BMS. P.C. has received speaker fees and sat on advisoryboards for MSD, BMS, Novartis and Pierre Fabre. S.R. is CEO of the charity MelanomaFocus. The remaining authors declare no competing interests.Ethics approval and consent to participate: Not applicableFunding: The DANTE study is funded by the National Institute for Health ResearchHealth Technology Assessment (HTA) Programme (project number 15/57/66). Theviews expressed are those of the author(s) and not necessarily those of the NHS, theNIHR or the Department of Health and Social Care. The funder has not been involvedin the writing of this article.Consent to publish: Not applicableData availability: Not applicablePublisher’s note: Springer Nature remains neutral with regard to jurisdictional claimsin published maps and institutional afﬁliations.Sarah Danson1, Jane Hook2, Helen Marshall2, Alexandra Smith2,Sue Bell2, Simon Rodwell3 and Pippa Corrie41University of Shefﬁeld and Shefﬁeld Teaching Hospitals NHSFoundation Trust, Shefﬁeld, UK; 2Leeds CTRU, University of Leeds,Leeds, UK; 3Melanoma Focus, Cambridge, UK and 4CambridgeUniversity Hospitals NHS Foundation Trust and University ofCambridge, Cambridge, UKCorrespondence: Sarah Danson (s.danson@shefﬁeld.ac.uk)REFERENCES1. da Veiga, C. R. P., da Veiga, C. P. & Drummond-Lage, A. P. Concern over cost ofand access to cancer treatments: a meta-narrative review of nivolumab andpembrolizumab studies. Crit. Rev. Oncol. Hematol. 129, 133–145 (2018).2. Hamid, O., Robert, C., Daud, A., Hodi, F. S., Hwu, W. J., Kefford, R. et al. Five-yearsurvival outcomes for patients with advanced melanoma treated with pem-brolizumab in KEYNOTE-001. Ann. Oncol. 30, 582–588 (2019).3. Robert, C., Schachter, J., Long, G. V., Arance, A., Grob, J. J., Mortier, L. et al.Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372,2521–2532 (2015).4. Wolchok, J. D., Chiarion-Sileni, V., Gonzalez, R., Rutkowski, P., Grob, J. J., Cowey, C.L. et al. Overall survival with combined nivolumab and ipilimumab in advancedmelanoma. N. Engl. J. Med. 377, 1345–1356 (2017).5. Robert, C., Ribas, A., Hamid, O., Daud, A., Wolchok, J. D., Joshua, A. M. et al.Durable complete response after discontinuation of pembrolizumab in patientswith metastatic melanoma. J. Clin. Oncol. 36, 1668–1674 (2018).6. Schachter, J., Ribas, A., Long, G. V., Arance, A., Grob, J. J., Mortier, L. et al. Pem-brolizumab versus ipilimumab for advanced melanoma: ﬁnal overall survivalresults of a multicenter, randomised, open-label phase 3 study (KEYNOTE-006).Lancet 390, 1853–1862 (2017).7. Khushalani, N. I. Duration of anti-programmed death-1 therapy in advanced mel-anoma: how much of a good thing is enough? J. Clin. Oncol. 36, 1649–1653 (2018).8. Jansen, Y. J. L., Rozeman, E. A., Mason, R., Goldringer, S. M., Geukes Foppen, M. H.,Hoejbergs, L. et al. Discontinuation of anti-PD-1 antibody therapy in the absenceof disease progression or treatment limiting toxicity: clinical outcomes inadvanced melanoma. Ann. Oncol. 30, 1154–1161 (2019).9. Tan, A. C., Emmett, L., Lo, S., Liu, V., Kapoor, R., Carlino, M. S. et al. FDG-PETresponse and outcome from anti-PD-1 therapy in metastatic melanoma. Ann.Oncol. 29, 2115–2120 (2018).10. Spigel D., McCleod M., Hussein M., Waterhouse D. M., Einhorn L., Horn L., et al.Randomized results of ﬁxed-duration (1-yr) vs continuous nivolumab in patients(pts) with advanced non-small cell lung cancer (NSCLC). Ann. Oncol. 2017; 28, 461(Suppl 5), abstract 12970 (2017).Open Access This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in anymedium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is not included in thearticle’s Creative Commons license and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directlyfrom the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.© The Author(s) 2019Comment21234567890();,:

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