Clinical Study

Melanoma recurrence patterns and management after adjuvant targeted therapy: a multicentre analysis

Abstract

Background

Adjuvant targeted therapy (TT) improves relapse free survival in patients with resected BRAF mutant stage III melanoma. The outcomes and optimal management of patients who relapse after adjuvant TT is unknown.

Methods

Patients from twenty-one centres with recurrent melanoma after adjuvant TT were included. Disease characteristics, adjuvant therapy, recurrence, treatment at relapse and outcomes were examined.

Results

Eighty-five patients developed recurrent melanoma; nineteen (22%) during adjuvant TT. Median time to first recurrence was 18 months and median follow-up from first recurrence was 31 months. Fifty-eight (68%) patients received immunotherapy (IT) or TT as 1st line systemic therapy at either first or subsequent recurrence and had disease that was assessable for response. Response to anti-PD-1 (±trial agent), combination ipilimumab-nivolumab, TT rechallenge and ipilimumab monotherapy was 63%, 62% 25% and 10% respectively. Twenty-eight (33%) patients had died at census, all from melanoma. Two-year OS was 84% for anti-PD-1 therapy (±trial agent), 92% for combination ipilimumab and nivolumab, 49% for TT and 45% for ipilimumab monotherapy (p = 0.028).

Conclusions

Patients who relapse after adjuvant TT respond well to subsequent anti-PD-1 based therapy and have outcomes similar to those seen when first line anti-PD-1 therapy is used in stage IV melanoma.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Flow chart of treatment at first recurrence of melanoma after adjuvant TT.
Fig. 2
Fig. 3

References

  1. 1.

    Wolchok, J. D., Chiarion-Sileni, V., Gonzalez, R., Rutkowski, P., Grob, J.-J., Lance Cowey, C. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345–1356 (2017).

    CAS  Article  Google Scholar 

  2. 2.

    Larkin, J. M. G., Chiarion-Sileni, V., Gonzalez, R., Grob, J.-J., Rutkowski, P., Lao, C. D. et al. 5-year survival outcomes of the CheckMate 067 phase 3 trial of nivolumab plus ipilimumab (NIVO+IPI) combination therapy in advanced melanoma. N. Engl. J. Med. 381, 1535–1546 (2019).

    CAS  Article  Google Scholar 

  3. 3.

    Long, G. V., Flaherty, K. T., Stroyakovskiy, D., Gogas, H., Levchenko, E., de Braud, F. et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann. Oncol. 28, 1631–1639 (2017).

    CAS  Article  Google Scholar 

  4. 4.

    Grob, J. J., Amonkar, M. M., Karaszewska, B., Schachter, J., Drummer, R., Mackiewicz, A. et al. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial. Lancet Oncol. 16, 1389–1398 (2015).

    CAS  Article  Google Scholar 

  5. 5.

    Robert, C., Grob, J. J., Stroyakovskiy, D., Karazewska, B., Hauschild, A., Levchenko, E. et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N. Engl. J. Med. 381, 626–636 (2019).

    CAS  Article  Google Scholar 

  6. 6.

    Gershenwald, J. E., Scolyer, R. A., Hess, K. R., Sondak, V. K., Long, G. V., Ross, M. I. et al. Melanoma staging: evidence-based changes in the american joint committee on cancer eighth edition cancer staging manual. CA Cancer J. Clin. 67, 472–492 (2017).

    Article  Google Scholar 

  7. 7.

    Kanaki, T., Stang, A., Gutzmer, R., Zimmer, L., Chorti, E., Sucker, A. et al. Impact of American joint committee on cancer 8th edition classification on staging and survival of patients with melanoma. Eur. J. Cancer 119, 18–29 (2019).

    Article  Google Scholar 

  8. 8.

    Eggermont, A. M. M., Chiarion-Sileni, V., Grob, J. J., Drummer, R., Wolchok, J. D., Schmidt, H. 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).

    CAS  Article  Google Scholar 

  9. 9.

    Eggermont, A. M. M., Chiarion-Sileni, V., Grob, J. J., Drummer, R., Wolchok, J. D., Schmidt, H. et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N. Engl. J. Med. 375, 1845–1855 (2016).

    CAS  Article  Google Scholar 

  10. 10.

    Eggermont A. M. M., Chiarion-Sileni V., Grob, J. J., Drummer R., Wolchok J. D., Schmidt H. et al. Ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results the EORTC 18071 double-blind phase 3 randomized trial. J. Clin. Oncol. 37, abstract 2512 (2019)

  11. 11.

    Tarhini, A. A., Lee, S. J., Hodi, F. S., Rao, U. N. M., Cohen, G. I., Hamid, O. et al. Phase III study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma: North American Intergroup E1609. J. Clin. Oncol. 38, 567–575 (2019).

    Article  Google Scholar 

  12. 12.

    Weber, J., Mandala, M., Del Vecchio, M., Gogas, H. J., Arance, A. M., Cowey, C. L. et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N. Engl. J. Med. 377, 1824–1835 (2017).

    CAS  Article  Google Scholar 

  13. 13.

    Weber, J., Del Vecchio, M., Mandala, M., Gogas, H., Arance, A. M., Dalle, S. et al. Adjuvant nivolumab (NIVO) versus ipilimumab (IPI) in resected stage III/IV melanoma: 3-year efficacy and biomarker results from the phase III CheckMate 238 trial. Ann. Oncol. 30(Suppl. 5), v533–563 (2019).

    Article  Google Scholar 

  14. 14.

    Eggermont, A. M. M., Blank, C. U., Mandala, M., Long, G. V., Atkinson, V., Dalle, S. et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N. Engl. J. Med. 378, 1789–1801 (2018).

    CAS  Article  Google Scholar 

  15. 15.

    Maio, M., Lewis, K., Dernidov, L., Mandala, M., Bondarenko, I., Ascierto, P. A. et al. Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol. 19, 510–520 (2018).

    CAS  Article  Google Scholar 

  16. 16.

    Long, G. V., Hauschild, A., Santinami, M., Atkinson, V., Mandala, M., Chiarion-Sileni, V. et al. Adjuvant Dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N. Engl. J. Med. 377, 1813–1823 (2017).

    CAS  Article  Google Scholar 

  17. 17.

    Hauschild, A., Drummer, R., Schadendorf, D., Santinami, M., Atkinson, V., Mandala, M. et al. Longer follow-up confirms relapse-free survival benefit with adjuvant dabrafenib plus trametinib in patients with resected BRAF V600–mutant stage III melanoma. J. Clin. Oncol. 36, 3441–3449 (2019).

    Article  Google Scholar 

  18. 18.

    Owen C. N., Shoushtri A. N., Chauhan D., Palmieri D. J., Lee B., Rohaan M. W. et al. Management of early melanoma recurrence despite adjuvant anti-PD-1 antibody therapy. Ann. Oncol. https://doi.org/10.1016/j.annonc.2020.04.471 (2020)

  19. 19.

    Hamid, O., Robert, C., Daud, A., Hodi, F. S., Hwu, W. J., Kefford, R. et al. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann. Oncol. 30, 582–588 (2019).

    CAS  Article  Google Scholar 

  20. 20.

    Frederick, D. T., Piris, A., Cogdill, A. P., Cooper, Z. A., Lezcano, C., Ferrone, C. R. et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin. Cancer Res. 19, 1225–1231 (2013).

    CAS  Article  Google Scholar 

  21. 21.

    Wilmott, J. S., Long, G. V., Howle, J. R., Haydu, L. E., Sharma, R. N., Thompson, J. F. et al. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin. Cancer Res. 18, 1386–1394 (2012).

    CAS  Article  Google Scholar 

  22. 22.

    Kakavand, H., Rawson, R. V., Pupo, G. M., Yang, J. Y. H., Menzies, A. M., Carlino, M. S. et al. PD-L1 expression and immune escape in melanoma resistance to MAPK inhibitors. Clin. Cancer Res. 23, 6054–6061 (2017).

    CAS  Article  Google Scholar 

  23. 23.

    Hugo, W., Shi, H., Sun, L., Piva, M., Song, C. Y., Kong, X. et al. Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell 162, 1271–1285 (2015).

    CAS  Article  Google Scholar 

  24. 24.

    Shi, H., Hugo, W., Kong, X., Hong, A., Koya, R. C., Moriceau, G. et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 4, 81–93 (2015).

    Google Scholar 

  25. 25.

    Schreuer, M., Jansen, Y., Planken, S., Chevolet, I., Seremet, T., Kruse, V. et al. Combination of dabrafenib plus trametinib for BRAF and MEK inhibitor pretreated patients with advanced BRAFV600-mutant melanoma: an open-label, single arm, dual-centre, phase 2 clinical trial. Lancet Oncol. 18, 464–472 (2017).

    CAS  Article  Google Scholar 

  26. 26.

    Valpione, S., Carlino, M. S., Mangana, J., Mooradian, M. J., McArthur, G., Schadendorf, D. et al. Rechallenge with BRAF-directed treatment in metastatic melanoma: A multi-institutional retrospective study. Eur. J. Cancer 91, 116–124 (2018).

    CAS  Article  Google Scholar 

  27. 27.

    Bhave, P., Pallan, L., Atkinson, V., Cohen, J. V., Chiarion-Sileni, V., Nyakas, M. et al. Melanoma recurrence after adjuvant targeted therapy: a multicenter analysis. J. Clin. Oncol. 38, abstract 10016 (2020).

Download references

Acknowledgements

An abstract of this study was presented at a poster discussion session during the American Society of Clinical Oncology Annual Scientific Meeting 2020.

Author information

Affiliations

Authors

Contributions

P.B. conceived the project; collected, collated and analysed the data, wrote and edited the original paper. L.P. provided data and edited the paper. G.V.L. revised the paper and helped in result interpretation. A.M.M. revised the paper and helped in result interpretation. V.A. provided data and edited the paper. J.V.C. provided data and edited the paper. R.J.S. revised the paper and helped in result interpretation. V.C-S. provided data and edited the paper. MN provided data and edited the paper. K.K. provided data and edited the paper. A.H. revised the paper and helped in result interpretation. R.P. provided data and edited the paper. C.T. provided data and edited the paper. P.A.A. revised the paper and helped in result interpretation. L.Z. provided data and edited the paper. D.S. revised the paper and helped in result interpretation. C.A. provided data and edited the paper. C.L. revised the paper and helped in result interpretation. A.M. provided data and edited the paper. M.S. revised the paper and helped in result interpretation. S.R. provided data and edited the paper. C.R. revised the paper and helped in result interpretation. T.L. provided data and edited the paper. S.P. provided data and edited the paper. J.M.V. provided data and edited the paper. C.U.B. revised the paper and helped in result interpretation. A.K. provided data and edited the manuscript. A.V.W. provided data and edited the paper. M.S.C. provided data and edited the paper. M.S. revised the paper and helped in result interpretation. A.H. conceived the project, played an important role in data analysis, wrote and edited the original paper. All authors approved the final version of the paper and agreed to be accountable for all aspects of the work, including ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Prachi Bhave.

Ethics declarations

Ethics approval and consent to participate

Ethics board approval was obtained for this project from Alfred Health. The requirement for consent from subjects to participate in the project was waived by the ethics board. The study was performed in accordance with the Declaration of Helsinki.

Data availability

Data supporting the results reported in this article is stored at Alfred Health and can be provided upon request.

Competing interests

P.B.: Travel support: MSD G.V.L.: Consultancy: Aduro, Amgen, Bristol-Myers Squibb, Mass-Array, Merck, MSD, Novartis, OncoSec Medical, Pierre Fabre, Roche, QBiotics, Skyline DX and Sandoz. A.M.M.: Consultancy: BMS, MSD, Novartis, Roche, Pierre-Fabre. Acknowledgement Cancer Institute NSW Fellowship and Melanoma Institute Australia. VA. Consultancy: BMS, MSD, Merck, Novartis, Pierre Fabre, Roche, NEKTAR. Speaker honoraria: BMS, MSD, Merck, Novartis. Travel support: BMS, Oncosec. J.V.C.: Consultancy: Sanofi-Genzyme, BMS. R.J.S.: Consultancy: Asana Biosciences, Bristol Myers Squibb, Novartis, Merck, Lovance. Research funding: Merck, Amgen. M.N.: Consultancy: Novartis, BMS, Pierre-Fabre. Speaker honoraria: Novartis, BMS, Pierre-Fabre. K.K.: Personal fees: Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Novartis, Amgen, Pierre Fabre, Medac. A.H.: Consultancy: Amgen, BMS, MerckSerono, MSD/Merck, Philogen, Pierre Fabre, Provectus, Regeneron, Roche, OncoSec, Sanofi-Genzyme, Sun Pharma, Novartis Pharma, Almirall Hermal. Speaker honoraria: Amgen, BMS, MSD/Merck, Pierre Fabre, Provectus, Regeneron, Roche, Sanofi-Genzyme Novartis Pharma. Research funding: Amgen, BMS, MerckSerono, MSD/Merck, Philogen, Pierre Fabre, Provectus, Regeneron Roche, Sanofi-Genzyme, Novartis Pharma. R.P.: Consultancy: Pierre Faber, Bayer, Octimet, Clovis Oncology, Novartis, Karus Therapeutics, Biosceptre, BMS, Cybrexa, Ellipses, CV6 Therapeutics, Astex Therapeutics, Sanofi Aventis. Speaker honoraria: AstraZeneca, Novartis, Bayer, Tesaro, BMS. Travel support: BMS, MSD. P.A.A.: Consultancy: Bristol Myers-Squibb, Roche-Genentech, Merck Sharp & Dohme, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, NewLink Genetics, Genmab, Medimmune, AstraZeneca, Syndax, SunPharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer-Ingelheim. Research funding: Bristol Myers-Squibb, Roche-Genentech, Array. Travel support: MSD. L.Z.: Consultancy: BMS, Novartis, Pierre Fabre, Sunpharma, Sanofi, MSD. Honoraria from Roche, BMS, MSD, Novartis, Pierre Fabre. Research funding: Novartis; Travel support: BMS, Pierre Fabre, Sanofi, Amgen, Novartis, Sunpharma. D.S.: Consultancy: BMS, Merck Serono, Amgen, Immunocore, Incyte, 4SC, Pierre Fabre, Mologen, Merck/MSD, Sanofi/Regeneron. Speaker honoraria: Roche/Genentech, Novartis, BMS, Merck Serono, Amgen, Immunocore, Incyte, 4SC, Pierre Fabre, Array BioPharma, InFlarX, Philogen, Regeneron, Merck/MSD, Sandoz/Hexal, Neracare. Research funding: Novartis, BMS. Travel support: Roche/Genentech, Novartis, BMS, Merck Serono, Amgen, Merck/MSD. C.A.: Travel support: Amgen, BMS, Roche. C.L.: Consultancy: Avantis Medical Systems, BMS, MSD, Novartis, Amgen, Roche, Merck Serono, Sanofi. Research funding: BMS, Roche. Speaker honoraria: BMS, MSD, Novartis, Amgen, Roche, Pierre Fabre, Pfizer, Incyte. Travel support: BMS, MSD, CR: Consultancy: BMS, Pierre Fabre, Novartis, Merck, MSD, Roche, Sanofi, Biothera, Curevac. T.L.: Consultancy: MSD, Pierre Fabre, Novartis. S.P.: Speaker honoraria: Merck CUB: Consultancy: BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures. Research funding: BMS, Novartis, NanoString. Stockowner: Uniti Cars. A.K.: Speaker honoraria: Novartis. Travel support: Novartis. A.V.W.: Travel support: BMS, Novartis, MSD. M.S.C.: Consultancy: BMS, MSD, Novartis, Amgen, Roche, Pierre Fabre, Nektar, Eisia, Sanofi, Merck Serono, Ideay, Q biotics. M.S.: Consultancy: BMS, Merch, MSD. Speaker honoraria: BMS, Merck, MSD. Research funding: BMS. Travel support: BMS, Merck, Roche. A.H.: Consultancy: Novartis, BMS, MSD, Pierre-Fabre. All remaining authors have declared no conflict of interest.

Funding information

G.V.L.: acknowledgements: NHMRC Practitioner Fellowship, the University of Sydney Medical Foundation and Melanoma Institute Australia. A.M.M.: Acknowledgements: Cancer Institute NSW Fellowship and Melanoma Institute Australia.

Additional information

Note This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bhave, P., Pallan, L., Long, G.V. et al. Melanoma recurrence patterns and management after adjuvant targeted therapy: a multicentre analysis. Br J Cancer (2020). https://doi.org/10.1038/s41416-020-01121-y

Download citation

Search