Clinical Trial Protocol

SOLTI-1503 PROMETEO TRIAL: combination of talimogene laherparepvec with atezolizumab in early breast cancer

https://orcid.org/0000-0001-8431-3183

Scientific Department, SOLTI Breast Cancer Research Group, Barcelona, Spain

Medical Oncology Department, Hospital Clínic de Barcelona, Barcelona, Spain

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Juan M Cejalvo

Medical Oncology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain

Breast Cancer Biology Research Group, Biomedical Research Institute INCLIVA, Valencia, Spain

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Mafalda Oliveira

Scientific Department, SOLTI Breast Cancer Research Group, Barcelona, Spain

Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain

Breast Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain

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Maria Vidal

Scientific Department, SOLTI Breast Cancer Research Group, Barcelona, Spain

Medical Oncology Department, Hospital Clínic de Barcelona, Barcelona, Spain

Translational Genomics and Targeted Therapies in Solid Tumours, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain

Medicine Department, University of Barcelona, Barcelona, Spain

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Estela Vega

Medical Oncology Department, Centro Integral Oncológico Clara Campal, Madrid, Spain

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Sergi Ganau

Radiology Department, Hospital Clínic de Barcelona, Barcelona, Spain

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Ana Julve

Radiology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain

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Esther Zamora

Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain

Breast Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain

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Ignacio Miranda

Radiology Department, Breast Imaging Unit, Vall d'Hebron University Hospital, Barcelona, Spain

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Ana Delgado

Radiology Department, Centro Integral Oncológico Clara Campal, Madrid, Spain

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Begoña Bermejo

Medical Oncology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain

Breast Cancer Biology Research Group, Biomedical Research Institute INCLIVA, Valencia, Spain

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Luis de la Cruz-Merino

Medical Oncology Department, Hospital Universitario Virgen Macarena. Sevilla, Spain

Medicine Department, Universidad de Sevilla, Sevilla, Spain

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Manel Juan

Scientific Department, SOLTI Breast Cancer Research Group, Barcelona, Spain

Translational Genomics and Targeted Therapies in Solid Tumours, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain

Biomedicine Department, University of Barcelona, Barcelona, Spain

Immunogenetics of the Autoinflammatory Response, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain

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Juan M Ferrero-Cafiero

Scientific Department, SOLTI Breast Cancer Research Group, Barcelona, Spain

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Jordi Canes

Scientific Department, SOLTI Breast Cancer Research Group, Barcelona, Spain

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Xavier Gonzalez

Scientific Department, SOLTI Breast Cancer Research Group, Barcelona, Spain

Medical Oncology Department Hospital Universitari General de Catalunya, Sant Cugat del Vallès, Spain

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Patricia Villagrasa

Scientific Department, SOLTI Breast Cancer Research Group, Barcelona, Spain

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Aleix Prat

*Author for correspondence:

E-mail Address: alprat@clinic.cat

https://orcid.org/0000-0003-2377-540X

Scientific Department, SOLTI Breast Cancer Research Group, Barcelona, Spain

Medical Oncology Department, Hospital Clínic de Barcelona, Barcelona, Spain

Translational Genomics and Targeted Therapies in Solid Tumours, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain

Medicine Department, University of Barcelona, Barcelona, Spain

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Published Online:7 Jul 2020https://doi.org/10.2217/fon-2020-0246

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Abstract

New treatment strategies such as immune checkpoint inhibitors and oncolytic viruses are opening new possibilities in cancer therapy. Preliminary results in melanoma and other tumors showed that the combination of talimogene laherparepvec with an anti-PD-1/PD-L1 or anti-CTLA4 has greater efficacy than either therapy alone, without additional safety concerns beyond those expected for each agent. The presence of residual cancer after neoadjuvant chemotherapy in early breast cancer patients is an unmet medical need. SOLTI-1503 PROMETEO is a window of opportunity trial, which evaluates the combination of talimogene laherparepvec in combination with atezolizumab in women with operable HER2-negative breast cancer who present residual disease after neoadjuvant chemotherapy. The primary end point is the rate of residual cancer burden 0/1.

Clinical Trial Registration: NCT03802604

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Coudert BP, Arnould L, Moreau L et al. Pre-operative systemic (neo-adjuvant) therapy with trastuzumab and docetaxel for HER2-overexpressing stage II or III breast cancer: results of a multicenter phase II trial. Ann. Oncol. 17(3), 409–414 (2006).
Medline CASGoogle Scholar
2. Colomer R, Saura C, Sánchez-Rovira P et al. Neoadjuvant management of early breast cancer: a clinical and investigational position statement. Oncologist 24(5), 603–611 (2019).
MedlineGoogle Scholar
3. Cortazar P, Zhang L, Untch M et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384(9938), 164–172 (2014). • Metanalysis shows the poor prognosis of residual disease following neoadjuvant chemotherapy in breast cancer patients.
MedlineGoogle Scholar
4. Minckwitz G, Fontanella C. State of the art in neoadjuvant therapy of breast cancer. EJC 11(Suppl. 2), 284–285 (2013).
MedlineGoogle Scholar
5. Wolff AC, Berry D, Carey LA et al. Research issues affecting preoperative systemic therapy for operable breast cancer. J. Clin. Oncol. 26(5), 806–813 (2008).
MedlineGoogle Scholar
6. Prowell TM, Pazdur R. Pathological complete response and accelerated drug approval in early breast cancer. N. Engl. J. Med. 366(26), 2438–2441 (2012).
Medline CASGoogle Scholar
7. Berry DA, Hudis CA. Neoadjuvant therapy in breast cancer as a basis for drug approval. JAMA Oncol. 1(7), 875–876 (2015).
MedlineGoogle Scholar
8. Gianni L, Pienkowski T, Im YH et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, Phase II trial. Lancet Oncol. 13(1), 25–32 (2012).
Medline CASGoogle Scholar
9. Von Minckwitz G, Untch M, Blohmer J-U et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J. Clin. Oncol. 30(15), 1796–1804 (2012).
MedlineGoogle Scholar
10. Karagiannis GS, Pastoriza JM, Wang Y et al. Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Sci. Transl. Med. 9(397), eaan0026 (2017).
MedlineGoogle Scholar
11. Von Minckwitz G, Rezai M, Loibl S et al. Capecitabine in addition to anthracycline-and taxane-based neoadjuvant treatment in patients with primary breast cancer: Phase III GeparQuattro study. J. Clin. Oncol. 28(12), 2015–2023 (2010).
Medline CASGoogle Scholar
12. Bear HD, Tang G, Rastogi P et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N. Engl. J. Med. 366(4), 310–320 (2012).
Medline CASGoogle Scholar
13. Reinisch M, Ataseven B, Kümmel S. Neoadjuvant dose-dense and dose-intensified chemotherapy in breast cancer-review of the literature. Breast Care 11(1), 13–20 (2016).
MedlineGoogle Scholar
14. Masuda N, Lee S-J, Ohtani S et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N. Engl. J. Med. 376(22), 2147–2159 (2017).
Medline CASGoogle Scholar
15. Von Minckwitz G, Huang C-S, Mano MS et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N. Engl. J. Med. 380(7), 617–628 (2019).
Medline CASGoogle Scholar
16. Loi S, Sirtaine N, Piette F et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J. Clin. Oncol. 31(7), 860–867 (2013).
Medline CASGoogle Scholar
17. Denkert C, Von Minckwitz G, Darb-Esfahani S et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 19(1), 40–50 (2018).
MedlineGoogle Scholar
18. Luen SJ, Salgado R, Fox S et al. Tumour-infiltrating lymphocytes in advanced HER2-positive breast cancer treated with pertuzumab or placebo in addition to trastuzumab and docetaxel: a retrospective analysis of the CLEOPATRA study. Lancet Oncol. 18(1), 52–62 (2017).
Medline CASGoogle Scholar
19. Adams S, Gray RJ, Demaria S et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J. Clin. Oncol. 32(27), 2959–2966 (2014).
MedlineGoogle Scholar
20. Nuciforo P, Pascual T, Cortés J et al. A predictive model of pathologic response based on tumor cellularity and tumor-infiltrating lymphocytes (CelTIL) in HER2-positive breast cancer treated with chemo-free dual HER2 blockade. Ann. Oncol. 29(1), 170–177 (2018).
Medline CASGoogle Scholar
21. Disis ML, Stanton SE. Immunotherapy in breast cancer: an introduction. Breast 37, 196–199 (2017).
MedlineGoogle Scholar
22. Griguolo G, Pascual T, Dieci MV, Guarneri V, Prat A. Interaction of host immunity with HER2-targeted treatment and tumor heterogeneity in HER2-positive breast cancer. J. Immunother. Cancer 7(1), 90 (2019).
MedlineGoogle Scholar
23. Ali HR, Provenzano E, Dawson SJ et al. Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann. Oncol. 25(8), 1536–1543 (2014).
Medline CASGoogle Scholar
24. Loi S, Giobbie-Hurder A, Gombos A et al. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, Phase Ib-II trial. Lancet Oncol. 20(3), 371–382 (2019).
Medline CASGoogle Scholar
25. Swaika A, Hammond WA, Joseph RW. Current state of anti-PD-L1 and anti-PD-1 agents in cancer therapy. Mol. Immunol. 67(2 Pt A), 4–17 (2015).
Medline CASGoogle Scholar
26. Herbst RS, Soria JC, Kowanetz M et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515(7528), 563–567 (2014).
Medline CASGoogle Scholar
27. Bluestone JA, Small EJ. The future of cancer treatment: will it include immunotherapy? Cancer Cell 22(1), 7–8 (2012).
Medline CASGoogle Scholar
28. Schmid P, Rugo HS, Adams S et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, Phase III trial. Lancet Oncol. 21(1), 44–59 (2019).
MedlineGoogle Scholar
29. Schmid P, Cortés J, Dent R et al. LBA8_PR KEYNOTE-522: phase III study of pembrolizumab (pembro)+ chemotherapy (chemo) vs placebo (pbo)+ chemo as neoadjuvant treatment, followed by pembro vs pbo as adjuvant treatment for early triple-negative breast cancer (TNBC). Ann. Oncol. 382(9), 810–821 (2020).
CASGoogle Scholar
30. Dieci MV, Criscitiello C, Goubar A et al. Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study. Ann. Oncol. 25(3), 611–618 (2014).
Medline CASGoogle Scholar
31. Miyashita M, Sasano H, Tamaki K et al. Prognostic significance of tumor-infiltrating CD8+ and FOXP3+ lymphocytes in residual tumors and alterations in these parameters after neoadjuvant chemotherapy in triple-negative breast cancer: a retrospective multicenter study. Breast Cancer Res. 17, 124 (2015).
MedlineGoogle Scholar
32. Loi S, Dushyanthen S, Beavis PA et al. RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors. Clin. Cancer Res. 22(6), 1499–1509 (2016).
Medline CASGoogle Scholar
33. Luen S, Salgado R, Dieci M et al. Prognostic implications of residual disease tumor-infiltrating lymphocytes and residual cancer burden in triple-negative breast cancer patients after neoadjuvant chemotherapy. Ann. Oncol. 30(2), 236–242 (2018).
Google Scholar
34. Pinard C, Debled M, Ben Rejeb H et al. Residual cancer burden index and tumor-infiltrating lymphocyte subtypes in triple-negative breast cancer after neoadjuvant chemotherapy. Breast Cancer Res. Treat. 179(1), 11–23 (2019).
MedlineGoogle Scholar
35. Hu JC, Coffin RS, Davis CJ et al. A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor. Clin. Cancer Res. 12(22), 6737–6747 (2006).
Medline CASGoogle Scholar
36. Senzer NN, Kaufman HL, Amatruda T et al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J. Clin. Oncol. 27(34), 5763 (2009).
Medline CASGoogle Scholar
37. Dummer R, Gyorki DE, Hyngstrom JR et al. One-year (yr) recurrence-free survival (RFS) from a randomized, open label phase II study of neoadjuvant (neo) talimogene laherparepvec (T-VEC) plus surgery (surgx) versus surgx for resectable stage IIIB-IVM1a melanoma (MEL). J. Clin. Oncol. 37(Suppl. 15), 9520–9520 (2019).
Google Scholar
38. Andtbacka RH, Collichio F, Harrington KJ et al. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III–IV melanoma. J. Immunother. Cancer 7(1), 145 (2019). •• First randomized Phase III data demonstrate superior efficacy achieved by talimogene laherparepvec in unresectable stage III–IV melanoma.
MedlineGoogle Scholar
39. Andtbacka RH, Kaufman HL, Collichio F et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 33(25), 2780–2788 (2015).
Medline CASGoogle Scholar
40. Puzanov I, Milhem MM, Andtbacka RHI et al. Primary analysis of a Phase Ib multicenter trial to evaluate safety and efficacy of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma. Clinical Oncology. 32(Suppl. 15),9029–9029 (2014).
Google Scholar
41. Chesney J, Puzanov I, Collichio F et al. Randomized, open-label Phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma. J. Clin. Oncol. 36(17), 1658 (2018).
Medline CASGoogle Scholar
42. Ribas A, Dummer R, Puzanov I et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell 170(6), 1109–1119. e1110 (2017).
Medline CASGoogle Scholar
43. Harrington KJ, Kong AH, Mach N et al. Safety and preliminary efficacy of talimogene laherparepvec (T-VEC) in combination (combo) with pembrobrolizumab (Pembro) in patients (pts) with recurrent or metastatic squamous cell carcinoma of the head and neck.Clinical Oncology. 36(Suppl. 15), 6036–6036 (2018).
Google Scholar
44. Kelly CM, Antonescu CR, Bowler T et al. Objective response rate among patients with locally advanced or metastatic sarcoma treated with talimogene laherparepvec in combination with pembrolizumab: a Phase II clinical trial. JAMA Oncol. 6(3), 402–408 (2020).
MedlineGoogle Scholar
45. Chang KJ, Senzer NN, Binmoeller K, Goldsweig H, Coffin R. Phase I dose-escalation study of talimogene laherparepvec (T-VEC) for advanced pancreatic cancer (ca). (Journal of Clinical Oncology. 30(Suppl. 15), e14546–e14546 (2012).
Google Scholar
46. Soliman H, Hogue D, Han H et al. Abstract CT040: a Phase I trial of talimogene laherparepvec combined with neoadjuvant chemotherapy for non-metastatic triple negative breast cancer. Cancer Res. 79(Suppl. 13), CT040–CT040 (2019).
Google Scholar
47. Ledford H. Cancer-fighting viruses win approval. Nature 526(7575), 622 (2015).
Medline CASGoogle Scholar
48. Raman SS, Hecht JR, Chan E. Talimogene laherparepvec: review of its mechanism of action and clinical efficacy and safety. Immunotherapy 11(8), 705–723 (2019). • Rationale for use of talimogene laherparepvec in combination with immune checkpoint inhibitors.
CASGoogle Scholar
49. Emens LA, Cruz C, Eder JP et al. Long-term clinical outcomes and biomarker analyses of atezolizumab therapy for patients with metastatic triple-negative breast cancer: a phase 1 study. JAMA Oncol. 5(1), 74–82 (2018). • Long-term outcomes from Phase I clinical trial of atezolizumab monotherapy in triple negative breast cancer.
Google Scholar
50. Adams S, Diamond JR, Hamilton E et al. Atezolizumab plus nab-paclitaxel in the treatment of metastatic triple-negative breast cancer with 2-year survival follow-up: a Phase Ib clinical trial atezolizumab plus nab-paclitaxel in the treatment of metastatic triple-negative breast canceratezolizumab plus nab-paclitaxel in the treatment of metastatic triple-negative breast cancer. JAMA Oncol. 5(3), 334–342 (2019).
MedlineGoogle Scholar
51. Schmid P, Adams S, Rugo HS et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N. Engl. J. Med. 379(22), 2108–2121 (2018). •• First randomized Phase III data demonstrate superior efficacy achieved by combining atezolizumab with nab-paclitaxel in first-line for triple-negative breast cancer.
Medline CASGoogle Scholar
52. Schmid P, Cortes J, Pusztai L et al. Pembrolizumab for early triple-negative breast cancer. N. Engl. J. Med. 382(9), 810–821 (2020). •• First randomized Phase III data demonstrate superior efficacy achieved by pembrolizumab in combination with neoadjuvant chemotherapy in triple negative breast cancer.
Medline CASGoogle Scholar
53. Loibl S, Untch M, Burchardi N et al. A randomised Phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study. Ann. Oncol. 30(8), 1279–1288 (2019).
Medline CASGoogle Scholar
54. Gianni L, Huang C-S, Egle D et al. Abstract GS3-04: pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple negative, early high-risk and locally advanced breast cancer. NeoTRIPaPDL1 Michelangelo randomized study. 80(Suppl. 4), (2020).
Google Scholar
55. Robert C, Schachter J, Long GV et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372(26), 2521–2532 (2015).
Medline CASGoogle Scholar
56. Symmans WF, Peintinger F, Hatzis C et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J. Clin. Oncol. 25(28), 4414–4422 (2007).
MedlineGoogle Scholar
57. Danaher P, Warren S, Lu R et al. Pan-cancer adaptive immune resistance as defined by the Tumor Inflammation Signature (TIS): results from The Cancer Genome Atlas (TCGA). J. Immunother. Cancer 6(1), 63 (2018).
MedlineGoogle Scholar
58. Parker JS, Mullins M, Cheang MC et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J. Clin. Oncol. 27(8), 1160 (2009).
MedlineGoogle Scholar
59. Rosner B. Fundamentals of biostatistics. Nelson Education (2015). https://onlinelibrary.wiley.com/doi/abs/10.1002/bimj.4710350205
Google Scholar

Vol. 16, No. 24

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History

Received 21 March 2020

Accepted 27 May 2020

Published online 7 July 2020

Published in print August 2020

Information

Keywords

Author contributions

A Prat, P Villagrasa and T Pascual designed the trial in collaboration with clinical and academic investigators (B Bermejo, M Oliveira, MJ Vidal, E Vega, S Ganau, A Julve, E Zamora, I Miranda, JM Cejalvo and A Delgado). A Prat, T Pascual, MJ Vidal, M Oliveira, JM Cejalvo, L de la Cruz-Merino and M Juan are Study Steering Committee members. X Gonzalez is Medical Monitor of the trial. This manuscript was principally written by A Prat, P Villagrasa and T Pascual with assistance from JM Ferrero-Cafiero, J Canes, and was critically reviewed, edited and approved by all authors.

Acknowledgments

We would like to thank the patients and their families/caregivers for their participation.

Role of the funder/sponsor

The funders had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.

Financial & competing interests disclosure

We thank AMGEN for their provision of Talimogene Laherparepvec and their financial contribution to this clinical study. We thank ROCHE for their provision of Atezolizumab and their financial contribution to this clinical study. Fundación SEOM (SEOM 2018 Grant: Fellowship for Training in Research in Reference Centers) to T Pascual. A Prat has declared personal honoraria from Pfizer, Novartis, Roche, MSD Oncology, Lilly and Daiichi Sankyo, travel, accommodations and expenses paid by Daiichi Sankyo, research funding from Nanostring Technologies, Roche and Novartis, consulting/advisory role for Nanostring Technologies, Roche, Novartis, Pfizer, Oncolytics Biotech, Amgen, Lilly, MSD, PUMA and Daiichi Sankyo, Inc. outside the submitted work. M Oliveira reports honoraria and consulting fees from Roche/Genentech, GSK, PUMA Biotechnology, AstraZeneca, Seattle Genetics, and Novartis; travel and accommodation paid by Roche, Pierre-Fabre, Novartis, GP Pharma, Grünenthal and Eisai; and grant/Research Support (to the Institution) from AstraZeneca, Philips Healthcare, Genentech, Roche, Novartis, Immunomedics, Seattle Genetics, GSK, Boehringer-Ingelheim, PUMA Biotechnology and Zenith Epigenetics outside the submitted work. M Vidal has declared personal honoraria from Pfizer, Novartis, Roche and Daiichi Sankyo, travel, accommodations and expenses paid by Roche and Pfizer, consulting/advisory role for Roche and Novartis. E Zamora reports personal fees and non-financial support from Roche, non-financial support from Pfizer personal fees from Novartis, non-financial support from Lilly, outside the submitted work. L de la Cruz-Merino reports being consultant or Advisory Role for MSD-Merck, Roche Farma, Bristol-Myers-Squibb, Pierre-Fabré, Amgen and Novartis; Research Funding from MSD-Merck, Roche Farma and Celgene. Speaking role for MSD-Merck, Roche Farma, Bristol-Myers-Squibb, Amgen and Grant support from Bristol-Myers-Squibb, Roche Farma. M Juan Teacher role for Kite-Gilead, advisory role for Grifols with sporadic personal honoraria. X González-Farré reports personal fees from SOLTI BREAST CANCER GROUP, during the conduct of the study; personal fees and non-financial support from Roche, and personal fees from Eisai outside the submitted work. P Villagrasa has received honoraria as Speaker from Nanostring. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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