Advertisement
Original Study|Articles in Press

Salvage surgery after first-line Alectinib for locally-advanced/metastatic ALK-rearranged NSCLC: pathological response and peri-operative results

  • Filippo Lococo
    Correspondence
    Corresponding author. Filippo Lococo, Unit of Thoracic Surgery, Fondazione Policlinico Gemelli IRCCS, Largo F. Vito n 8, 00168 Rome, Italy
    Affiliations
    Unit of Thoracic Surgery, Fondazione Policlinico Gemelli IRCCS, Rome, Italy

    IRCCS Humanitas Clinical and Research Center - Humanitas Cancer Center, Rozzano, Milan, Italy
    Search for articles by this author
  • Alessandra Cancellieri
    Affiliations
    Unit of Pathology, Fondazione Policlinico Gemelli IRCCS, Rome, Italy

    IRCCS Humanitas Clinical and Research Center - Humanitas Cancer Center, Rozzano, Milan, Italy
    Search for articles by this author
  • Marco Chiappetta
    Affiliations
    Unit of Thoracic Surgery, Fondazione Policlinico Gemelli IRCCS, Rome, Italy

    IRCCS Humanitas Clinical and Research Center - Humanitas Cancer Center, Rozzano, Milan, Italy
    Search for articles by this author
  • Alessandro Leonetti
    Affiliations
    Oncology Unit, University Hospital of Parma, Italy

    IRCCS Humanitas Clinical and Research Center - Humanitas Cancer Center, Rozzano, Milan, Italy
    Search for articles by this author
  • Giuseppe Cardillo
    Affiliations
    Department of Thoracic Surgery, Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy

    IRCCS Humanitas Clinical and Research Center - Humanitas Cancer Center, Rozzano, Milan, Italy
    Search for articles by this author
  • Francesca Zanelli
    Affiliations
    Unit of Oncology, Azienda USL-IRCCS of Reggio Emilia, Reggio Emilia, Italy

    IRCCS Humanitas Clinical and Research Center - Humanitas Cancer Center, Rozzano, Milan, Italy
    Search for articles by this author
  • Giuseppe Mangiameli
    Affiliations
    Division of Thoracic Surgery, IRCCS Humanitas Research Hospital, Milan, Italy

    IRCCS Humanitas Clinical and Research Center - Humanitas Cancer Center, Rozzano, Milan, Italy
    Search for articles by this author
  • Luca Toschi
    Affiliations
    Division of Thoracic Surgery, IRCCS Humanitas Research Hospital, Milan, Italy

    IRCCS Humanitas Clinical and Research Center - Humanitas Cancer Center, Rozzano, Milan, Italy
    Search for articles by this author
  • Gianluca Guggino
    Affiliations
    IRCCS Humanitas Clinical and Research Center - Humanitas Cancer Center, Rozzano, Milan, Italy

    Thoracic Surgery Unit, Antonio Cardarelli Hospital, Naples
    Search for articles by this author
  • Francesco Romano
    Affiliations
    IRCCS Humanitas Clinical and Research Center - Humanitas Cancer Center, Rozzano, Milan, Italy

    Oncology Unit, Antonio Cardarelli Hospital, Naples
    Search for articles by this author
  • Giovanni Leuzzi
    Affiliations
    IRCCS Humanitas Clinical and Research Center - Humanitas Cancer Center, Rozzano, Milan, Italy

    Thoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
    Search for articles by this author
  • Claudia Proto
    Affiliations
    IRCCS Humanitas Clinical and Research Center - Humanitas Cancer Center, Rozzano, Milan, Italy

    Department of Medical Oncology, Thoracic Oncology Unit, Fondazione IRCSS, Istituto Nazionale dei Tumori Milano, Milan, Italy
    Search for articles by this author
  • Lorenzo Spaggiari
    Affiliations
    IRCCS Humanitas Clinical and Research Center - Humanitas Cancer Center, Rozzano, Milan, Italy

    Department of Thoracic Surgery, IEO-European Institute of Oncology IRCCS, Milan, Italy
    Search for articles by this author
  • Filippo De Marinis
    Affiliations
    IRCCS Humanitas Clinical and Research Center - Humanitas Cancer Center, Rozzano, Milan, Italy

    Division of Thoracic Oncology, IEO-European Institute of Oncology IRCCS, Milan, Italy
    Search for articles by this author
  • Emanuele Vita
    Affiliations
    IRCCS Humanitas Clinical and Research Center - Humanitas Cancer Center, Rozzano, Milan, Italy

    Department of Oncology, Fondazione Policlinico Gemelli IRCCS, Rome, Italy
    Search for articles by this author
  • Luca Ampollini
    Affiliations
    IRCCS Humanitas Clinical and Research Center - Humanitas Cancer Center, Rozzano, Milan, Italy

    Department of Medicine and Surgery, University of Parma, Parma, Italy
    Search for articles by this author
  • Stefano Margaritora
    Affiliations
    Unit of Thoracic Surgery, Fondazione Policlinico Gemelli IRCCS, Rome, Italy

    IRCCS Humanitas Clinical and Research Center - Humanitas Cancer Center, Rozzano, Milan, Italy
    Search for articles by this author
  • Marcello Tiseo
    Affiliations
    Oncology Unit, University Hospital of Parma, Italy

    IRCCS Humanitas Clinical and Research Center - Humanitas Cancer Center, Rozzano, Milan, Italy

    Department of Oncology, Fondazione Policlinico Gemelli IRCCS, Rome, Italy
    Search for articles by this author
  • Emilio Bria
    Affiliations
    IRCCS Humanitas Clinical and Research Center - Humanitas Cancer Center, Rozzano, Milan, Italy

    Department of Oncology, Fondazione Policlinico Gemelli IRCCS, Rome, Italy
    Search for articles by this author
Published:March 18, 2023DOI:https://doi.org/10.1016/j.cllc.2023.03.008

      Abstract

      Background

      The role of salvage surgery after tyrosine kinase inhibitors in advanced oncogene-addicted NSCLC is largely unexplored.

      Patients

      We aimed to describe the pathological features and surgical early-outcomes of ALK positive NSCLC patients undergoing surgery after first-line alectinib treatment. We retrospectively collected and analyzed multicentric data of 10 patients treated with alectinib for advanced-stage ALK-positive lung adenocarcinoma who underwent anatomical surgical resection from 01/2020 to 12/2021. All patients were treatment naive and received alectinib (600mg twice daily). Surgery was always proposed after multidisciplinary discussion. The primary endpoints were pathological response and surgical feasibility (technical intra-operative complications, post-operative outcomes).

      Results

      Alectinib was received for a mean of 212 days before surgery (42-415 days) and was generally interrupted about one week before surgery (range: 0-32 days) with no patient experienced grade 4 toxicity. All patients received an R0 resection with surgery consisting of lobectomy in 8 cases with bilobectomy and (left) pneumonectomy in one case each. Intra-operative difficulties were described in 7 cases (70%), mostly due to perivascular fibrosis or thickening of mediastinal lymph nodal tissues. Major and minor complications occurred in 0 and 3 cases (30%), respectively. A pathological complete response and major pathological response (defined as 0% and <10% viable tumor cells, respectively) were observed in 50% and 90% of cases, respectively. Despite short follow-up, only one tumor recurrence was observed (in the only patient who did not resume alectinib after surgery).

      Interpretation

      Despite some technical intra-operative difficulties, salvage surgery was safe and feasible after Alectinib for advanced lung adenocarcinoma.

      Microabstract

      Results of “salvage surgery” after first-line Alectinib treatment has never been explored till now. We retrospectively collected and analyzed 10 highly-selected patients treated with alectinib for advanced-stage ALK-positive lung cancer who underwent anatomical surgical resection after discussion at local multidisciplinary tumor board. No patient experienced grade 4 toxicity. All patients received an R0 resection. Intra-operative difficulties were described in 70% of cases but major and minor complications occurred in 0 and 3 cases (30%) only, respectively. High rates of pathological complete response (50%) and major pathological response (90%) were observed in this cohort. Despite a short follow-up, only one tumor recurrence was observed.
      In conclusion, despite some technical intra-operative difficulties, salvage surgery was safe and feasible in selected advanced lung cancer cases with good response after Alectinib treatment.

      Keywords

      Abbreviation:

      :CR (Complete Response), MPR (Major Pathological Response), PCR (Pathological Complete Response), PR (Partial Response), ALK (Anaplastic Lymphome Kinase), CT (computed tomography), EBUS (Endobronchial Ultrasound), FNAB (Fine-needle biopsy), NSCLC (Non Small Cell Lung Cancer), PET (Positron emission Tomography), RECIST (Response Evaluation Criteria in Solid Tumors), TBNA (Trans-bronchial needle-aspiration), TKI (Tyrosine Kinase Inhibitors), VATS (video assisted thoracic surgery)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Clinical Lung Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Mitsudomi T.
        • Morita S.
        • Yatabe Y.
        • Negoro S.
        • Okamoto I.
        • Tsurutani J.
        • et al.
        Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial.
        Lancet Oncol. 2010; 11: 121-128https://doi.org/10.1016/S1470-2045(09)70364-X
        • Solomon B.J.
        • Mok T.
        • Kim D.W.
        • Wu Y.L.
        • Nakagawa K.
        • Mekhail, E T.
        • et al.
        First-line crizotinib versus chemotherapy in ALKpositive lung cancer.
        N. Engl. J. Med. 2014; 371: 2167-2177https://doi.org/10.1056/NEJMoa1408440
        • Rotow J.
        • Bivona T.G.
        Understanding and targeting resistance mechanisms in NSCLC.
        Nat. Rev. Cancer. 2017; 17: 637-658https://doi.org/10.1038/nrc.2017.84
        • Girard N
        • Moro-Sibilot D
        • Bouée S
        • Emery C
        • Torreton E
        • Le Lay K
        • et al.
        Treatment sequence of first and second generation tyrosine kinase inhibitor followed by osimertinib in EGFR-mutated non-small-cell lung cancer: a real life study.
        Future Oncol. 2020; 16 (JunEpub 2020 Apr 30. PMID: 32352321): 1115-1124https://doi.org/10.2217/fon-2020-0084
        • Hashimoto K.
        • Horinouchi H.
        • Ohtsuka T.
        • Kohno M.
        • Izumi Y.
        • Hayashi Y.
        • et al.
        Salvage surgery for a super-responder by gefitinib therapy for advanced lung cancer.
        Gen. Thorac. Cardiovasc. Surg. 2012; 60: 851-854https://doi.org/10.1007/s11748-012-0087-2
        • Hishida T.
        • Yoshida J.
        • Aokage K.
        • Nagai K.
        • Tsuboi M.
        Long-term outcome of surgical resection for residual or regrown advanced non-small cell lung carcinomas following EGFR-TKI treatment: report of four cases.
        Gen. Thorac. Cardiovasc. Surg. 2016; 64: 429-433https://doi.org/10.1007/s11748-014-0508-5
        • Peters S
        • Camidge DR
        • Shaw AT
        • Gadgeel S
        • Ahn JS
        • Kim DW
        • et al.
        Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer.
        N Engl J Med. 2017; 377: 829-838https://doi.org/10.1056/NEJMo a1704795
        • Leonetti A
        • Minari R
        • Boni L
        • Gnetti L
        • Verzè M
        • Ventura L
        • et al.
        Phase II, Open-label, Single-arm, Multicenter Study to Assess the Activity and Safety of Alectinib as Neoadjuvant Treatment in Surgically Resectable Stage III ALK-positive NSCLC: ALNEO Trial.
        Clin Lung Cancer. 2021; 22 (SepEpub 2021 Feb 24. PMID: 33762169): 473-477https://doi.org/10.1016/j.cllc.2021.02.014
        • Solomon BJ
        • Mok T
        • Kim DW
        • Wu YL
        • Nakagawa K
        • Mekhail T
        • et al.
        First-line crizotinib versus chemotherapy in ALK-positive lung cancer.
        N Engl J Med. 2014; 371 (Dec 42167-77Erratum in: N Engl J Med. 2015 Oct 15;373(16):1582. PMID: 25470694)https://doi.org/10.1056/NEJMoa1408440
        • Lococo F
        • Sassorossi C
        • Nachira D
        • Chiappetta M
        • Petracca Ciavarella L
        • Vita E
        • Boldrini L
        • Evangelista J
        • Cesario A
        • Bria E
        • Margaritora S
        Prognostic Factors and Long-Term Survival in Locally Advanced NSCLC with Pathological Complete Response after Surgical Resection Following Neoadjuvant Therapy.
        Cancers (Basel). 2020; 12 (Nov 30PMID: 33265905; PMCID: PMC7759985): 3572https://doi.org/10.3390/cancers12123572
        • Yatabe Y.
        ALK FISH and IHC: you cannot have one without the other.
        J Thorac Oncol. 2015; 10 (AprPMID: 25789831): 548-550https://doi.org/10.1097/JTO.0000000000000461
        • Nero C
        • Duranti S
        • Giacomini F
        • Minucci A
        • Giacò L
        • Piermattei A
        • Genuardi M
        • Pasciuto T
        • Urbani A
        • Daniele G
        • Lorusso D
        • Pignataro R
        • Tortora G
        • Normanno N
        • Scambia G.
        Integrating a Comprehensive Cancer Genome Profiling into Clinical Practice: A Blueprint in an Italian Referral Center.
        J Pers Med. 2022; 12 (Oct 20PMID: 36294885; PMCID: PMC9605534): 1746https://doi.org/10.3390/jpm12101746
        • Pataer A
        • Weissferdt A
        • Vaporciyan AA
        • Correa AM
        • Sepesi B
        • Wistuba II
        • Heymach JV
        • Cascone T
        • Swisher SG.
        Evaluation of Pathologic Response in Lymph Nodes of Patients With Lung Cancer Receiving Neoadjuvant Chemotherapy.
        J Thorac Oncol. 2021; 16 (AugEpub 2021 Apr 20. PMID: 33857666): 1289-1297https://doi.org/10.1016/j.jtho.2021.03.029
        • Kobayashi AK
        • Nakagawa K
        • Nakayama Y
        • Ohe Y
        • Yotsukura M
        • Uchida S
        • Asakura K
        • Yoshida Y
        • Watanabe SI.
        Salvage Surgery Compared to Surgery After Induction Chemoradiation Therapy for Advanced Lung Cancer.
        Ann Thorac Surg. 2022; 114 (DecEpub 2021 Nov 26. PMID: 34843695): 2087-2092https://doi.org/10.1016/j.athoracsur.2021.10.036
        • Wang Q
        • Gao W
        • Gao F
        • Jin S
        • Qu T
        • Lin F
        • Zhang C
        • Zhang J
        • Zhang Z
        • Chen L
        • Guo R
        Efficacy and acquired resistance of EGFR-TKI combined with chemotherapy as first-line treatment for Chinese patients with advanced non-small cell lung cancer in a real-world setting.
        BMC Cancer. 2021; 21 (May 25PMID: 34034713; PMCID: PMC8152122): 602https://doi.org/10.1186/s12885-021-08291-9
        • Ohtaki Y
        • Shimizu K
        • Suzuki H
        • Suzuki K
        • Tsuboi M
        • Mitsudomi T
        • Takao M
        • Murakawa T
        • Ito H
        • Yoshimura K
        • Okada M
        • Chida M
        • Japanese Association for Chest Surgery
        Salvage surgery for non-small cell lung cancer after tyrosine kinase inhibitor treatment.
        Lung Cancer. 2021; 153 (MarEpub 2021 Jan 10. PMID: 33482408): 108-116https://doi.org/10.1016/j.lungcan.2020.12.037
        • Fournel L
        • Falcoz PE
        • Mansuet-Lupo A
        • Garelli E
        • Lococo F
        • Alifano M.
        A bicenter study on adjuvant surgery following treatment with tyrosine kinase inhibitors in patients with advanced lung adenocarcinoma.
        Interact Cardiovasc Thorac Surg. 2018; 27 (Oct 1PMID: 29672751): 598-601https://doi.org/10.1093/icvts/ivy120
        • Hashimoto H
        • Komori K
        • Kameda K
        • Taguchi S
        • Ozeki Y.
        Successful salvage surgery followed by second ALK-TKI after alectinib failure in a patient with ALK-positive NSCLC.
        Surg Case Rep. 2022; 8 (Apr 2PMID: 35366157; PMCID: PMC8976869): 59https://doi.org/10.1186/s40792-022-01408-7
        • Hu Y
        • Ren S
        • Wang R
        • Han W
        • Xiao P
        • Wang L
        • Yu F
        • Liu W
        Case Report: Pathological Complete Response to Neoadjuvant Alectinib in a Patient With Resectable ALK-Positive Non-Small Cell Lung Cancer.
        Front Pharmacol. 2022; 13 (Jul 6PMID: 35873553; PMCID: PMC9299059)816683https://doi.org/10.3389/fphar.2022.816683
        • Tsuboi M
        • Weder W
        • Escriu C
        • Blakely C
        • He J
        • Dacic S
        • Yatabe Y
        • Zeng L
        • Walding A
        • Chaft JE.
        Neoadjuvant osimertinib with/without chemotherapy versus chemotherapy alone for EGFR-mutated resectable non-small-cell lung cancer: NeoADAURA.
        Future Oncol. 2021; 17 (NovEpub 2021 Jul 19. PMID: 34278827; PMCID: PMC8530153): 4045-4055https://doi.org/10.2217/fon-2021-0549
        • Hellmann MD
        • Chaft JE
        • William Jr, WN
        • Rusch V
        • Pisters KM
        • Kalhor N
        • Pataer A
        • Travis WD
        • Swisher SG
        • Kris MG
        University of Texas MD Anderson Lung Cancer Collaborative Group. Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint.
        Lancet Oncol. 2014; 15 (JanPMID: 24384493; PMCID: PMC4734624): e42-e50https://doi.org/10.1016/S1470-2045(13)70334-6
        • Cottrell TR
        • Thompson ED
        • Forde PM
        • Stein JE
        • Duffield AS
        • Anagnostou V
        • Rekhtman N
        • Anders RA
        • Cuda JD
        • Illei PB
        • Gabrielson E
        • Askin FB
        • Niknafs N
        • Smith KN
        • Velez MJ
        • Sauter JL
        • Isbell JM
        • Jones DR
        • Battafarano RJ
        • Yang SC
        • Danilova L
        • Wolchok JD
        • Topalian SL
        • Velculescu VE
        • Pardoll DM
        • Brahmer JR
        • Hellmann MD
        • Chaft JE
        • Cimino-Mathews A
        • Taube JM.
        Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC).
        Ann Oncol. 2018; 29 (Aug 1PMID: 29982279; PMCID: PMC6096736): 1853-1860https://doi.org/10.1093/annonc/mdy218