Editorial
Immunotherapy in refractory SCLC: the caterpillar struggling to become a butterfly
Antonio Passaro
, Valeria Stati, Filippo de Marinis
Corresponding author
antonio.passaro@ieo.it
Corresponding author. Antonio Passaro, MD, PhD, Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Milan, Via G. Ripamonti, 435 - 20141 Milan, Italy. Tel.: +39 02 57489482; fax: +39 02 94379235.
Corresponding author. Antonio Passaro, MD, PhD, Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Milan, Via G. Ripamonti, 435 - 20141 Milan, Italy. Tel.: +39 02 57489482; fax: +39 02 94379235.
Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Milan
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Antonio Passaro, MD, PhD, Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Milan, Via G. Ripamonti, 435 - 20141 Milan, Italy. Tel.: +39 02 57489482; fax: +39 02 94379235." ] ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">In the era of immunotherapy we got used to it very well discovering day by day positive results in different settings and diseases in particular non-small cell lung cancer, in which the use of different agents such as anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1) and/or anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) increased significantly survival outcomes with durable disease remission.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The development of these new agents, benefited from the evolution of biomarker for patient's selection starting from PD-L1 up to the TMB, still under evaluation but with a consistent amount of data that are good for hope.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2–4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Thanks to these driving clinical premises coming from the robust experience on NSCLC, the development of immune-checkpoint inhibitors (ICIs) moved to SCLC, also due to the biological rationale and its potential clinical use. Indeed, SCLC showed high association with smoking habit and high mutational burden, characterized by mutations in such tumour-suppressor gene as TP53 and RB1, Notch and MYC family members, often induced by tobacco carcinogens.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Considering these biological characteristics suggesting that SCLC may be highly immunogenic and could respond very well to ICIs, different randomized clinical trials (RCTs) were developed to investigate the role of these new agents for the treatment of extensive-stage small-cell lung cancer.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5–7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Preliminary shreds of evidence supporting the activity of ICIs in relapsing SCLC were reported in phase I/II CheckMate 032 trials, evaluating nivolumab monotherapy and two dose levels of combined nivolumab and ipilimumab. In this trial, in which patients were eligible regardless tumour programmed death ligand 1 (PD-L1) expression, overall response rate (ORR) resulted in 10% in the nivolumab monotherapy arm and 19% in the combination.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Based on these early and positive data, though based on an investigator assessment, FDA granted an accelerated approval to nivolumab for the treatment of patients with metastatic refractory SCLC in August 2018 and the NCCN guidelines recommend nivolumab<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>ipilimumab as a new standard of- care option. In particular, this new indication was based on the duration of response (DoR) achieved in the CheckMate 032 trial, showing an ORR of 12% and a median DoR of 12.9 months, with 62% of patients responding at 12 months and 39% still responding at 18 months.</p><p id="par0025" class="elsevierStylePara elsevierViewall">In addition to these efficacy achievements, this trial did not show a significant difference between positive (≥ 1) and negative tumors for PD-L1 expression in terms of ORR and survival, unlike what happened in non-small cell lung cancer.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Riding this wave, different randomized and non-randomized clinical trials starting to evaluate the role of ICIs as atezolizumab<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>, pembrolizumab<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,12</span></a> or durvalumab<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> in the same setting, showing not encouraging results, also in the PD-L1 enriched population. Atezolizumab was evaluated in the IFCT-1603 non-comparative phase II study, showing an ORR of 2.3% and progression-free survival (PFS) of 1.4 months.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Pembrolizumab, in the PD-L1 positive (≥ 1) setting was investigated in two different trials of relapsing SCLC: the KEYNOTE 028 and the KEYNOTE 158, a very limited PFS of 1.9 and 2.0 months, respectively. Also, durvalumab failed to demonstrate an increase in survival in the same clinical set, achieving a PFS of 1.5 months and ORR 10%.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,12</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Although these results were reported with high emphasis underlining the antitumor activity of ICIs in patients with pretreated or relapsed SCLC, in reality, failed to show the promising and heralded efficacy in this particular setting.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Nevertheless, these preliminary although unconvincing data, a randomized phase III trial (CheckMate 331) was conducted to evaluated nivolumab in monotherapy versus a standard second-line with either topotecan or amrubicin upon investigator's choice, in patients with relapsed SCLC following platinum-based chemotherapy, having an overall survival (OS) as a primary endpoint.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Although the results are not yet published in comprehensive form, a press release announced that the treatment with nivolumab did not improve overall survival, confirming the previous results achieved in the other phase I/II clinical trials, investigating the same topic.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Overall, these results confirmed that significant unmet needs remain unanswered, moving us to think if there is a really please for immunotherapy in relapsed SCLC.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Despite biological background suggested us the potential role of ICI in this setting, tumour immune escape in SCLC remains a hurdle to effective treatment, worsen different mechanism including immunogenicity, antigen modulation and tumour-induced immune suppression results in therapy resistance.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">To better optimize results and improving the survival outcome of patients suffering from refractory SCLC, we need immune-biomarker based clinical trials, even if theoretically the biological premises would not require it. This is highly recommended due to SCLC presents a highly aggressive growth rate and “tying to believe” cannot be a winning philosophy, but a careful selection of patients guided by biomarkers can be the only driver that can lead us to see the light in this arduous path. Notwithstanding nowadays multiple immunotherapy trials are currently enrolling patients with SCLC in different stage and setting of disease, several presents the same bias and limited data about accurate and preplanned biomarkers selections.</p><p id="par0060" class="elsevierStylePara elsevierViewall">The role of immunotherapy should be carefully considered in SCLC, also based on the results of combination treatment with atezolizumab plus standard platinum-based chemotherapy of IMpower 133 clinical trials, that although showing a statistically significant improvement for the combo arm, the median change in overall survival was only about 2 months (12.3 vs 10.3 months, HR 0.70; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.007), completely different from the results achieved with immunotherapy in the other histology as adenocarcinoma or squamous cell carcinoma, confirming the high difference of biology among the different histology.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Despite this improvement, representing a meaningful advance in this extremely aggressive malignancy, suggest us to improve our research and patient's selection.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Hoping that there will be a safe harbor for second-line immunotherapy in the SCLC, nowadays this opportunity remains limited and cannot be considered a viable therapeutic option for our patients.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflicts of interest</span><p id="par0070" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:16 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immune Checkpoint Inhibitors in the Management of Lung Cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "S. 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Jeet" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Cureus" "fecha" => "2018 Sep 10" "numero" => "9" "paginaInicial" => "e3254" ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L. Horn" 1 => "A.S. Mansfield" 2 => "A. Szczęsna" 3 => "L. Havel" 4 => "M. Krzakowski" 5 => "M.J. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 6 | 6 | 12 |
| 2024 October | 42 | 38 | 80 |
| 2024 September | 45 | 26 | 71 |
| 2024 August | 36 | 34 | 70 |
| 2024 July | 37 | 34 | 71 |
| 2024 June | 32 | 27 | 59 |
| 2024 May | 35 | 35 | 70 |
| 2024 April | 36 | 33 | 69 |
| 2024 March | 35 | 25 | 60 |
| 2024 February | 37 | 28 | 65 |
| 2024 January | 27 | 28 | 55 |
| 2023 December | 20 | 22 | 42 |
| 2023 November | 34 | 45 | 79 |
| 2023 October | 30 | 43 | 73 |
| 2023 September | 20 | 33 | 53 |
| 2023 August | 18 | 25 | 43 |
| 2023 July | 24 | 31 | 55 |
| 2023 June | 23 | 21 | 44 |
| 2023 May | 38 | 34 | 72 |
| 2023 April | 27 | 17 | 44 |
| 2023 March | 47 | 25 | 72 |
| 2023 February | 49 | 27 | 76 |
| 2023 January | 17 | 17 | 34 |
| 2022 December | 39 | 23 | 62 |
| 2022 November | 43 | 42 | 85 |
| 2022 October | 49 | 43 | 92 |
| 2022 September | 68 | 35 | 103 |
| 2022 August | 74 | 40 | 114 |
| 2022 July | 65 | 49 | 114 |
| 2022 June | 66 | 28 | 94 |
| 2022 May | 50 | 48 | 98 |
| 2022 April | 25 | 41 | 66 |
| 2022 March | 42 | 45 | 87 |
| 2022 February | 28 | 44 | 72 |
| 2022 January | 52 | 52 | 104 |
| 2021 December | 32 | 40 | 72 |
| 2021 November | 141 | 56 | 197 |
| 2021 October | 37 | 66 | 103 |
| 2021 September | 27 | 37 | 64 |
| 2021 August | 44 | 39 | 83 |
| 2021 July | 30 | 19 | 49 |
| 2021 June | 46 | 27 | 73 |
| 2021 May | 45 | 42 | 87 |
| 2021 April | 109 | 91 | 200 |
| 2021 March | 81 | 42 | 123 |
| 2021 February | 61 | 42 | 103 |
| 2021 January | 60 | 30 | 90 |
| 2020 December | 37 | 19 | 56 |
| 2020 November | 46 | 27 | 73 |
| 2020 October | 58 | 34 | 92 |
| 2020 September | 52 | 43 | 95 |
| 2020 August | 40 | 26 | 66 |
| 2020 July | 35 | 25 | 60 |
| 2020 June | 42 | 35 | 77 |
| 2020 May | 41 | 30 | 71 |
| 2020 April | 35 | 12 | 47 |
| 2020 March | 40 | 24 | 64 |
| 2020 February | 33 | 24 | 57 |
| 2020 January | 32 | 34 | 66 |
| 2019 December | 44 | 26 | 70 |
| 2019 November | 35 | 28 | 63 |
| 2019 October | 36 | 18 | 54 |
| 2019 September | 32 | 33 | 65 |
| 2019 August | 40 | 25 | 65 |
| 2019 July | 34 | 25 | 59 |
| 2019 June | 41 | 38 | 79 |
| 2019 May | 29 | 38 | 67 |
| 2019 April | 44 | 34 | 78 |
| 2019 March | 51 | 41 | 92 |
| 2019 February | 95 | 75 | 170 |
| 2019 January | 115 | 73 | 188 |
| 2018 December | 44 | 42 | 86 |
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