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Multicenter Study
. 2020 Nov;69(11):2209-2221.
doi: 10.1007/s00262-020-02613-9. Epub 2020 May 30.

Clinicopathologic correlates of first-line pembrolizumab effectiveness in patients with advanced NSCLC and a PD-L1 expression of ≥ 50

Alessio Cortellini  1   2 , Marcello Tiseo  3   4 , Giuseppe L Banna  5 , Federico Cappuzzo  6 , Joachim G J V Aerts  7 , Fausto Barbieri  8 , Raffaele Giusti  9 , Emilio Bria  10   11 , Diego Cortinovis  12 , Francesco Grossi  13 , Maria R Migliorino  14 , Domenico Galetta  15 , Francesco Passiglia  16 , Daniele Santini  17 , Rossana Berardi  18 , Alessandro Morabito  19 , Carlo Genova  20 , Francesca Mazzoni  21 , Vincenzo Di Noia  22 , Diego Signorelli  23 , Alessandro Tuzi  24 , Alain Gelibter  25 , Paolo Marchetti  9   25   26 , Marianna Macerelli  27 , Francesca Rastelli  28 , Rita Chiari  29 , Danilo Rocco  30 , Stefania Gori  31 , Michele De Tursi  32 , Giovanni Mansueto  33 , Federica Zoratto  34 , Matteo Santoni  35 , Marianna Tudini  36 , Erika Rijavec  13 , Marco Filetti  9 , Annamaria Catino  15 , Pamela Pizzutilo  15 , Luca Sala  12 , Fabrizio Citarella  17 , Russano Marco  17 , Mariangela Torniai  18 , Luca Cantini  7   18 , Giada Targato  27 , Vincenzo Sforza  19 , Olga Nigro  24 , Miriam G Ferrara  10   11 , Ettore D'Argento  10 , Sebastiano Buti  3 , Paola Bordi  3 , Lorenzo Antonuzzo  21 , Simona Scodes  6 , Lorenza Landi  6 , Giorgia Guaitoli  8 , Cinzia Baldessari  8 , Luigi Della Gravara  30 , Maria Giovanna Dal Bello  20 , Robert A Belderbos  7 , Paolo Bironzo  16 , Simona Carnio  16 , Serena Ricciardi  14 , Alessio Grieco  14 , Alessandro De Toma  23 , Claudia Proto  23 , Alex Friedlaender  37 , Ornella Cantale  5 , Biagio Ricciuti  38   39 , Alfredo Addeo  37 , Giulio Metro  40 , Corrado Ficorella  41   42 , Giampiero Porzio  41   42
Affiliations
Multicenter Study

Clinicopathologic correlates of first-line pembrolizumab effectiveness in patients with advanced NSCLC and a PD-L1 expression of ≥ 50

Alessio Cortellini et al. Cancer Immunol Immunother. 2020 Nov.

Abstract

Background: Single-agent pembrolizumab represents the standard first-line option for metastatic non-small-cell lung cancer (NSCLC) patients with a PD-L1 (programmed death-ligand 1) expression of ≥ 50%.

Methods: We conducted a multicenter retrospective study aimed at evaluating the clinicopathologic correlates of pembrolizumab effectiveness in patients with treatment-naïve NSCLC and a PD-L1 expression of ≥ 50%.

Results: One thousand and twenty-six consecutive patients were included. The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively. ECOG-PS ≥ 2 (p < 0.0001) and bone metastases (p = 0.0003) were confirmed to be independent predictors of a worse ORR. Former smokers (p = 0.0002), but not current smokers (p = 0.0532) were confirmed to have a significantly prolonged PFS compared to never smokers at multivariate analysis. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a worse PFS. Previous palliative RT was significantly related to a shortened OS (p = 0.0104), while previous non-palliative RT was significantly related to a prolonged OS (p = 0.0033). Former smokers (p = 0.0131), but not current smokers (p = 0.3433) were confirmed to have a significantly prolonged OS compared to never smokers. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a shortened OS. A PD-L1 expression of ≥ 90%, as assessed by recursive partitioning, was associated with significantly higher ORR (p = 0.0204), and longer and OS (p = 0.0346) at multivariable analysis.

Conclusion: Pembrolizumab was effective in a large cohort of NSCLC patients treated outside of clinical trials. Questions regarding the effectiveness in clinical subgroups, such as patients with poorer PS and with liver/bone metastases, still remain to be addressed. We confirmed that the absence of tobacco exposure, and the presence of bone and liver metastasis are associated with worse clinical outcomes to pembrolizumab. Increasing levels of PD-L1 expression may help identifying a subset of patients who derive a greater benefit from pembrolizumab monotherapy.

Keywords: Bone metastases; Liver metastases; PD-L1; Performance status; Radiotherapy; Smoking status.

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Conflict of interest statement

Dr. Alessio Cortellini received speaker fees and grant consultancies by Astrazeneca, MSD, BMS, Roche, Novartis, Istituto Gentili, Astellas and Ipsen. Dr. Emilio Bria received speaker and travel fees from MSD, Astra-Zeneca, Pfizer, Helsinn, Eli-Lilly, BMS, Novartis and Roche. Dr. Emilio Bria received grant consultancies by Roche and Pfizer. Dr. Marcello Tiseo received speaker fees and grant consultancies by Astrazeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda and Pierre Fabre. Dr. Alessandro Morabito received speaker fees by Astra, Roche, BMS, MSD, Boehringer, Pfizer, Takeda. Dr. Francesca Mazzoni received grant consultancies by MSD and Takeda. Dr. Raffaele Gisti received speaker fees and grant consultancies by Astrazeneca and Roche. Dr. Francesco Passiglia received grant consultancies by MSD and Astrazeneca. Dr. Paolo Bironzo received grant consultancies by Astrazeneca and Boehringer-Ingelheim. Dr. Alex Friedlaender received grant consultancies by Roche, Pfizer, Astellas and BMS. Dr. Alfredo Addeo received grant consultancies by Takeda, MSD, BMJ, Astrazeneca, Roche and Pfizer. Dr. Rita Chiari received speaker fees by BMS, MSD, Takeda, Pfizer, Roche and Astrazeneca. Dr. Carlo Genova received speaker fees/grant consultancies by Astrazeneca, BMS, Boehringer-Ingelheim, Roche and MSD.

Figures

Fig. 1
Fig. 1
ROC curve analysis according to PD-L1 expression of ORR (a).  Multiple comparison graphs of PD-L1 TPS according to the smoking status (b) and to the tissue specimen (c)
Fig. 2
Fig. 2
Kaplan–Meier survival curves. a Median PFS in the overall study population was 9 months (95% CI 6.9–9.5; 599 events); b median OS in the overall study population was 17.2 months (95% CI 15.3–22.3; 598 censored patients); c median PFS of patient with ECOG-PS 0–1 and ECOG-PS ≥ 2 was 10.4 months (95% CI 8.7–13.0; 453 events) and 2.6 months (95% CI 1.9–3.30; 146 events), respectively; d median OS of patient with ECOG-PS 0–1 and ECOG-PS ≥ 2 was 22.8 months (95% CI 18.6–27.5; 543 censored patients) and 3.9 months (95% CI 2.9–5.3; 55 censored patients)
Fig. 3
Fig. 3
Kaplan–Meier survival curves of PFS (a) and OS (b) according to the computed PD-L1 TPS optimal cutoffs. Kaplan–Meier survival curves according to the smoking status of PFS (c) and OS (d), and according to previous RT of PFS (e) and OS (f)
Fig. 4
Fig. 4
Kaplan–Meier survival curves according to baseline CNS, bone and liver metastases. Median PFS of patients with and without baseline CNS metastases was 5.9 months (95% CI 3.9–7.1; 115 events) and 8.6 months (95% CI 7.5–10.2; 484 events), respectively (S1A). Median OS of patients with and without baseline CNS metastases was 15.0 months (95% CI 9.6–22.3; 99 censored patients) and 18.5 months (95% CI 16.1–27.5; 499 censored patients), respectively (S1B). Median PFS of patients with and without baseline bone metastases was 4.5 months (95% CI 3.4–5.7; 224 events) and 11.1 months (95% CI 9.2–13.4; 375 events), respectively (S1C). Median OS of patients with and without baseline bone metastases was 10.9 months (95% CI 8.1–12.8; 155 censored patients) and 27.5 months (95% CI 18.5–27.5; 443 censored patients), respectively (S1D). Median PFS of patients with and without baseline liver metastases was 3.7 months (95% CI 2.5–4.9; 125 events) and 9.8 months (95% CI 8.0–11.3; 474 events), respectively (S1E). Median OS of patients with and without baseline liver metastases was 8.2 months (95% CI 5.7–11.1; 62 censored patients) and 19.9 months (17.1–27.5; 536 censored patients), respectively (S1F)
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