Long-term outcomes from pembrolizumab monotherapy in patients with advanced NSCLC, PD-L1 expression = 50 %, and poor performance status: Transformer-based AI to characterize prognostic complexity
Por:
Cortellini, A, Garbo, E, La Cava, G, Citarella, F, Santo, V, Brunetti, L, Pinato, DJ, Naidoo, J, Loza, M, Genova, C, Gettinger, S, Kim, SY, Jayakrishnan, R, El Zarif, T, Russano, M, Pecci, F, Di Federico, A, Montrone, M, Owen, DH, Signorelli, D, Li, MJ, Camerini, A, Halmos, B, Vincenzi, B, Metro, G, Yendamuri, S, Grossi, F, Josephides, E, Tomasik, B, Giusti, R, Bria, E, Sebastian, M, Rost, M, Acker, F, Landi, L, Mazzoni, F, Morabito, A, Leonetti, A, Cantini, L, Mountzios, G, Kalvapudi, S, O'Reilly, D, Karapanagiotou, E, Monnet, I, Baena, J, Macerelli, M, Majem, M, Piedra, A, Cortinovis, DL, Tonini, G, Minuti, G, Mezquita, L, Gorria, T, Beninato, T, Lo Russo, G, Prelaj, A, De Giglio, A, Biello, F, Nana, FA, Dingemans, AMC, Aerts, JG, Ferrara, R, Abu Hejleh, T, Takada, K, Naqash, AR, Garassino, MC, Wakelee, HA, Nassar, A, Ricciuti, B, Soda, P, Caruso, CM, Guarrasi, V
Publicada:
1 nov 2025
Ahead of Print:
1 oct 2025
Resumen:
Background: The use of first-line single agent immunotherapy in patients with advanced NSCLC and ECOG PS > 2 remains controversial, as this frail population has been largely excluded from pivotal clinical trials. Real-world evidence suggests that although median survival is poor, a subset of these patients may achieve long-term benefit. Methods: We analyzed data from the Pembro-Real 5Y registry, a global real-world dataset with > 5 years followup. The cohort included patients with advanced NSCLC, PD-L1 TPS > 50 %, treated with first line pembrolizumab outside of clinical trials. Univariable analyses were conducted to identify descriptive characteristics associated with survival. To address the complexity of long-term outcome prediction, we integrated Elastic Net regression and a transformer-based AI model (NAIM). The Elastic Net model was employed to mitigate collinearity and select relevant prognostic factors, while NAIM was used to explore non-linear, time-dependent interactions between variables. Endpoints included overall survival (OS) and 5-year survival rates. Results: Out of 1050 patients, 161 patients with ECOG PS > 2 were included, showing a median OS of 5.4 months (95 % CI: 3.8-7.8), and a 5-year survival rate of 13.0 % (95 % CI: 8.1-19.9). Univariable analysis indicated that no single baseline variable was strongly predictive of 5-year survival, except for TMB, KRAS, and BRAF status, which were significantly limited by missingness. Elastic Net identified only two significant predictors of 5-year survival: high TMB (with unstable confidence intervals) and KRAS mutation. NAIM provided a dynamic perspective, confirming that bone metastases and baseline corticosteroid use were strong predictors of early mortality, whereas BMI increase and systemic health markers/host factors (e.g., hypertension and dyslipidemia) gained importance in long-term survivors. However, NAIM exhibited a notable performance drop from training to validation suggesting overfitting and the challenge of modeling long-term outcomes using baseline static variables. Conclusions: Despite the overall poor prognosis, a subset of patients with ECOG PS > 2 achieves long-term survival with pembrolizumab monotherapy, indicating that performance status alone should not preclude treatment in all cases. Our analysis highlights the limitations of traditional statistical approaches and AI-driven models in predicting long-term benefit in this heterogeneous population. Future efforts should focus on refining hybrid modeling strategies and incorporating prospective validation to better identify those who may benefit from immunotherapy beyond short-term expectations.
Filiaciones:
Cortellini, A:
Fdn Policlin Univ Campus Biomed, Operat Res Unit Med Oncol, Via Alvaro del Portillo 200, I-00128 Rome, Italy
Univ Campus Biomed Roma, Dept Med & Surg, Via Alvaro del Portillo 200, I-00128 Rome, Italy
Imperial Coll London, Dept Surg & Canc, Hammersmith Hosp Campus,Du Cane Rd, London, England
Garbo, E:
Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA USA
La Cava, G:
Fdn Policlin Univ Campus Biomed, Operat Res Unit Med Oncol, Via Alvaro del Portillo 200, I-00128 Rome, Italy
Univ Campus Biomed Roma, Dept Med & Surg, Via Alvaro del Portillo 200, I-00128 Rome, Italy
Citarella, F:
Univ Campus Biomed Roma, Dept Med & Surg, Via Alvaro del Portillo 200, I-00128 Rome, Italy
Santo, V:
Fdn Policlin Univ Campus Biomed, Operat Res Unit Med Oncol, Via Alvaro del Portillo 200, I-00128 Rome, Italy
Univ Campus Biomed Roma, Dept Med & Surg, Via Alvaro del Portillo 200, I-00128 Rome, Italy
Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA USA
Brunetti, L:
Fdn Policlin Univ Campus Biomed, Operat Res Unit Med Oncol, Via Alvaro del Portillo 200, I-00128 Rome, Italy
Univ Campus Biomed Roma, Dept Med & Surg, Via Alvaro del Portillo 200, I-00128 Rome, Italy
Imperial Coll London, Dept Surg & Canc, Hammersmith Hosp Campus,Du Cane Rd, London, England
Pinato, DJ:
Imperial Coll London, Dept Surg & Canc, Hammersmith Hosp Campus,Du Cane Rd, London, England
Univ Piemonte Orientale, AOU Maggiore della Carita, Translat Med Dept, Novara, Italy
Naidoo, J:
Beaumont Hosp, Beaumont RCSI Canc Ctr, Dept Oncol, Dublin, Ireland
RCSI Univ Hlth Sci, Dublin, Ireland
Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD USA
Loza, M:
Stanford Univ, Stanford Canc Inst, Div Oncol, Dept Med, Stanford, CA USA
Genova, C:
IRCCS Osped Policlin San Martino, Acad Oncol Unit, Genoa, Italy
Univ Genoa, Dept Internal Med & Med Specialties, Genoa, Italy
Gettinger, S:
Yale Sch Med, Yale Canc Ctr, Dept Internal Med, Sect Med Oncol, New Haven, CT USA
Kim, SY:
Yale Sch Med, Yale Canc Ctr, Dept Internal Med, Sect Med Oncol, New Haven, CT USA
Jayakrishnan, R:
Yale Sch Med, Yale Canc Ctr, Dept Internal Med, Sect Med Oncol, New Haven, CT USA
El Zarif, T:
Yale Sch Med, Yale Canc Ctr, Dept Internal Med, Sect Med Oncol, New Haven, CT USA
Russano, M:
Fdn Policlin Univ Campus Biomed, Operat Res Unit Med Oncol, Via Alvaro del Portillo 200, I-00128 Rome, Italy
Pecci, F:
Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA USA
Di Federico, A:
Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA USA
Montrone, M:
IRCCS Ist Tumori Giovanni Paolo II, Med Thorac Oncol Unit, I-70124 Bari, Italy
Owen, DH:
Ohio State Univ, Comprehens Canc Ctr, Dept Internal Med, Div Med Oncol, Columbus, OH USA
Ohio State Univ, Pelotonia Inst Immunooncol, OSUCCC James, Columbus, OH 43210 USA
Signorelli, D:
Grande Osped Metropolitano Niguarda, Niguarda Canc Ctr, Milan, Italy
Li, MJ:
Ohio State Univ, Comprehens Canc Ctr, Dept Internal Med, Div Med Oncol, Columbus, OH USA
Camerini, A:
Versilia Hosp, Med Oncol, Azienda USL Toscana Nord Ovest, Lido Di Camaiore, Italy
Halmos, B:
Albert Einstein Coll Med, Montefiore Med Ctr, Dept Oncol, Bronx, NY USA
Vincenzi, B:
Fdn Policlin Univ Campus Biomed, Operat Res Unit Med Oncol, Via Alvaro del Portillo 200, I-00128 Rome, Italy
Univ Campus Biomed Roma, Dept Med & Surg, Via Alvaro del Portillo 200, I-00128 Rome, Italy
Metro, G:
Azienda Osped Univ Perugia, Santa Maria della Misericordia Hosp, Med Oncol, Perugia, Italy
Yendamuri, S:
Roswell Pk Comprehens Canc Ctr, Dept Thorac Surg, Buffalo, NY USA
Grossi, F:
Univ Insubria, Dept Med & Technol Innovat, Med Oncol Div, Varese, Italy
Josephides, E:
Guys & St Thomas Hosp NHS Trust, Med Oncol, London, England
Tomasik, B:
Med Univ Gdansk, Fac Med, Dept Oncol & Radiotherapy, Gdansk, Poland
Med Univ Gdansk, Ctr Expt Cardiooncol, Gdansk, Poland
Giusti, R:
St Andrea Hosp Rome, Med Oncol Unit, Rome, Italy
Bria, E:
Univ Cattolica Sacro Cuore, Fdn Policlin Univ Agostino Gemelli IRCCS, Rome, Italy
Osped Isola Tiberina Gemelli Isola, Rome, Italy
Sebastian, M:
Univ Hosp Frankfurt, Dept Med Hematol Oncol 2, Frankfurt, Germany
Rost, M:
Univ Hosp Frankfurt, Dept Med Hematol Oncol 2, Frankfurt, Germany
Acker, F:
Univ Hosp Frankfurt, Dept Med Hematol Oncol 2, Frankfurt, Germany
Landi, L:
IRCCS Natl Canc Inst Regina Elena, Clin Trials Ctr Phase & Precis Med 1, Rome, Italy
Mazzoni, F:
Careggi Univ Hosp, Med Oncol Unit, Florence, Italy
Morabito, A:
IRCCS Fdn G Pascale, Ist Nazl Tumori, Thorac Med Oncol, I-80131 Naples, Italy
Leonetti, A:
Univ Hosp Parma, Med Oncol Unit, Parma, Italy
Cantini, L:
Fortrea Inc, Durham, NC USA
Mountzios, G:
Henry Dunant Hosp Ctr, Dept Med Oncol 4, Athens, Greece
Henry Dunant Hosp Ctr, Clin Trials Unit, Athens, Greece
Kalvapudi, S:
Roswell Pk Comprehens Canc Ctr, Dept Thorac Surg, Buffalo, NY USA
O'Reilly, D:
Beaumont Hosp, Beaumont RCSI Canc Ctr, Dept Oncol, Dublin, Ireland
Karapanagiotou, E:
Guys & St Thomas Hosp NHS Trust, Med Oncol, London, England
Monnet, I:
Ctr Hosp Intercommunal, Serv Pneumol, Creteil, France
Baena, J:
Hosp Univ 12 Octubre, Madrid, Spain
Macerelli, M:
Azienda Sanit Univ Friuli Cent ASUFC, Dept Oncol, Udine, Italy
Majem, M:
Hosp Santa Creu & Sant Pau, Dept Med Oncol, Barcelona, Spain
Piedra, A:
Hosp Santa Creu & Sant Pau, Dept Med Oncol, Barcelona, Spain
Cortinovis, DL:
Univ Milano Bicocca, Fdn IRCCS San Gerardo dei Tintori Monza, Dept Clin Med, Div Med Oncol, Via GB Pergolesi 33, I-20900 Monza, Italy
Tonini, G:
Fdn Policlin Univ Campus Biomed, Operat Res Unit Med Oncol, Via Alvaro del Portillo 200, I-00128 Rome, Italy
Univ Campus Biomed Roma, Dept Med & Surg, Via Alvaro del Portillo 200, I-00128 Rome, Italy
Minuti, G:
IRCCS Natl Canc Inst Regina Elena, Clin Trials Ctr Phase & Precis Med 1, Rome, Italy
Mezquita, L:
Hosp Clin Barcelona, Med Oncol Dept, Barcelona, Spain
Gorria, T:
Hosp Clin Barcelona, Med Oncol Dept, Barcelona, Spain
Beninato, T:
Fdn IRCCS Ist Nazl Tumori, Med Oncol Dept, Milan, Italy
Lo Russo, G:
Fdn IRCCS Ist Nazl Tumori, Med Oncol Dept, Milan, Italy
Prelaj, A:
Fdn IRCCS Ist Nazl Tumori, Med Oncol Dept, Milan, Italy
De Giglio, A:
Univ Bologna, Dept Med & Surg Sci DIMEC, Bologna, Italy
Biello, F:
Univ Piemonte Orientale, AOU Maggiore della Carita, Translat Med Dept, Novara, Italy
Nana, FA:
UCLouvain, Clin Univ St Luc, Div Pneumol, B-1200 Brussels, Belgium
Dingemans, AMC:
Univ Med Ctr, Erasmus MC Canc Inst, Dept Pulm Med, Rotterdam, Netherlands
Aerts, JG:
Univ Med Ctr, Erasmus MC Canc Inst, Dept Pulm Med, Rotterdam, Netherlands
Ferrara, R:
Univ Vita Salute San Raffaele, IRCCS Osped San Raffaele, Dept Med Oncol, Milan, Italy
Abu Hejleh, T:
King Hussein Canc Ctr, Dept Internal Med, Med Oncol, Amman, Jordan
Univ Iowa, Dept Internal Med Hematol Oncol & Blood & Marrow T, Iowa City, IA USA
Takada, K:
Saiseikai Fukuoka Gen Hosp, Dept Surg, Fukuoka, Japan
Naqash, AR:
Univ Oklahoma, Stephenson Canc Ctr, Med Oncol TSET Phase Program 1, Oklahoma City, OK USA
Garassino, MC:
Univ Chicago, Dept Med, Sect Hematol Oncol, Chicago, IL USA
Wakelee, HA:
Stanford Univ, Stanford Canc Inst, Div Oncol, Dept Med, Stanford, CA USA
Nassar, A:
Yale Sch Med, Yale Canc Ctr, Dept Internal Med, Sect Med Oncol, New Haven, CT USA
Ricciuti, B:
Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA USA
Soda, P:
Univ Campus Biomed Roma, Dept Engn, Res Unit Artificial Intelligence & Comp Syst, Rome, Italy
Umea Univ, Dept Diagnost & Intervent, Radiat Phys, Biomed Engn, Umea, Sweden
Caruso, CM:
Univ Campus Biomed Roma, Dept Engn, Res Unit Artificial Intelligence & Comp Syst, Rome, Italy
Guarrasi, V:
Univ Campus Biomed Roma, Dept Engn, Res Unit Artificial Intelligence & Comp Syst, Rome, Italy
Green Submitted, Bronze
|