Background: The proven efficacy of mTOR inhibitors (mTORIs), tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs) in metastatic renal cell carcinoma (RCC) suggests that these agents should be investigated as adjuvant therapy with the aim of eliminating undetectable microscopic residual disease after curative resection. The aim of our study was to compare the efficacy of these treatments using an innovative method of reconstructing individual patient data. Methods: Nine phase III trials describing adjuvant RCC treatments were selected. The IPDfromKM method was used to reconstruct individual patient data from Kaplan–Meier (KM) curves. The combination treatments were compared with the control arm (placebo) for disease-free survival (DFS). Multi-treatment KM curves were used to summarize the results. Standard statistical tests were performed. These included hazard ratio and likelihood ratio tests for heterogeneity. Results: In the overall population, the study showed that two ICIs (nivolumab plus ipilimumab and pembrolizumab) and one TKI (sunitinib) were superior to the placebo, whereas both TKIs and mTORIs were inferior. As we assessed DFS as the primary endpoint for the adjuvant comparison, the overall survival benefit remains unknown. Conclusions: This novel approach to investigating survival has allowed us to conduct all indirect head-to-head comparisons between these agents in a context where no “real” comparative trials have been conducted.

Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) are the standard of care for first-line maintenance in advanced ovarian cancer, but their benefit varies by BRCA and homologous recombination deficiency (HRD) status, and no head-to-head comparisons are available. Methods: We conducted an indirect comparison of PARPi regimens using reconstructed individual patient data (IPD) from Kaplan–Meier curves of phase III randomized trials (SOLO1, PRIMA, PAOLA1, ATHENA, FLAMES). Progression-free survival (PFS) was the primary endpoint; overall survival (OS) was exploratory. Subgroups were defined as BRCA−mutated (BRCA+), BRCA−/HRD+, and BRCA−/HRD−. Safety outcomes were assessed through a network meta-analysis of adverse drug reactions (ADRs). Results: In BRCA+ patients, olaparib + bevacizumab achieved the largest PFS improvement (HR = 0.27; 95%CI: 0.19–0.39), followed by olaparib monotherapy, while niraparib performed significantly worse. In BRCA−/HRD+, olaparib + bevacizumab was superior to niraparib and rucaparib, with restricted mean survival time (RMST) gains of 3–4 months. In BRCA−/HRD−, PARPi produced only a modest benefit, with no advantage over bevacizumab monotherapy. Exploratory OS analysis confirmed long-term survival with olaparib in BRCA+ but not in the other subgroups. Safety analysis indicated olaparib had the most favorable hematological profile, while niraparib was associated with the highest rates of severe anemia, thrombocytopenia, and neutropenia, despite showing lower gastrointestinal toxicity and fatigue incidence. Conclusions: PARPi efficacy depends strongly on BRCA and HRD status. Olaparib-based regimens provide the greatest clinical benefit with acceptable safety in BRCA+ and HRD+ disease, whereas PARPi appear to be of limited value in HRD-negative ovarian cancer.

Background: Patients with locally advanced/metastatic urothelial cancer have been conventionally treated with platinum-based chemotherapy. Recently, numerous new treatments have been proposed to improve overall survival (OS) and reduce adverse effects, but no direct head-to-head comparisons among these agents are available. Methods: The treatments evaluated in our analyses included (a) monotherapy with immune checkpoint inhibitors (ICI); (b) combinations of an ICI with chemotherapy; and (c) combinations of an ICI with other drugs. Using OS as the endpoint, a series of indirect comparisons were performed to rank the most effective regimens against both chemotherapy and each other. Our analysis was based on the application of an artificial intelligence software program (IPDfromKM method) that reconstructs individual patient data from the information reported in the graphs of Kaplan–Meier curves. Results: A total of five studies published in six articles were included. In our main analysis, nivolumab plus chemotherapy showed better OS compared to chemotherapy (HR = 0.70, 95% CI: 0.59–0.82), while durvalumab plus tremelimumab showed no OS benefit (HR = 0.95, 95% CI 0.82–1.11). More interestingly, enfortumab vedotin plus pembrolizumab significantly prolonged OS compared to both chemotherapy alone (HR = 0.53, 95% CI 0.45–0.63) and nivolumab plus chemotherapy (HR = 0.76, 95% CI 0.60–0.97). Discussion and conclusion: Among new treatments for locally advanced and metastatic urothelial cancer, enfortumab vedotin plus pembrolizumab showed the best efficacy in terms of OS. Our results support the use of this combination as a first-line treatment in this setting.

Background: Immune checkpoint inhibitors (ICIs), either alone or in combination with platinum-based chemotherapy, are effective in the first-line treatment of metastatic, non-oncogene-addicted, non-small cell lung cancer (NSCLC). However, when NSCLC patients progress, the efficacy of available treatment options is limited. Methods: We undertook a meta-analysis that compared combination regimens with the current standard of care. Only randomized controlled trials (RCTs) were included (endpoint, overall survival [OS]). Our analysis used an artificial intelligence software program that reconstructs individual patient data from Kaplan–Meier curves. Hazard ratio (HR) with 95% confidence interval (CI) was the main parameter. Heterogeneity was based on Wald’s test and likelihood ratio test. Results: Five RCTs were included, whose experimental arms included five different combinations. In our analysis, these combination regimes showed no OS benefit compared to chemotherapy (HR = 1.066, 95%CI, 0.9311 to 1.221; p = 0.35). Among the five control arms, cross-trial heterogeneity was remarkably low (likelihood ratio test = 3.76 on 4 df, p = 0.40; Wald test = 3.83 on 4 df, p = 0.40. Discussion: In conclusion, five new second-line combination treatments for patients with NSCLC were not found to determine any benefit in terms of OS in comparison with the current standard of care.

Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) are the standard of care for first-line maintenance in advanced ovarian cancer, but their benefit varies by BRCA and homologous recombination deficiency (HRD) status, and no head-to-head comparisons are available. Methods: We conducted an indirect comparison of PARPi regimens using reconstructed individual patient data (IPD) from Kaplan–Meier curves of phase III randomized trials (SOLO1, PRIMA, PAOLA1, ATHENA, FLAMES). Progression-free survival (PFS) was the primary endpoint; overall survival (OS) was exploratory. Subgroups were defined as BRCA-mutated (BRCA+), BRCA-/HRD+, and BRCA-/HRD-. Safety outcomes were assessed through a network meta-analysis of adverse drug reactions (ADRs). Results: In BRCA+ patients, olaparib+bevacizumab achieved the largest PFS improvement (HR = 0.27, 95% CI 0.19–0.39), followed by olaparib monotherapy, while niraparib performed significantly worse. In BRCA-/HRD+, olaparib+bevacizumab was superior to niraparib and rucaparib, with restricted mean survival time (RMST) gains of 3–4 months. In BRCA-/HRD-, PARPi produced only modest benefit, with no advantage over bevacizumab monotherapy. Exploratory OS analysis confirmed long-term survival with olaparib in BRCA+ but not in the other subgroups. Safety analysis indicated olaparib had the most favorable hematological profile, while niraparib was associated with the highest rates of severe anemia, thrombocytopenia, and neutropenia, despite showing lower gastrointestinal toxicity and fatigue incidence. Conclusions: PARPi efficacy depends strongly on BRCA and HRD status. Olaparib-based regimens provide the greatest clinical benefit with acceptable safety in BRCA+ and HRD+ disease, whereas PARPi appear of limited value in HRD-negative ovarian cancer.

Background: Extensive-stage small cell lung cancer (ES-SCLC) carries a poor prognosis, with fewer than 7% of patients surviving for five years. While immune checkpoint inhibitors (ICIs) combined with platinum–etoposide have reshaped first-line treatment, no head-to-head trials exist comparing available regimens, leaving the optimal therapeutic choice undefined. Methods: A systematic literature search identified phase III randomized controlled trials (RCTs) evaluating first-line ICI-based regimens in ES-SCLC. Individual patient data (IPD) were reconstructed from Kaplan–Meier curves using the IPDfromKM algorithm. Indirect treatment comparisons were performed using Cox proportional hazards models, with chemotherapy alone as the common comparator. The indirect comparison of tiragolumab efficacy was unanchored due to the design of the SKYSCRAPER-02 study. Restricted mean survival time (RMST), truncated at 27 months, was calculated as an additional measure of treatment effect. Results: Six RCTs were included. All ICI-based regimens improved overall survival (OS) compared to chemotherapy alone, except ipilimumab (HR 0.97, 95% CI 0.86–1.09). Serplulimab demonstrated the most favorable OS benefit (HR 0.55, 95% CI 0.48–0.64; RMST 16.73 months), representing a gain of approximately 4 months over chemotherapy alone and 1.8–2.3 months over atezolizumab and durvalumab. The addition of tiragolumab to atezolizumab plus chemotherapy yielded no significant advantage over atezolizumab alone. Conclusions: This IPD-based indirect comparison suggests that serplulimab plus chemotherapy may offer the most favorable OS estimates S benefit among first-line ICI regimens for ES-SCLC, while durvalumab and atezolizumab remain effective standards of care. These findings are hypothesis-generating and highlight the need for prospective head-to-head comparative studies.