Luna Del Bono

Background: Pirtobrutinib has recently emerged as a promising first-line treatment option for chronic lymphocytic leukemia (CLL). Unlike currently established regimens, which are generally based on doublet combinations, pirtobrutinib can be administered as monotherapy. No head-to-head trials comparing pirtobrutinib with contemporary first-line combinations are currently available; hence, indirect comparative evidence may help define its potential role. Methods: A non-anchored indirect comparison based on reconstructed individual patient data (IPD) was conducted using published Kaplan–Meier curves from randomized controlled trials evaluating first-line treatments for CLL. Progression-free survival (PFS) was the endpoint of interest. Reconstructed IPD were generated using WebPlotDigitizer and the IPDfromKM algorithm. Then, Kaplan–Meier curves were plotted based on these patients, and the values of the restricted mean survival time (RMST) at 36 months were determined. Regarding PFS, pirtobrutinib monotherapy was compared indirectly with acalabrutinib plus obinutuzumab, venetoclax plus obinutuzumab, and venetoclax plus ibrutinib. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using univariate Cox models. The non-inferiority of pirtobrutinib monotherapy versus doublet regimens was assessed according to a non-inferiority margin set at HR = 1.15. Finally, the value-based prices of the new treatments were estimated based on a willingness-to-pay threshold of euro 30,000 per disease-free year gained and compared with the corresponding real prices in the Italian market. Results: The analysis included four randomized trials. Compared with pirtobrutinib monotherapy, HRs for PFS were 0.5544 (95%CI, 0.2696–1.1397) versus venetoclax plus obinutuzumab, 0.4583 (95%CI, 0.2066–1.0200) versus venetoclax plus ibrutinib, and 1.4453 (95%CI, 0.6684–3.1240) versus acalabrutinib plus obinutuzumab. Pirtobrutinib met the non-inferiority criterion compared with venetoclax plus obinutuzumab and venetoclax plus ibrutinib, but not with acalabrutinib plus obinutuzumab; however, these results were negatively affected by the small number of events in the pirtobrutinib arm, which generated wide CIs. In the preliminary pharmacoeconomic analysis, venetoclax plus obinutuzumab showed the most favorable profile in the comparison of value-based price vs. real price. Conclusions: This exploratory non-anchored analysis suggests that pirtobrutinib monotherapy may provide PFS outcomes broadly comparable to current first-line combination regimens for CLL. Given the methodological limitations inherent to indirect comparisons, prospective head-to-head studies are needed to clarify the optimal positioning of pirtobrutinib in treatment-naïve CLL.

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.

Background: Pirtobrutinib has recently emerged as a promising first-line treatment option for chronic lymphocytic leukemia (CLL). Unlike currently established regimens, which are generally based on doublet combinations, pirtobrutinib can be administered as monotherapy. Because no head-to-head trials comparing pirtobrutinib with contemporary first-line combinations are currently available, indirect comparative evidence may help define its potential role. Methods: A non-anchored indirect comparison based on reconstructed individual patient data (IPD) was conducted using published Kaplan-Meier curves from randomized controlled trials evaluating first-line treatments for CLL. Progression-free survival (PFS) was the endpoint of interest. Reconstructed IPD were generated using WebPlotDigitizer and the IPDfromKM algorithm. Pirtobrutinib monotherapy was compared indirectly with acalabrutinib plus obinutuzumab, venetoclax plus obinutuzumab, and venetoclax plus ibrutinib. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using univariate Cox models. Results: The analysis included four randomized trials. Compared with pirtobrutinib monotherapy, HRs for PFS were 0.5544 (95%CI, 0.2696-1.1397) versus venetoclax plus obinutuzumab, 0.4583 (95%CI, 0.2066-1.0200) versus venetoclax plus ibrutinib, and 1.4453 (95%CI, 0.6684-3.1240) versus acalabrutinib plus obinutuzumab. Confidence intervals were wide and crossed unity in all comparisons, indicating substantial statistical uncertainty. Visual inspection of reconstructed Kaplan-Meier curves did not suggest inferior PFS for pirtobrutinib relative to established doublet regimens. Conclusions: This exploratory non-anchored analysis suggests that pirtobrutinib monotherapy may provide PFS outcomes broadly comparable to current first-line combination regimens for CLL. Given the methodological limitations inherent to indirect comparisons, prospective head-to-head studies are needed to clarify the optimal positioning of pirtobrutinib in treatment-naïve CLL.

In metastatic ALK-positive non-small cell lung cancer (mNSCLC), ALK tyrosine kinase inhibitors (ALKi) represent the established standard of care. While second- and third-generation ALKi (including alectinib, brigatinib, ensartinib, envonalkib, and lorlatinib) have demonstrated superior efficacy compared with the first-generation inhibitor crizotinib in randomized trials, the absence of direct head-to-head comparisons limits the definition of their relative clinical benefit. We performed an updated indirect comparison of next-generation ALKi using data from pivotal randomized controlled trials. Seven first-line trials in ALK-positive mNSCLC were identified, and individual patient data were reconstructed from published Kaplan-Meier curves to estimate treatment effects using Cox proportional hazards models and restricted mean survival time (RMST) analyses, with crizotinib as a common comparator. All next-generation ALKi demonstrated significant progression-free survival (PFS) benefit versus crizotinib. In indirect comparisons, lorlatinib showed superior PFS compared with alectinib [hazard ratio (HR) 0.61; 95% confidence interval (CI): 0.43–0.85], brigatinib (HR 0.48; 95% CI: 0.33–0.71), ensartinib (HR 0.60; 95% CI: 0.40–0.90), and envonalkib (HR 0.42; 95% CI: 0.28–0.62). RMST analyses indicated increasing separation between lorlatinib and alectinib over time, suggesting a more sustained PFS benefit with lorlatinib. Among patients with baseline brain metastases (BMs), lorlatinib showed the strongest PFS effect compared with alectinib, brigatinib, ensartinib, and envonalkib. For overall survival (OS), alectinib demonstrated a statistically significant benefit versus crizotinib, while no significant differences were observed among next-generation ALKi. This indirect comparison indicates that lorlatinib provides the most durable PFS and the strongest intracranial disease control, although ALKis are characterized by distinct toxicity profiles. In the absence of clear OS differences at present, first-line treatment selection should integrate efficacy, intracranial activity, tolerability, and emerging molecular features within a personalized therapeutic framework.

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: 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: 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: 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 5 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 current standard of care.

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: 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 head-to-head direct comparison is available. Methods: We considered: a) monotherapy with immune checkpoint inhibitors (ICI); b) combinations of an ICI with chemotherapy; c) combinations of an ICI with other drugs. An indirect comparison was performed to identify the regimens most effective in prolonging OS compared to each other and to chemotherapy. Results: A total of 6 articles were included. In our final analysis, nivolumab plus chemotherapy showed better OS compared to chemotherapy (HR= 0.70, 95%CI: .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 + pembrolizumab showed the best efficacy in terms of OS. Our results support the use of this combination as first-line treatment in this setting.