Evaluating new methods for estimating the hypothetical estimand on overall survival in the presence of different effective subsequent therapies - a simulation study with application to a clinical trial

11552 Background: Liposarcomas (LPS) are among the most common soft tissue sarcoma subtypes. Well-differentiated (WD) and dedifferentiated (DD) LPS are characterized by CDK4 and MDM2 amplification. Both subtypes have variable sensitivity to chemotherapy. However, effective systemic treatment options remain limited for unresectable or metastatic disease. Our group previously reported two phase 2 trials of the CDK4/6 inhibitor (CDK4/6i) palbociclib (PD0332991) in advanced WD/DD LPS, which established proof-of-concept for targeting CDK4 in this disease. Palbociclib demonstrated prolonged progression-free survival (PFS) and was included in the NCCN Compendium for LPS. However, prospective data on overall survival (OS) in this population remain limited. We now report OS analysis approximately 8.5 years after the last patient was enrolled. Methods: Patients with advanced WD/DD LPS were enrolled in two non-randomized phase 2 trials of palbociclib: cohort A received 200 mg daily for 14 days on a 21-day cycle, while cohort B received 125 mg daily for 21 days on a 28-day cycle. Survival outcomes were analyzed using Kaplan-Meier methods, and baseline factors were evaluated for association with PFS and OS. Subsequent anti-cancer therapies, including surgery and systemic treatments, were recorded and analyzed. Results: Among 90 enrolled patients, 88 were evaluable for PFS. Median follow-up was 17 months for cohort A and 21 months for cohort B. Updated median PFS was 18.2 weeks (95% CI: 17.7–36.4 weeks) in cohort A and 18.8 weeks (95% CI: 12–23.4 weeks) in cohort B. Median OS was 25.6 months (95% CI: 17.2–40.0 months) in cohort A and 24.1 months (95% CI: 17.5–38.4 months) in cohort B. Across both cohort, patients with pure WD histology were underrepresented, comprising 15 of the 90 patients. Patients with pure WD histology demonstrated longer PFS compared to patients with DD or WD/DD histology (HR: 0.55; 95% CI: 0.30–0.99). However, no significant difference in OS was observed between histologic groups (HR: 0.64; 95% CI: 0.35–1.16). Surgery was performed on 35 patients (39%) post-palbociclib, of which 5 patients had pure WD histology. Analyses on subsequent therapies, including surgery and systemic treatments, will be presented at the meeting. Conclusions: This study provides updated long-term outcomes for palbociclib in advanced WD/DD LPS. Palbociclib demonstrated consistent PFS and OS across dosing regimens, offering a tolerable alternative to chemotherapy for patients who may not be candidates for cytotoxic agents. While PFS and OS outcomes remain modest, these data reaffirm the role of CDK4/6i in the management of this disease and underscore the need for novel therapeutic strategies. Future efforts should focus on biomarker-driven approaches and combination therapies to optimize outcomes in this challenging disease. Clinical trial information: NCT01209598 .

A Matching-Adjusted Indirect Treatment Comparison of Daratumumab-Bortezomib-Melphalan-Prednisone Versus Lenalidomide-Dexamethasone Continuous, Lenalidomide-Dexamethasone 18 Months, and Melphalan-Prednisone-Thalidomide

142 Background: AA + prednisone (P) significantly increased OS, time to opiate use, and was well tolerated at the COU-AA-302 final analysis. Here we further characterize OS benefit adjusting for crossover therapy and for baseline prognostic factors. Methods: Patients (N = 1,088) were randomized 1:1 to receive AA (1 g) + P (5 mg po BID) vs P. Co-primary end points were radiographic progression-free survival and OS. Median time to events with 95% CI was estimated using the Kaplan-Meier method. Stratified log-rank test was used to test the difference in treatment effect. Adjustment for crossover utilized the iterative parameter estimate (IPE) and impact of baseline prognostic factors was examined via the multivariate Cox proportional hazard model. Results: With a median follow-up of 49.2 months and 741 deaths (96% of required), AA + P significantly reduced the risk of death vs P (19%) and prolonged median OS (34.7 vs 30.3 months) (Table). 44% of patients initially receiving P alone subsequently received AA + P as crossover per protocol (17%) or as subsequent therapy (27%). IPE adjustment resulted in a 26% reduction in the risk of death (Table). By multivariate analysis, AA + P treatment led to a 21% reduction in the risk of death; baseline prostate-specific antigen (PSA), lactate dehydrogenase (LDH), hemoglobin, alkaline phosphatase (ALP), bone metastases, and age were significant OS prognostic factors (Table). Conclusions: AA + P yielded a statistically significant improvement in OS. Greater improvement in OS was observed after adjusting for the 44% of patients originally on P who ultimately received AA + P. Adjusting for baseline prognostic factors also demonstrated an AA + P OS benefit. Clinical trial information: NCT00887198. [Table: see text]

BACKGROUND The open-label randomized phase III IMELDA trial demonstrated that adding CAP to maintenance BEV until disease progression after initial BEV + docetaxel (DOC) provides statistically significant and clinically meaningful improvements in both progression-free survival (PFS [primary endpoint]; hazard ratio [HR] 0.38, 95% CI 0.27–0.55; log-rank p<0.001; median 4.3 vs 11.9 months with BEV vs BEV + CAP, respectively) and OS (HR 0.43, 95% CI 0.26–0.69; median 23.7 vs 39.0 months, respectively) [Gligorov, Lancet Oncol 2014]. The type and extent of post-progression therapy were not collected prospectively; to address questions from the oncology community and provide further insight into the observed OS benefit with CAP, we collected these data retrospectively in the post-IMELDA study. METHODS In IMELDA, patients (pts) with HER2-negative measurable mBC and no prior chemotherapy for mBC received 3-6 cycles of BEV + DOC. Pts with a response or stable disease were randomized to BEV alone or BEV + CAP (BEV 15 mg/kg d1 q3w; CAP 1000 mg/m2 bid d1-14 q3w) until disease progression, unacceptable toxicity, or consent withdrawal. OS from randomization was a secondary endpoint. In post-IMELDA, data until study closure were collected retrospectively from available records of pts randomized in IMELDA. Ethics, consent, and feasibility reasons prevented some sites participating in post-IMELDA. RESULTS Post-IMELDA data were available from 118 (64%) of the 185 randomized pts. Of these, all but 8 had received further systemic anticancer therapy and 92 of 118 (78%) had received chemotherapy. Post-progression treatment exposure and efficacy are shown below. In Cox regression models stratified by further anticancer therapy after stopping study therapy, HRs were 0.30 (95% CI 0.19–0.48) for PFS and 0.50 (95% CI 0.30–0.82) for OS. Sensitivity analyses using two extremes of imputation (assuming all pts with missing follow-up data did vs did not receive further anticancer therapy) supported OS findings. ParameterBEV (n=59)BEV + CAP (n=59)Any further systemic anticancer therapy, n (%)56 (95)54 (92)Chemotherapy 49 (83)43 (73) CAP34 (58)7 (12) Non-CAP-containing43 (73)41 (69)Targeted therapy/immunotherapy 12 (20)3 (5) BEV8 (14)1 (2)Endocrine therapy 24 (41)31 (53)Other 11 (19)10 (17)Median PFS, months (95% CI)4.3 (2.7–7.4)15.0 (9.9–19.3)Subgroup with further anticancer therapy 4.3 (3.5–7.4)14.1 (9.9–19.3)Median OS, months (95% CI)22.3 (12.1–29.8)36.5 (27.6–NE)Subgroup with further anticancer therapy 22.9 (16.5–31.7)36.5 (24.0–NE)NE=not estimable CONCLUSIONS Post-IMELDA is limited by retrospective collection of data from only two-thirds of randomized pts and only until the date of study closure (thus potentially underestimating crossover to CAP). Nevertheless, these analyses suggest that the OS benefit from adding CAP to maintenance BEV in the IMELDA trial was robust despite extensive post-progression therapy in both treatment arms and crossover to CAP in more than half of pts randomized to maintenance BEV alone. Ongoing and future mBC trials should include prospective collection of information on subsequent therapy. Citation Format: Mustacchi G, Bines J, Alba E, Cortes P, Doval D, de Ducla S, Button P, Gligorov J. Impact of post-progression therapy on overall survival (OS) in the IMELDA randomized phase III trial evaluating the addition of capecitabine (CAP) to maintenance bevacizumab (BEV) for HER2-negative metastatic breast cancer (mBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-15-06.

Postprogression survival for first-line chemotherapy of patients with advanced non-small-cell lung cancer

Background: In patients with non-small-cell lung cancer (NSCLC), the effects of second-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies. Therefore, using individual-level data, we aimed to determine the relationships between progression-free survival (PFS) and post-progression survival (PPS) with OS in patients with advanced NSCLC treated with docetaxel monotherapy as second-line chemotherapy. Methods: Between April 2002 and December 2014, data from 86 patients with advanced NSCLC who underwent second-line docetaxel monotherapy following first-line treatment with platinum combination chemotherapy were analyzed. The relationships of PFS and PPS with OS were analyzed at the individual level. Results: Spearman rank correlation and linear regression analyses showed that PPS was strongly associated with OS (r = 0.86, p < 0.05, R² = 0.93), whereas PFS was moderately correlated with OS (r = 0.50, p < 0.05, R² = 0.21). Performance status at the end of second-line treatment and the number of regimens after progression beyond second-line chemotherapy were significantly associated with PPS (p < 0.05). Conclusions: In patients with advanced NSCLC with unknown oncogenic driver mutations undergoing docetaxel monotherapy as second-line chemotherapy, when compared with PFS, PPS had a stronger association with OS. This finding suggests that subsequent treatment after disease progression following second-line docetaxel monotherapy has a significant influence on OS.

BackgroundThe effects of first‐line chemotherapy on overall survival (OS) might be confounded by subsequent therapies in patients with small‐cell lung cancer (SCLC). Therefore, the objective of our study was to determine the relationships between progression‐free survival (PFS) or post‐progression survival (PPS) and OS after first‐line chemotherapy in elderly patients with extensive disease‐SCLC (ED‐SCLC), using individual level data.MethodsBetween July 1998 and December 2014, we analyzed 57 cases of elderly patients with ED‐SCLC who were treated with carboplatin and etoposide as first‐line chemotherapy. The relationships between PFS and PPS with OS were analyzed at an individual level.ResultsSpearman rank correlation and linear regression analyses showed that PPS was strongly correlated with OS (r = 0.92, P < 0.05, R2 = 0.83) and PFS was moderately correlated with OS (r = 0.76, P < 0.05, R2 = 0.25). The best response at second‐line treatment and the number of regimens after progression beyond first‐line chemotherapy were both significantly associated with PPS (P < 0.05).ConclusionsPPS has a stronger impact on OS than PFS in elderly ED‐SCLC patients after first‐line chemotherapy. In addition, the response at second‐line treatment and the number of additional regimens after first‐line treatment are significant independent prognostic factors for PPS. These results suggest that OS in elderly ED‐SCLC patients may be influenced by treatments subsequent to first‐line chemotherapy; however, this remains to be verified with prospective studies.

P2-17-4 - The Relationships of pfs, pps and Tumor Response with Os in Patients with Nsclc Treated with Gefitinib as First-Line

Background: Among patients with non-small cell lung cancer (NSCLC), the impact of first-line treatment on overall survival (OS) may be influenced by subsequent therapies. Thus, using patient-level data, we assessed the relationships of progression-free survival (PFS) and post-progression survival (PPS) with OS among patients with high-programmed death-ligand 1 (PD-L1) expression undergoing first-line pembrolizumab monotherapy for NSCLC. Methods: We reviewed data from 133 patients with high PD-L1 expression undergoing first-line pembrolizumab monotherapy for NSCLC at 6 Japanese centers between February 2017 and December 2018. The correlations of PFS and PPS with OS were evaluated at the patient level. Results: Linear regression analyses and Spearman’s rank correlation coefficient revealed that PPS was strongly correlated with OS (r = 0.76, p < 0.05, R² = 0.65), while PFS was only moderately correlated with OS (r = 0.71, p < 0.05, and R² = 0.4). Furthermore, PPS was significantly associated with performance status at the end of pembrolizumab monotherapy, as well as the use of platinum-based combination chemotherapy after pembrolizumab monotherapy (both p < 0.05). Conclusions: Among patients with high PD-L1 expression undergoing first-line pembrolizumab monotherapy for NSCLC, PPS was more strongly correlated with OS, relative to the relationship between PFS and OS. Therefore, subsequent treatment appears to significantly influence OS in patients with disease progression following first-line pembrolizumab monotherapy.

Background: In patients with non-small-cell lung cancer (NSCLC), the effects of second-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies. Therefore, using individual-level data, we aimed to determine the relationships between progression-free survival (PFS) and post-progression survival (PPS) with OS in patients with advanced NSCLC treated with docetaxel monotherapy as second-line chemotherapy. Methods: Between April 2002 and December 2014, data from 86 patients with advanced NSCLC who underwent second-line docetaxel monotherapy following first-line treatment with platinum combination chemotherapy were analyzed. The relationships of PFS and PPS with OS were analyzed at the individual level. Results: Spearman rank correlation and linear regression analyses showed that PPS was strongly associated with OS (r = 0.86, p < 0.05, R 2 = 0.93), whereas PFS was moderately correlated with OS (r = 0.50, p < 0.05, R 2 = 0.21). Performance status at the end of second-line treatment and the number of regimens after progression beyond second-line chemotherapy were significantly associated with PPS (p < 0.05). Conclusions: In patients with advanced NSCLC with unknown oncogenic driver mutations undergoing docetaxel monotherapy as second-line chemotherapy, when compared with PFS, PPS had a stronger association with OS. This finding suggests that subsequent treatment after disease progression following second-line docetaxel monotherapy has a significant influence on OS.

The effects of first-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies in patients with non-small cell lung cancer (NSCLC). We examined whether progression-free survival (PFS), post-progression survival (PPS), or tumor response could be valid surrogate endpoints for OS after first-line chemotherapies in advanced NSCLC by using individual-level data, given the lack of research in this area. Between April 2009 and June 2011, 50 patients with advanced non-squamous NSCLC treated with cisplatin and pemetrexed as first-line chemotherapy were analyzed. The relationships of PFS, PPS, and tumor response with OS were analyzed at the individual level. Spearman rank correlation analysis and linear regression analysis showed that PPS was strongly correlated with OS (r = 0.89, P < 0.05, R2 = 0.79), PFS was moderately correlated with OS (r = 0.67, P < 0.05, R2 = 0.39), and tumor shrinkage was weakly correlated with OS (r = 0.36, P < 0.05, R2 = 0.14). Performance status at the beginning of second-line treatment, the best response to second-line treatment, and number of regimens used after progression following first-line chemotherapy were significantly associated with PPS (P < 0.05). Analysis of individual-level data suggested that PPS could be used as a surrogate for OS in patients with advanced non-squamous NSCLC with unknown oncogenic driver mutations and therefore limited options for subsequent chemotherapy. Our findings also suggest that subsequent treatment after disease progression following first-line chemotherapy may greatly influence OS. These results should be validated in other larger populations.

P1.07-048 Clinical Impact of the Relationship between Post-Progression Survival and Overall Survival in Extensive Disease Small Cell Lung Cancer Patients

Background. The effects of first-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies in patients with small-cell lung cancer (SCLC). Therefore, by using individual-level data, we aimed to determine the relationships between progression-free survival (PFS) or postprogression survival (PPS) and OS after first-line chemotherapies in patients with extensive disease-SCLC (ED-SCLC) treated with carboplatin plus etoposide. Methods. Between July 1998 and December 2014, we analyzed 63 cases of patients with ED-SCLC who were treated with carboplatin and etoposide as first-line chemotherapy. The relationships of PFS and PPS with OS were analyzed at the individual level. Results. Spearman rank correlation analysis and linear regression analysis showed that PPS was strongly correlated with OS (r = 0.90, p < 0.05, and R2 = 0.71) and PFS was moderately correlated with OS (r = 0.72, p < 0.05, and R2 = 0.62). Type of relapse (refractory/sensitive) and the number of regimens administered after disease progression after the first-line chemotherapy were both significantly associated with PPS (p < 0.05). Conclusions. PPS has a stronger relationship with OS than does PFS in ED-SCLC patients who have received first-line chemotherapy. These results suggest that treatments administered after first-line chemotherapy affect the OS of ED-SCLC patients treated with carboplatin plus etoposide.

OBJECTIVES:The effects of first-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies in patients with small cell lung cancer (SCLC). We examined whether progression-free survival (PFS), post-progression survival (PPS), and tumor response could be valid surrogate endpoints for OS after first-line chemotherapies for patients with extensive SCLC using individual-level data.METHODS:Between September 2002 and November 2012, we analyzed 49 cases of patients with extensive SCLC who were treated with cisplatin and irinotecan as first-line chemotherapy. The relationships of PFS, PPS, and tumor response with OS were analyzed at the individual level.RESULTS:Spearman rank correlation analysis and linear regression analysis showed that PPS was strongly correlated with OS (r = 0.97, p < 0.05, R2= 0.94), PFS was moderately correlated with OS (r = 0.58, p < 0.05, R2= 0.24), and tumor shrinkage was weakly correlated with OS (r = 0.37, p < 0.05, R2= 0.13). The best response to second-line treatment, and the number of regimens employed after progression beyond first-line chemotherapy were both significantly associated with PPS ( p ≤ 0.05).CONCLUSION:PPS is a potential surrogate for OS in patients with extensive SCLC. Our findings also suggest that subsequent treatment after disease progression following first-line chemotherapy may greatly influence OS.

Targeted Agents in Chronic Lymphocytic Leukemia (CLL): Advancements in Overall Survival Outcomes?