Post-progression Treatments Research Articles

Efficacy of subsequent therapies in patients with advanced ovarian cancer who relapse after first-line olaparib maintenance: results of the PAOLA-1/ENGOT-ov25 trial

BackgroundUse of first-line PARP inhibitor maintenance therapy is increasing in advanced ovarian cancer. Understanding the efficacy of first subsequent therapy (FST) in patients experiencing disease progression in the first-line setting is important to optimize post-progression treatments. We evaluated the efficacy of FST in patients from PAOLA-1/ENGOT-ov25 (NCT02477644) who received first-line olaparib maintenance. Patients and methodsThis post hoc analysis evaluated the efficacy of subsequent chemotherapy following disease progression by assessing time from FST to second subsequent therapy (SST) according to whether progression occurred during versus after first-line olaparib maintenance and FST type. A multivariate Cox model was used in the olaparib plus bevacizumab arm to identify prognostic factors influencing the efficacy of subsequent chemotherapy. ResultsOf 806 randomized patients, 544 (67.5%) progressed and received subsequent chemotherapy. The median time from FST to SST was shorter in patients in the olaparib plus bevacizumab arm who progressed during first-line olaparib maintenance (6.1 months) than in those who progressed after first-line olaparib maintenance (11.4 months). Multivariate analysis indicated that progression after (versus during) first-line olaparib maintenance influenced time from FST to SST (hazard ratio 0.65, 95% CI 0.50-0.84; P=0.0011) independently of platinum-free interval or clinical risk. Among patients who progressed and received platinum-based chemotherapy with a PARP inhibitor as FST, the efficacy of subsequent therapies was also dependent upon whether progression occurred during versus after first-line olaparib maintenance. ConclusionsThese results suggest that the timing of disease progression relative to first-line olaparib maintenance may impact the efficacy of subsequent platinum-based chemotherapy. Although results should be interpreted with caution, across all subgroups, including patients who received platinum-based chemotherapy with PARP inhibitor rechallenge as FST, the median time from FST to SST was longer if progression occurred after versus during first-line olaparib maintenance.

Correlation of multiple endpoints in the first-line chemotherapy of advanced gastric cancer: Pooled analysis of individual patient data from Japanese Phase III trials.

Individual-level surrogates are important for management in patients treated for advanced gastric cancer (AGC). This study aimed to comprehensively investigate the correlation of multiple clinical endpoints in the first-line chemotherapy of AGC. Individual patient data (IPD) were collected from four Japanese Phase III trials comparing S-1-based first-line chemotherapies (SPIRITS, START, GC0301/TOP-002, and G-SOX trials). Patients without Response Evaluation Criteria in Solid Tumors (RECIST)-based radiological assessments were excluded. Spearman's rank correlation coefficient was tested for correlation among overall survival (OS), progression-free survival (PFS), and postprogression survival (PPS). OS, PFS, and PPS were compared between responders (best response: complete response or partial response) and nonresponders (best response: stable disease or progressive disease). The study included a total of 1492 patients. Eighty percent of the patients (n = 1190) received subsequent chemotherapies after the failure of each trial's treatment protocol. PFS moderately correlated with OS (Spearman correlation coefficient = 0.66, p < 0.005), whereas the correlation between PPS and OS was strong (Spearman correlation coefficient = 0.87, p < 0.005). Responders had significantly longer OS (median, 17.7 vs. 9.1 months, p < 0.005), PFS (median, 6.9 vs. 2.8 months, p < 0.005), and PPS (median, 10.5 vs. 6.0 months, p < 0.005) than nonresponders. Our results reacknowledged the mild surrogacy of PFS and importance of postprogression treatments in patients with AGC receiving first-line chemotherapy. Consistent longer survival outcomes in better RECIST categories suggested that tumor response might be a useful individual-level surrogate.

Platinum-based chemotherapy and PARP inhibitors for patients with a germline BRCA pathogenic variant and advanced breast cancer (LATER-BC): retrospective multicentric analysis of post-progression treatments

IntroductionPatients with breast cancer (BC) harbouring a germinal BRCA pathogenic variant (gBRCA-PV) may have an enhanced sensitivity to platinum-based chemotherapy (PBC) and PARP inhibitors (PARPi). As reported in ovarian cancer, however, sensitivity and resistance to these treatments could partially overlap. In patients with a gBRCA-PV and advanced BC (aBC), it remains unclear whether prior exposure to PARPi/PBC affects tumour response to subsequent PBC/PARPi, respectively. MethodsWe conducted a retrospective, multicentric study to investigate the clinical benefit of post-PBC PARPi and vice versa in patients with a gBRCA-PV and aBC. Patients included had received (neo)adjuvant PBC and then PARPi in advanced setting (group 1), PBC followed by PARPi (group 2) or PARPi followed by PBC (group 3), both in advanced setting. We reported median progression-free survival (mPFS) and disease control rate (DCR) in each group. ResultsA total of 67 patients from six centres were included. PARPi-mPFS in advanced setting was 6.1 months in patients in group 1 (N = 12), while PARPi-DCR was 67%. In group 2 (N = 36), PARPi-mPFS was 3.4 months and PARPi-DCR was 64%. Age < 65 years and platinum-free interval (PFI) > 6 months were associated with longer PARPi-PFS; previous PBC-PFS > 6 months and PBC in first to second line were associated with longer PARPi-DCR. Patients in group 3 (N = 21) reported a PBC-mPFS of 1.8 months and a PBC-DCR of 14%. PARPi-PFS ≥ 9 months and PARPi-FI ≥ 6 months were associated with better PBC-DCR. ConclusionsSensitivity and resistance to PARPi and PBC partially overlap in patients with a gBRCA-PV and aBC. Evidence of PARPi activity emerged in patients who progressed on previous PBC.

Matching-adjusted indirect treatment comparisons (MAIC) of sotorasib vs trifluridine/tipiracil (T/T) and regorafenib as monotherapy in chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC).

3560 Background: In the single-arm phase 1/2 CodeBreaK 100 study (NCT03600883) evaluating sotorasib monotherapy in KRAS G12C-mutated mCRC patients whose disease progressed on or after fluoropyrimidine, oxaliplatin, and irinotecan treatment, the overall response rate was 12%, and the median progression-free survival (PFS) and overall survival (OS) was 4.2 and 13.4 months, respectively (data cutoff March 2021, n = 91). To compare the efficacy and safety of sotorasib with standard of care (SOC) T/T and regorafenib as monotherapy treatments, MAICs were performed. Methods: Clinical outcomes and adverse events (AEs) were compared from representative studies in mCRC patients who received sotorasib 960 mg once daily in CodeBreaK 100, T/T in the phase 3 RECOURSE study (NCT01607957, n = 534), and regorafenib in the phase 3 CORRECT study (NCT01103323, n = 505). By weighting individual patient-level data from CodeBreak 100, differences in available baseline characteristics considered to be prognostic factors, including age, race, sex, type of cancer (colon vs. rectum), ECOG performance status, time from diagnosis of metastatic disease, number of metastatic sites, number of prior lines of therapy, and prior bevacizumab treatment, were adjusted with the MAIC. MAICs compared sotorasib with T/T and regorafenib separately. Odds ratios (ORs) were estimated for objective response rates, hazard ratios (HRs) were used for PFS and OS. AEs were compared descriptively. Results: The effective sample size of sotorasib with matched characteristics consisted of 29 and 56 patients in the T/T and regorafenib comparison, respectively. The MAIC results showed that treatment with sotorasib increases the likelihood of response to treatment, with an adjusted OR of 8.5 vs T/T and 16.1 vs regorafenib. Sotorasib decreased the risk of progression or death by 41% vs T/T and 45% vs regorafenib (Table). Grade 3+ treatment-emergent AEs occurred in 37%, 69%, and 78% of sotorasib-, T/T-, and regorafenib-treated patients, respectively. Conclusions: The analyses suggest that sotorasib monotherapy is associated with a statistically significant and clinically meaningful improvement in response rates, PFS and OS vs. T/T and regorafenib in heavily pretreated chemorefractory KRAS G12C-mutated mCRC patients. The analyses are limited by the decreased sample size for sotorasib, the lack of KRAS G12C-specific data in SOC studies, and the impact of differences in post-progression treatments on OS across studies. [Table: see text]

225P Platinum-based chemotherapy and PARP Inhibitors for BRCA mutated metastatic breast cancer (LATER-BC): Retrospective multicentre analysis of post-progression treatments

225P Platinum-based chemotherapy and PARP Inhibitors for BRCA mutated metastatic breast cancer (LATER-BC): Retrospective multicentre analysis of post-progression treatments

Abstract P4-01-42: Pooled analysis of post-progression treatments after first-line ribociclib + endocrine therapy in patients with HR+/HER2− advanced breast cancer in the MONALEESA-2, -3, and -7 studies

Abstract Background: The MONALEESA (ML) studies showed significant PFS &amp; OS benefits for 1L ribociclib (RIB) + endocrine therapy (ET) in patients (pts) with pre/peri &amp; postmenopausal advanced breast cancer. The benefit of RIB beyond study treatment (tx) was also observed, with improvements in PFS2 &amp; delays in time to 1st subsequent chemotherapy (CT). While there is currently no preferred tx for the next line post-progression on a CDK4/6 inhibitor (CDK4/6i), except alpelisib in pts with a PIK3CA mutation, guidelines encourage multiple lines of ET or ET-based therapies before switching to CT (except for visceral crisis). This pooled exploratory analysis of the ML studies examined outcomes of various tx strategies post progression on RIB + ET. Methods: Data from pts receiving 1L therapy in ML-2, -3, &amp; -7 (NSAI cohort only &amp; excluding pts with early relapse [≤ 12 mo after end of (neo)adjuvant ET] whose prognosis is closer to that of 2L pts) were pooled &amp; pts receiving 1st subsequent therapies after progression were analyzed. Three groups of subsequent therapies were assessed: ET only, CT, &amp; targeted therapy. Subsequent CT comprises CT +/- any other therapy; targeted therapy includes CDK4/6i, mTORi, PI3Ki, AKTi, etc, +/- ET. Subsequent CT &amp; targeted therapy groups are mutually exclusive. Median duration of study tx, 1st subsequent therapy, &amp; OS (from randomization to death) were analyzed by KM methods. Weighted Cox regressions were performed using inversed propensity scoring matching method (inverse probability tx weighting [IPTW]) to ensure compatible pt characteristics between tx arms. These are not randomized comparisons; only baseline characteristics were used for the estimation of propensity scores in the IPTW, imbalance of prognostic factors at progression may exist. Results: Median follow-up time was 74 mo. 461 pts treated with RIB (81%) &amp; 440 (86%) with PBO discontinued study tx &amp; received a subsequent therapy. In the RIB arms, the most common 1st subsequent therapies were ET only (40%), CT (29%), combination with targeted therapy (28%), &amp; other (4%); for the PBO arms, 34% received CT as a 1st subsequent therapy &amp; 31% each received ET only or combination with targeted therapy (5% received other). In 14% &amp; 20% of pts in the RIB &amp; PBO arms, the 1st subsequent therapy was a CDK4/6i, of these 31% &amp; 12% were RIB. In general, regardless of type of 1st subsequent therapy, the duration of both the study tx &amp; the 1st subsequent therapy was longer for pts treated with RIB vs PBO (Table). In both RIB &amp; PBO arms, pts who received subsequent CT had the shortest duration on study tx, whereas those who received subsequent targeted therapy combination had the longest. Among pts on 1L RIB + ET, after matching pre-randomization baseline characteristics, subsequent CDK4/6i use was associated with the longest mOS (84 [84-NE] mo), followed by ET only (60 [51-68] mo), then a non-CDK4/6i targeted therapy (52 [43-72] mo); post-progression CT was associated with the shortest mOS (37 [32-48] mo). Conclusions: This large, pooled analysis of the ML studies shows that, in general, duration of any subsequent therapy was numerically longer post-1L RIB + ET vs PBO + ET, &amp; subsequent CT was used less frequently for pts on RIB vs PBO. Both findings confirm that upfront tx with RIB does not worsen pt outcomes. This trend in enhancement of outcomes of subsequent therapies seen with 1L RIB suggests a post-tx effect that merits further exploration. Citation Format: Erika Hamilton, Laura M. Spring, Peter A. Fasching, Sandra Franco, Richard H DeBoer, Javier Cortés, Kevin Kalinsky, Dejan Juric, Aditya Bardia, Sina Haftchenary, Agnes Lteif, Juan Pablo Zarate, Liyi Cen, Patrick Neven. Pooled analysis of post-progression treatments after first-line ribociclib + endocrine therapy in patients with HR+/HER2− advanced breast cancer in the MONALEESA-2, -3, and -7 studies [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-42.

The Evolving Scenario in the Assessment of Radiological Response for Hepatocellular Carcinoma in the Era of Immunotherapy: Strengths and Weaknesses of Surrogate Endpoints.

Hepatocellular carcinoma (HCC) is a challenging malignancy characterised by clinical and biological heterogeneity, independent of the stage. Despite the application of surveillance programs, a substantial proportion of patients are diagnosed at advanced stages when curative treatments are no longer available. The landscape of systemic therapies has been rapidly growing over the last decade, and the advent of immune-checkpoint inhibitors (ICIs) has changed the paradigm of systemic treatments. The coexistence of the tumour with underlying cirrhosis exposes patients with HCC to competing events related to tumour progression and/or hepatic decompensation. Therefore, it is relevant to adopt proper clinical endpoints to assess the extent of treatment benefit. While overall survival (OS) is the most accepted endpoint for phase III randomised controlled trials (RCTs) and drug approval, it is affected by many limitations. To overcome these limits, several clinical and radiological outcomes have been used. For instance, progression-free survival (PFS) is a useful endpoint to evaluate the benefit of sequential treatments, since it is not influenced by post-progression treatments, unlike OS. Moreover, radiological endpoints such as time to progression (TTP) and objective response rate (ORR) are frequently adopted. Nevertheless, the surrogacy between these endpoints and OS in the setting of unresectable HCC (uHCC) remains uncertain. Since most of the surrogate endpoints are radiology-based (e.g., PFS, TTP, ORR), the use of standardised tools is crucial for the evaluation of radiological response. The optimal way to assess the radiological response has been widely debated, and many criteria have been proposed over the years. Furthermore, none of the criteria have been validated for immunotherapy in advanced HCC. The coexistence of the underlying chronic liver disease and the access to several lines of treatments highlight the urgent need to capture early clinical benefit and the need for standardised radiological criteria to assess cancer response when using ICIs in mono- or combination therapies. Here, we review the most commonly used clinical and radiological endpoints for trial design, as well as their surrogacy with OS. We also review the criteria for radiological response to treatments for HCC, analysing the major issues and the potential future perspectives.

Determinants of Survival and Post-Progression Outcomes by Sorafenib-Regorafenib Sequencing for Unresectable Hepatocellular Carcinoma.

Simple SummaryThe optimal subsequent treatment and the determinants of survival after sorafenib–regorafenib failure in patients with hepatocellular carcinoma (HCC) remain unclear. The aim of this study was to delineate the determinants of response and survival after regorafenib and evaluate the post-progression outcomes in the era of multiple-line sequential systemic therapy. We retrospectively enrolled 108 patients with unresectable HCC receiving regorafenib after sorafenib failure and reported the predictors of progression-free survival, overall survival, post-progression survival, as well as the next-line treatments after regorafenib failure. We showed that some well-known survival predictors of sorafenib treatment and the response to prior sorafenib also had a prognostic role in patients with HCC undergoing regorafenib treatment. Preserved liver function and subsequent systemic therapy play important roles in survival after regorafenib failure. We conclude that the survival outcomes of regorafenib for HCC have improved in the era of multi-line sequential therapy. Preserved liver function and next-line therapy are important prognostic factors after regorafenib failure.The predictors of response and survival in patients with hepatocellular carcinoma (HCC) receiving regorafenib remain unclear. This study aimed to delineate the determinants of response and survival after regorafenib and evaluate post-progression treatment and outcomes. We retrospectively enrolled 108 patients with unresectable HCC receiving regorafenib after sorafenib failure. Progression-free survival (PFS), overall survival (OS), post-progression survival (PPS) and post-progression treatments were evaluated. The median PFS, OS and PPS were 3.1, 13.1 and 10.3 months, respectively. Achieving disease control by prior sorafenib, early AFP reduction and hand-foot skin reaction (HFSR) were associated with significantly better radiologic responses. By multivariate analysis, the time to progression on prior sorafenib, HFSR and early AFP reduction were associated with PFS; ALBI grade, portal vein invasion, HFSR and early AFP reduction were associated with OS. ALBI grade at disease progression, main portal vein invasion, high tumor burden and next-line therapy were associated with PPS. The median PPS was 12 months in patients who received next-line therapy, and the PPS was comparable between patients who received next-line targeted agents and immunotherapy. In conclusion, survival outcomes of regorafenib for HCC have improved in the era of multi-line sequential therapy. Preserved liver function and next-line therapy are important prognostic factors after regorafenib failure.

Abstract P2-12-09: Correlation between pathologic complete response (pCR), event-free survival (EFS)/disease-free survival (DFS) and overall survival (OS) in neoadjuvant and/or adjuvant (NAdj/Adj) hormone receptor positive (HR+) and human epidermal growth factor receptor-2 negative (HER2-) breast cancer (BC)

Abstract Background OS, the “gold standard” endpoint in oncology studies, is challenging to measure in earlier stages of BC because of considerably long survival. Further, during extended patient follow-up, treatment effect on OS can become impacted by multiple factors such as non-malignant causes of death, treatment cross-over, and post-progression treatments, making it difficult to isolate the true treatment effect. As an alternative, surrogate endpoints (SE) such as DFS, EFS, and pCR can be used to ascertain meaningful benefit in true endpoint (TE). While studies have previously explored the association of such SEs with OS in different BC populations, there is a dearth in literature of studies reporting on correlation in the NAdj/Adj settings in the HR+/HER2- BC population. The aim of this study is to conduct a correlation analysis between various SE-TE pairs (DFS/EFS vs OS, pCR vs OS and pCR vs DFS/EFS) in this population, from data reported in studies identified from a systematic literature review (SLR). For each pair of endpoints, both absolute and relative treatment effects were evaluated. Methods An SLR was conducted in NAdj/Adj setting for HR+/HER2- BC to identify studies that reported any two of pCR, DFS/EFS and OS. The search was carried out using MEDLINE, Embase, Cochrane Library databases (2000 onward), four BC-related conference proceedings (2018-2020) and clinical trial registries. Relative treatment effect sizes were quantified in terms of HRs for DFS/EFS and OS, and odds ratios (ORs) for pCR. Absolute treatment effects were analyzed in terms of survival probability of EFS/DFS and OS at landmark time points and pCR rates. A weighted least squares regression analysis was carried out to determine the strength of association between the various TE-SE pairs. The regression analysis was carried out on log scale for relative treatment effects and on linear scale for absolute treatment effects. Pearson correlation coefficient (r) was used to quantify the strength of association; coefficient of determination (R2) was also reported to evaluate goodness-of-fit. Sensitivity analyses were performed by considering linear scale (for relative outcomes only), using inverse of variance as weights, and by removing outliers. Results A total of 135 publications were identified in the SLR. Regression analysis showed that there is a statistically significant positive association (r= 0.91; 95%CI, 0.83-0.96, p &amp;lt;0.0001) between log(HROS) and log (HRDFS/EFS), with R2 = 0.83. The correlation between log (HRDFS/EFS) and log(ORpCR) was not strong (r= 0.24; 95% CI, -0.63-0.84; p, 0.603). Correlation of ORpCR with HROS was not conducted due to inadequate data points (n=3). For the absolute outcomes, landmark DFS/EFS at 1 year and 2 years were each found to be moderately correlated with OS at 4 and 5 years. The correlation between pCR rate and landmark DFS/EFS and OS was not strong. The association between the pairs of the endpoints was consistent across all the sensitivity analyses. Conclusions Results of this regression analysis suggest that relative treatment effect on DFS/EFS is strongly associated with relative treatment effect on OS in HR+HER2- BC and could be used as a surrogate for OS. Correlation analysis for HR(DFS/EFS) vs. HR(OS) and OR(pCR) vs. HR(DFS/EFS)Model# studies# observationsPearson coefficient, r (95% CI)p-valueCoefficient of determination, R2 (95% CI)Slope (95% CI)P-valueHRDFS/EFS vs. HROS24320.91 (0.83-0.96)&amp;lt;0.00010.83 (0.69-0.89)0.99 (0.83-1.16)&amp;lt;.0001ORpCR vs. HRDFS/EFS570.24 (-0.63-0.84)0.60.06 (0-0.47)0.23 (-0.86-1.31)0.6099 Citation Format: Anagha Gogate, Inkyu Kim, Sandip Ranjan, Amit Kumar, Eros Papademetriou, Hitesh Bhandari, Ravi Potluri. Correlation between pathologic complete response (pCR), event-free survival (EFS)/disease-free survival (DFS) and overall survival (OS) in neoadjuvant and/or adjuvant (NAdj/Adj) hormone receptor positive (HR+) and human epidermal growth factor receptor-2 negative (HER2-) breast cancer (BC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-12-09.

Biomarker-Directed Phase II Platform Study in Patients With EGFR Sensitizing Mutation-Positive Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy (ORCHARD)

IntroductionOsimertinib, a third-generation, irreversible, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), selectively inhibits both EGFR-TKI sensitizing (EGFRm) and EGFR T790M resistance mutations and has demonstrated efficacy in non-small cell lung cancer (NSCLC) CNS metastases. Most patients with EGFRm NSCLC treated with osimertinib will eventually develop resistance. ORCHARD (NCT03944772) is a phase II study aiming to characterize first-line osimertinib resistance and identify post-progression treatments. MethodsAdults aged ≥ 18 years (Japan ≥ 20 years), with EGFRm locally advanced/metastatic NSCLC will be allocated to one of three groups after first-line osimertinib progression, based on molecular profiling from a post-progression tumor biopsy. Group A will evaluate patients with protocol-determined biomarkers of resistance treated with novel osimertinib combination therapies, Group B will evaluate patients without a detectable protocol-determined biomarker treated with non-biomarker selected therapies that are chemotherapy- or EGFR-TKI-based, and Group C (observational) includes patients with histologically transformed disease, and/or a biomarker with an available therapy not investigated in ORCHARD. Group C patients will be treated as per local practice and followed to assess overall survival. The study's platform design allows for adaptability to include emerging treatments related to novel resistance mechanisms. The primary endpoint is confirmed objective response rate (investigator assessed). Other endpoints are progression-free survival, duration of response, overall survival, pharmacokinetics and safety. ConclusionsORCHARD aims to characterize mechanisms of resistance to first-line osimertinib and explore treatments to overcome acquired resistance. The modular design allows for additional biomarker-directed cohorts and treatment options as understanding of osimertinib resistance mechanisms evolves.

P76.27 ORCHARD: A Biomarker-Directed Phase 2 Platform Study in pts with Advanced EGFRm NSCLC Progressing on First-Line Osimertinib

Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing (EGFRm) and EGFR T790M resistance mutations, and has demonstrated efficacy in EGFRm advanced NSCLC, including central nervous system metastases. Most patients’ (pts) tumors develop resistance to osimertinib through secondary EGFR mutations (including C797S, G724S and L718V/Q) and off-target genomic alterations (including MET amplification and gene fusions). Data suggest that off-target alterations such as ALK and RET fusions may be resistance mechanisms to first-line osimertinib in some pts (each <5%). The ORCHARD study (NCT03944772) aims to better characterize resistance mechanisms to first-line osimertinib, and evaluate post-progression treatments. The flexible, platform-based design allows for new cohorts and treatment arms, for broader exploration of targeting resistance mechanisms. Previously presented: WCLC 2019 (Yu H, et al. J Thorac Oncol;14[10 suppl]:S647). In this open-label, multicenter, multidrug, biomarker-directed Phase 2 platform-based study (Figure), adult pts with locally advanced/metastatic EGFRm NSCLC whose disease progressed on first-line osimertinib are eligible. Treatment is assigned per molecular characterization of a mandatory tissue biopsy from a progressing lesion, analyzed by next-generation sequencing (Foundation Medicine Inc.). The protocol has recently been amended: Group A now includes treatment arms for pts with ALK/RET rearrangements, who will receive osimertinib plus alectinib/selpercatinib, respectively. The ‘MET alterations’ arm has been expanded from MET-amplification to also include MET exon 14 skipping, and the ‘EGFR alterations’ arm has been expanded from EGFR-amplification to also include mutations at the EGFR L718/G724 residue, or insertion in EGFR exon 20. Group B encompasses pts with no identifiable resistance mechanism; Group C is observational, for pts whose tumors harbor resistance mechanisms not currently addressed within the study. Tumor assessments (RECIST 1.1) will be performed every 6 weeks for 24 weeks, and every 9 weeks thereafter until disease progression or treatment discontinuation. Interim analyses will be performed on the first 16 pts in each cohort who have had the opportunity for two post-baseline RECIST assessments; individual cohorts may be stopped (if there is <10% probability for objective response rate [ORR] to be above target value [45%, equaling ≤4 of the 16 pts with confirmed responses]), or expanded to 30–40 pts for further evaluation. Primary endpoint: confirmed ORR (investigator assessed); secondary endpoints include: progression-free survival, duration of response, overall survival, and pharmacokinetics. Safety will also be reported. A summary of the observed genomic landscape during enrolment will be presented. osimertinib, non-small cell lung cancer, resistance

PCN28 Relationship between Surrogate Endpoints and Overall Survival in Studies That Prohibited Crossover or Reported Balanced Post-Progression Treatments; Pooled Analysis in Advanced NSCLC Patients

We evaluated the relationship between two surrogate endpoints and overall survival (OS) in advanced NSCLC studies that did not allow for crossover or reported balanced post-progression treatments. Two systematic reviews in advanced NSCLC patients receiving first- and further-line therapy were performed. The relationship between the absolute difference in the objective response rate (ORR) or median progression-free survival (mPFS) and the absolute difference in mOS was assessed using the correlation coefficient (R). The analysis used data reported in phase III trials and was restricted to predefined data cut in trials that did not allow crossover and reported balanced post-progression treatments. When the upper limit of R’s 95% confidence interval (CI) is >0.7, the surrogate threshold effect (STE) was estimated. In total, 73 RCTs (38,891 patients) were included in all line settings. Both ORR (%) and mPFS had strong associations with mOS (ORR and mOS: R= 0.574, 95% CI: 0.396-0.710; mPFS and mOS: 0.690, 95% CI: 0.503-0.816). STE estimation indicated that trials that show a statistically significant treatment effect size of ≥40% ORR or ≥3.7 median PFS months could be expected to show significant OS benefit with sufficient certainty. Results were consistent in different line settings. Presented STE calculation can be used to interpret treatment effect on either ORR or PFS when used as primary endpoints.

Patterns of progression and subsequent management of patients with BRCA1/2 mutated platinum-sensitive recurrent epithelial ovarian cancer (EOC) progressing on olaparib versus placebo: the SOLO2/ENGOT Ov-21 trial (NCT01874353).

6070 Background: Olaparib maintenance is a standard treatment of BRCA1/2 mutated platinum-sensitive recurrent EOC. Despite improvement in PFS, olaparib (O) resistance often occurs and the optimal management of post-olaparib progression remains undefined. Methods: Data of patients who participated in the SOLO-2 trial and progressed were analyzed. Primary objective was to depict the patterns of progression of patients treated with O compared to placebo (P). Secondary objectives include description of post-progression treatments. Results: 106/195 (54%) and 80/99 (81%) patients had a RECIST progression in the O and P arms respectively. As permitted in the protocol, 37 (35%) pts continued O despite a RECIST progression and 10 remained on treatment at the date of data base cut-off of the primary endpoint. Median duration of O post progression was 3.2 months (range: 1 to 19.4). In the placebo arm, only 20% of the patients with progressive disease continued placebo during a median of 1.6 months (range:1.1 to 16.1). Patterns of sites of progressive disease were similar in the O and P arms respectively in terms of liver (21% vs 18%), lung (4% vs 3%), lymph node (20% vs 16%) peritoneal (48% vs 32%) or brain metastases (0% vs 2%). Number of sites of relapsing disease were similar in the O and P arm respectively (1 (68% vs 64), ≥2 (32% vs 36%). A total of 54 (51%) patients in the O arm and 42 (53%) in the P arm received subsequent platinum-based therapy. In both arms, 8% received bevacizumab and 6% received no further treatment. Median PFS with first post-study platinum-based and non platinum-based therapy were 7.1 months and 5.6 months respectively. In the P arm, 18 (23) patients received PARP inhibitors following the first subsequent chemotherapy. Conclusions: Patterns of disease progression and subsequent chemotherapy were similar in patients receiving O or P in the SOLO2 trial. Instead of switching to chemotherapy, continuing O at the time of RECIST progression was an option for 35% of the patients. Clinical trial information: NCT01874353.

Abstract P5-11-18: Real-world evidence of efficacy and activity of palbociclib plus endocrine therapy and post-progression treatments in HR+/HER2- metastatic breast cancer patients: The PALPract study

Abstract Background: Several randomized clinical trials clearly demonstrated that adding palbociclib (P) to endocrine therapies (ET), such as letrozole (LT) or fulvestrant (FLV), significantly improves outcome both in first-line/endocrine sensitive and second-line/endocrine resistant hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2) metastatic breast cancer (MBC) patients (pts). The aims of the present study were to assess efficacy, activity and toxicity of P combined with either LT or FLV in a real world setting, and to study the efficacy and activity of treatments administered after progression to P + ET. Methods: Records of 245 consecutive HR+/HER2- MBC patients from 14 Italian cancer centers were reviewed in this observational study. Primary end-point was progression-free survival (PFS) obtained with P+ET; secondary end-points were overall response rates (ORR) and clinical benefit rate (CBR) obtained with P+ET and with post-progression treatments, as well as overall survival (OS), PFS to subsequent treatment lines and post-progression survival (PPS). Results: Overall 245 pts were treated with P+ET from April 2014. Of them, 116 (47%) received it in first-line setting, 70 (28%) in second-line and the rest (68 pts, 25%) in subsequent lines. Median age was 60 (35-80) years and median ECOG performance status was 0. Seventy-three pts (30%) had more than two metastatic sites and 75 (31%) had visceral metastasis. Ninenty-one (37%) pts received P+LT and 92 (37%) were treated with P+FLV. For 15 (6%) premenopausal pts an LHRH analogue was added to P+ET. In 77 (41%) patients a biopsy of a metastatic lesion was performed. Among the 116 pts treated in first-line setting, median PFS was 14.7 (95% CI 12.0-17.3) and 15.1 (95%CI 8.6-21.6) months for pts receiving P+LT and P+FLV, respectively. ORR was 48% (95% CI: 39-57%) and CBR was 75% (95% CI, 66-82%). Four (3%) complete responses (CR), 52 (45%) partial responses (PR), 31 (27%) stable disease (SD) and 11 (9%) progression disease (PD) were observed as best response; 18 pts were not yet evaluable. Among the 70 pts treated in second-line setting, median PFS was 10.8 (95%CI 0-24.3) and 7.9 (95%CI 3.3-12.5) months, for pts receiving P+LT and P+FLV, respectively. The ORR was 26% (95% CI: 16-38) and the CBR was 66% (95% CI, 53-76). One CR (1%), 17 PR (24%), 28 SD (40%) and 13 PD (18.5%) were observed as best response, while 9 were not yet evaluable. Best response was achieved after a median of 5 cycle. At time of the current analysis, 50 pts experienced PD during P+ET. Of them, 38 (76%) received chemotherapy (capecitabine, eribulin, nab-paclitaxel, paclitaxel+bevacizumab, vinoreline) and 12 (24%) ET. To date, only 5 pts progressed during these therapies, preventing us for evaluating secondary end-points regarding efficacy and activity. The most frequent adverse event (AE) was grade 3-4 neutropenia (31%), with febrile neutropenia reported in 5 (2%) cases. Main non-hematological AEs were fatigue and gastrointestinal symptoms (diarrhea and stypsis). Conclusions: Our findings confirm the efficacy and safety of P+ET as first/second-line treatment for HR+/HER2- MBC pts, even in a non-selected, real world population. Since data regarding the efficacy and activity of post-progression therapies were not mature at the time of the current analysis, they will be subsequently presented. Citation Format: Alessandra Fabi, Michelangelo Russillo, Mariangela Ciccarese, Simone Scagnoli, Francesco Schettini, Giuseppe Buono, Vito Lo Russo, Grazia Arpino, Rosalba Rossella, Giuseppina Sarobba, Marianna Giampaglia, Patrizia Pellegrini, Simonetta Stani, Michela Palleschi, Vincenzo Adamo, Francesca Morelli, Maria Agnese Fabbri, Cecilia Nistico, Gianluigi Ferretti, Giovanna Catania, Simona Pisegna, Diana Giannarelli, Francesco Cognetti. Real-world evidence of efficacy and activity of palbociclib plus endocrine therapy and post-progression treatments in HR+/HER2- metastatic breast cancer patients: The PALPract study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-18.

Olaparib as maintenance therapy in patients with BRCA 1–2 mutated recurrent platinum sensitive ovarian cancer: Real world data and post progression outcome

ObjectivesOlaparib is approved as maintenance therapy in patients with BRCA mutated platinum sensitive (PS) recurrent ovarian cancer (OC) after response to last platinum based therapy. Few data are available regarding the use out of the registration trials and on response to further treatments after progression. Materials ad methodsIn this non interventional, retrospective study, patients treated with olaparib in 13 centers, according to the label, have been collected and analyzed. Primary objectives of the study are to describe effectiveness and safety of olaparib in a real world setting with a focus on post progression treatments and response. Results234 patients were analyzed. All patients were BRCA mutated and most of them had germline mutations. Around 50% of the patients received olaparib after 3 or more lines of platinum based chemotherapy achieving a radiologic complete (CR) or partial response. 12.4% patients with stable disease were also included. Median PFS was 14.7 months (95% CI:12.6–18), with statistically longer PFS in patients with normal serum Ca125 at baseline, a CR after last platinum based therapy and that received olaparib after second platinum based therapy. Median OS was not reached. Most frequent G3-G4 toxicity was anaemia (6%) with dose discontinuation and dose reduction in 11 (4.7%) and 49 (20.9%) of cases, respectively. Among 66 patients receiving further treatment after olaparib progression and evaluable for response, ORR was 22.2, 11.1% and 9.5% in patients with Platinum Free interval (PFI) of more than 12 months, between 6 and 12 months and less than 6 months, respectively. ConclusionsOlaparib is effective and safe in real world setting. Data on post-progression treatments seem to suggest cross resistance with chemotherapy and need to be confirmed in larger studies because of the potential importance in clinical practice decisions.

Osimertinib beyond disease progression in T790M EGFR-positive NSCLC patients: a multicenter study of clinicians' attitudes.

In most cases, T790M EGFR-positive NSCLC patients receiving osimertinib developed "non-drugable" progression, as the patients with common EGFR-sensitizing mutations were treated with first-line osimertinib. In both settings, chemotherapy represents the standard treatment and local ablative treatments (LATs) are potential useful options in the case of oligo-progression. We conducted a study on "post-progression" (pp) outcomes of T790M EGFR-positive NSCLC patients treated with osimertinib, according to the therapeutic strategy applied: osimertinib beyond progression (± LATs), "switched therapies" or best supportive care only (BSC). 144 consecutive patients were evaluated: 53 (36.8%) did not received post-progression treatments (BSC), while 91 (63.2%) patients received at least 1 subsequent treatment; 50 patients (54.9%) received osimertinib beyond disease progression [19 (20.9%) of them with adjunctive LATs] and 41 (45.1%) a switched therapy. Median ppPFS (progression-free survival) and median ppOS (overall survival) of patients who received osimertinib beyond progression vs. switched therapies were 6.4months vs. 4.7months, respectively [HR 0.57 (95% CI 0.35-0.92), p = 0.0239] and 11.3months vs 7.8months, respectively [HR 0.57 (95% CI 0.33-0.98), p = 0.0446]. Among patients who received osimertinib beyond progression with and without LATs median ppPFS was 6.4months and 5.7months, respectively [HR 0.90 (95% CI 0.68-1.18), p = 0.4560], while median ppOS was 20.2months and 9.9months, respectively [HR 0.73 (95% CI 0.52-1.03), p = 0.0748]. At the univariate analysis, the only factor significantly related to the ppPFS was the therapeutic strategy in favor of osimertinib beyond progression (± LATs). Moreover, the only variable which was significantly related to ppOS at the multivariate analysis was osimertinib beyond progression (± LATs). Our study confirmed that in clinical practice, in case of "non-druggable" disease progression, maintaining osimertinib beyond progression (with adjunctive LATs) is an effective option.

Clinical Modality of Resistance and Subsequent Management of Patients with Advanced Non-small Cell Lung Cancer Failing Treatment with Osimertinib.

BackgroundThe third-generation epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) osimertinib has become the standard treatment for patients with pretreated EGFR-mutated non-small cell lung cancer (NSCLC) who acquire the T790M resistance mutation. However, no standard treatment after osimertinib failure has been established.ObjectiveThis study was undertaken to explore the clinical resistance modality upon failure of osimertinib therapy and to assess post-progression treatments in a real-world setting.Patients and MethodsMedical data were retrospectively collected in our cancer center of patients with advanced NSCLC treated between 1 March 2017 and 1 July 2018, and who developed resistance to osimertinib.ResultsA total of 65 patients were analyzed. Clinical resistance modality varied among patients: 15 (23.1%) with local progression, 29 (44.6%) with gradual progression, and 21 (32.3%) with dramatic progression. Most patients experienced intrathoracic progression only (40/65, 61.5%), while ten (15.4%) cases presented intracranial failure only. Upon progressive disease, 20 patients (30.8%) received subsequent chemotherapy, and showed a trend for longer median overall survival (OS) than in those receiving a non-chemotherapy regimen (25.0 vs. 11.8 months, p = 0.106). Thirty-nine patients (60.0%) continued osimertinib beyond progression with a median post-progression treatment duration of 4.1 months. No significant difference in median OS was seen between patients who continued osimertinib and those who discontinued osimertinib (18.9 vs. 15.1 months, p = 0.802). In subgroup analyses, OS was improved in patients who experienced dramatic progression and were treated with chemotherapy, but data were immature for patients with local or gradual progression.ConclusionsChemotherapy could be an effective option after osimertinib failure in unselected patients.

Do Surrogate Endpoints Better Correlate with Overall Survival in Studies That Did Not Allow for Crossover or Reported Balanced Postprogression Treatments? An Application in Advanced Non–Small Cell Lung Cancer

BackgroundIn previous studies, correlation between overall survival (OS) and surrogate endpoints like objective response rate (ORR) or progression-free survival (PFS) in advanced non-small cell lung cancer (NSCLC) was poor. This can be biased by crossover and postprogression treatments. ObjectivesTo evaluate the relationship between these two surrogate endpoints and OS in advanced NSCLC studies that did not allow for crossover or reported balanced post-progression treatments. MethodsA systematic review in patients with advanced NSCLC receiving second- and further-line therapy was performed. The relationship between the absolute difference in ORR or median PFS (mPFS) and the absolute difference in median OS (mOS) was assessed using the correlation coefficient (R) and weighted regression models. The analysis was repeated in predefined data cuts based on crossover and balance of postprogression treatments. When the upper limit of R’s 95% confidence interval (CI) was more than 0.7, the surrogate threshold effect (STE) was estimated. ResultsIn total, 146 randomized clinical trials (43,061 patients) were included. The mean ORR, mPFS, and mOS were 12.2% ± 11.2%, 3.2 ± 1.3 months, and 9.6 ± 4.1 months, respectively. The correlation coefficients of ORR and mPFS were 0.181 (95% CI 0.016–0.337) and 0.254 (95% CI 0.074–0.418), respectively, with mOS. Nevertheless, in trials that did not allow crossover and reported balanced postprogression treatments, the correlation coefficients of ORR and mPFS were 0.528 (95% CI 0.081–0.798) and 0.778 (95% CI 0.475–0.916), respectively, with mOS. On the basis of STE estimation, in trials showing significant treatment effect size of 41.0% or more ORR or 4.15 or more mPFS months, OS benefit can be expected with sufficient certainty. ConclusionsCrossover and postprogression treatments may bias the relationship between surrogate endpoints and OS. Presented STE calculation can be used to interpret treatment effect on either ORR or PFS when used as primary endpoints.

Objective response rate and progression-free survival as surrogate endpoints for overall survival and the impact of crossover and unbalanced post-progression treatments: A systematic review and meta-analysis in second- and further-line therapy of advanced non-small cell lung cancer.

e20609 Background: Correlations between overall survival (OS) and objective response rate (ORR) or progression-free survival (PFS) are poor. We aimed to evaluate the impact of crossover and unbalanced subsequent treatments on ORR and PFS as surrogate endpoints for OS in patients with advanced NSCLC receiving second- and further-line therapy. Methods: A systematic literature review of randomized clinical trials of systemic treatment for patients with stage IIIB/IV NSCLC receiving second- and further-line therapy was performed. Weighted (by trial size) linear regression models were fitted with the absolute difference in ORR or median PFS as an independent variable and the absolute difference in median OS as a dependent variable. The analysis was repeated in predefined subsets based on crossover and balance of post-progression therapies. Surrogate threshold effect (STE) was estimated using prediction intervals. Results: 146 trials (43,061 patients) fulfilled the eligibility criteria. In all treatment arms, the mean ORR, median PFS, and median OS were 12.2% (standard deviation [SD] 11.2%), 3.2 months (SD 1.3), and 9.6 months (SD 4.1), respectively. ORR and PFS had very weak (R = 0.181; 95% CI: 0.016-0.337) and weak (R = 0.254; 95% CI: 0.074-0.418) relationships, respectively, with OS. However, within trials that did not allow crossover and reported balanced post-progression treatments, ORR and PFS had moderate (R = 0.528; 95% CI: 0.081-0.798) and strong (R = 0.778; 95% CI: 0.475-0.916) relationships, respectively, with OS. STE estimation indicated that trials that show statistically significant treatment effect size of ≥41.0% ORR or ≥4.15 median PFS months can be expected to show significant OS benefit with sufficient certainty. Conclusions: Surrogacy of ORR and PFS for OS might be better estimated in trials that do not allow crossover and report balanced post-progression treatments. Presented STE calculation can be used to estimate the expected effect on OS when either ORR or PFS are used as primary endpoints.

Objective response rate and progression-free survival as surrogate endpoints for overall survival and the impact of crossover and unbalanced post-progression treatments: A systematic review and meta-analysis in first-line therapy of advanced non-small cell lung cancer.

9049 Background: Correlations between overall survival (OS) and objective response rate (ORR) or progression-free survival (PFS) are poor. We aimed to evaluate the impact of crossover and unbalanced subsequent treatments on ORR and PFS as surrogate endpoints for OS in patients with advanced NSCLC receiving first-line therapy. Methods: A systematic literature review of randomized clinical trials of systemic treatment for patients with stage IIIB/IV NSCLC receiving first-line therapy was performed. Weighted (by trial size) linear regression models were fitted with the absolute difference in ORR or median PFS as an independent variable and the absolute difference in median OS as a dependent variable. The analysis was repeated in predefined subsets based on crossover and balance of post-progression therapies. Surrogate threshold effect (STE) was estimated using prediction intervals. Results: 317 trials (78,644 patients) fulfilled the eligibility criteria. In all treatment arms, the mean ORR, median PFS, and median OS were 28.2% (standard deviation (SD) = 12.4%), 5.1 months (SD = 2.1), and 10.4 months (SD = 2.5), respectively. ORR and PFS had weak (R = 0.351; 95% CI: 0.251-0.443) and (R = 0.397; 95% CI: 0.267-0.512) associations with OS, respectively. However, within phase III trials that did not allow crossover and reported balanced post-progression treatments, both ORR and PFS had stronger associations with OS (ORR and OS: R = 0.601, 95% CI: 0.399-0.747; PFS and OS: R = 0.695, 95% CI: 0.446-0.844). STE estimation indicated that trials that show statistically significant treatment effect size of ≥43% ORR or ≥3.2 median PFS months can be expected to show significant OS benefit with sufficient certainty. Conclusions: Surrogacy of ORR and PFS for OS might be better estimated in trials that do not allow crossover and report balanced post-progression treatments. Presented STE calculation can be used to estimate the expected effect on OS when either ORR or PFS are used as primary endpoints.