Post-progression Survival Research Articles

Systemic and Oligo-Acquired Resistance to PD-(L)1 Blockade in Lung Cancer.

Clinical patterns and the associated optimal management of acquired resistance to PD-(L)1 blockade are poorly understood. All cases of metastatic lung cancer treated with PD-(L)1 blockade at Memorial Sloan Kettering were reviewed. In acquired resistance (complete/partial response per RECIST, followed by progression), clinical patterns were distinguished as oligo (OligoAR ≤ 3 lesions of disease progression) or systemic (sAR). We analyzed the relationships between patient characteristics, burden/location of disease, outcomes, and efficacy of therapeutic interventions. Of 1,536 patients, 312 (20%) had an initial response and 143 developed AR (9% overall, 46% of responders). OligoAR was the most common pattern (80/143, 56%). Baseline tumor mutational burden, depth of response, and duration of response were significantly increased in oligoAR compared with sAR (P < 0.001, P = 0.03, P = 0.04, respectively), whereas baseline PD-L1 and tumor burden were similar. Post-progression, oligoAR was associated with improved overall survival (median 28 months vs. 10 months, P < 0.001) compared with sAR. Within oligoAR, post-progression survival was greater among patients treated with locally-directed therapy (e.g., radiation, surgery; HR, 0.41; P = 0.039). Fifty-eight percent of patients with oligoAR treated with locally-directed therapy alone are progression-free at last follow-up (median 16 months), including 13 patients who are progression-free more than 2 years after local therapy. OligoAR is a common and distinct pattern of acquired resistance to PD-(L)1 blockade compared with sAR. OligoAR is associated with improved post-progression survival and some cases can be effectively managed with local therapies with durable benefit.

P1713: VENETOCLAX IN COMBINATION WITH OBINUTUZUMAB IN FIRST LINE CHRONIC LYMPHOCYTIC LEUKEMIA IN ARGENTINA: A COST-EFFECTIVENESS ANALYSIS

Background: The efficacy of venetoclax plus obinutuzumab (VenG) was examined in the CLL14 clinical trial, in unfit Chronic Lymphocytic Leukemia (CLL) patients who have not been previously treated. Aims: The aim of the study was to estimate the cost-effectiveness of VenG in the treatment of first-line unfit CLL patients in Argentina Methods: A three-state partitioned-survival model (with health states of progression-free survival (PFS), post-progression survival (PPS) and death), developed in accordance with NICE and ISPOR decision modelling guidelines, was adapted to Argentina setting and was used to estimate the accumulated costs and outcomes in terms of life years (LY) and quality-adjusted life years (QALY). A 30-year time horizon and the Social Security’s payer’s perspective were assumed. Cost-effectiveness was estimated by comparing a 12-month fixed duration of VenG versus (vs.) chlorambucil-obinutuzumab (ClbG) based on the CLL14 clinical trial. Other comparators included treat-to-progression therapies, such as ibrutinib (IBR), and a 6-month course of bendamustine + rituximab (BR). Using a network meta-analysis, the relative efficacy of VenG and ClbG vs. other selected comparators was estimated. Health state utilities and adverse event (AE) disutilities were derived from a systematic literature review and published health-technology assessment reports. To generate total quality-adjusted life years (QALYs), these health state utilities and AE disutilities were applied to the relative efficacy data. The cost of medication was based on country level drug prices. The healthcare resources used were validated by local experts through a Delphi panel methodology. Costs of resources used for routine medical attention and the management of adverse events were based on tariffs from social security system of Argentina. Costs were expressed in Argentine Pesos (AR$) (exchange rate 1 US dollars ($) = 100.75AR$, July 2021). A 5% annual discount rate was applied for costs and outcomes. Cost-effectiveness results are presented in terms of incremental cost per QALY. A new treatment that is both lower in total cost and more efficacious (in QALYs) vs. identified comparator treatments is described as being “dominant”. Uncertainty in the model was tested through one-way sensitivity analyses (OWSA) and probabilistic sensitivity analyses (PSA) Results: Over a 30-year time horizon, the total discounted costs were, for VenG, $117,250.19; ClbG, $167,675.26; BR, $206,951.64; and IBR, $432,243.36. The benefits in the cost-effectiveness model (CEM) were measured in terms of total discounted QALYs which were 5.634 for VenG, 5.350 for ClbG, 4.996 for BR and 5.161 for IBR. The incremental discounted QALYs of VenG was: 0.284 vs. ClbG, 0.639 vs. BR, and 0.473 vs. IBR. Thus, VenG with a 12-month fixed duration, has lower total costs and is more efficacious (“dominant”) over all comparators in the CEM. OWSA analyses show that the results are robust, and in the PSA VenG is dominant over all the comparators considered, ICER is ≤$ 6,011.20 (1 GDP per capita for Argentina, 2020), /QALY in 97% of the iterations CE Results - VenG ClbG BR IBR Costs $ 117,250.19 $ 167,675.26 $ 206,951.64 $ 432,243.36 LYs 12.80 12.80 11.88 11.88 QALYs 5.634 5.350 4.996 5.161 Incremental cost (vs VenG) $ -50,425.06 $ -89,701.44 $ -314,993.17 Incremental QALYs 0.284 0.639 0.473 Cost/QALYs gained Dominant Dominant Dominant Summary/Conclusion: This study shows that in Argentina, VenG would be dominant treatment option (better results and lower costs) compared with ClbG, BR and IBR in the treatment of first-line unfit CLL patients.

Abstract 6138: High Globo-H expression associated with poor survival of gastric cancer patients and enriched PD-L1 expression

Abstract Background: Globo series antigens have been implicated in playing important roles in enhancing tumor growth through protecting tumor cells from apoptosis, suppressing T cell activity in the tumor microenvironment and promoting endothelial cell angiogenesis. Globo-H (GH), a globo-series glycosphingolipid (GSL) antigen that is synthesized by key enzymes β1,3-galactosyltransferase V (β3GalT5), fucosyltransferase (FUT) 1 and 2, is highly expressed on a variety of epithelial cancers rendering it a promising target for cancer immunotherapy. GH is reported to associate the EGFR mutant and PD-L1 expression in non-small cell lung cancer (NSCLC) patients. In addition, GH-targeting antibody-drug conjugate (ADC) OBI-999 has been demonstrated an excellent tumor growth inhibition potency in animal models across multiple cancer types including gastric cancer (GC). This study aims to further investigate the GH roles in GC. Methods: Prognostic roles of β3GalT5, FUT1 and FUT2 in GC patients were accessed through the “Kaplan-Meier plotter” database. The level of GH expression was evaluated in clinical adenocarcinoma samples from 105 patients with GC by immunohistochemistry (IHC) using H-score. Microwestern protein array analysis was performed in sorted GC NCI-N87 cells. FACS methods were also employed to measure the levels of PD-L1 and phospho-EGFRs in multiple cancer cell lines. Results: Significant correlations were observed between high mRNA expression of synthesized key enzymes and worse overall survival (OS)/post-progression survival for all 498 GC patients. Positive GH expression (H score≥20; 33.3%) was significantly associated with a poor disease specific survival in all samples (at 15 years; p=0.029), a poor OS in poorly differentiated tumors (p=0.033), and invasiveness (p=0.013), indicating GH expression was a potential prognostic factor in GC. Sorted NCI-N87 cells with high level of endogenous GH expression showed a relatively greater proliferative activity compared with cells expressing low level of GH. Microwestern array analysis on sorted cells indicated upregulations of phospho-AKT/P38/JNK, Cyclin D1 and Cyclin E1 protein in high GH expression NCI-N87 cells, which implicated a mechanistic link between high GH and tumor promoting signals in GC. In addition, GH level was shown to be correlated with cell surface expression level of PD-L1 in NCI-N87, SNU-16, HCC-1428, ACHN, and TKI-resistant H1975 NSCLC cancer cells. Higher phospho-EGFRs (Tyr1068 and Tyr1173) were detected in high GH level of H1975 cells, which is consistent with the results from previous studies showing association between GH level and EGFR mutant/PD-L1 expression in NSCLC. Conclusions: GH level was associated with the survival of GC patients and positively correlated with cell surface PD-L1 expression in vitro. Therefore, GH-targeting therapy has a potential application for the treatment of GC patients. Citation Format: Tzer-Min Kuo, Hui-Ting Hsu, Cheng-Yen Wei, Ming-Tain Lai, Chun-Te Chen. High Globo-H expression associated with poor survival of gastric cancer patients and enriched PD-L1 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6138.

Mechanisms of Resistance to First-Line Osimertinib in Hispanic Patients With EGFR Mutant Non-Small Cell Lung Cancer (FRESTON-CLICaP)

IntroductionOsimertinib is a third generation EGFR-TKI inhibitor approved in the first-line setting for patients with advanced non-small cell lung cancer (NSCLC). Additionally, it represents the treatment of choice in patients who present with T790M mutations and evidence of relapse of the disease. Effectiveness and safety of this drug have been studied in multiple clinical trials and observational studies, however, information regarding outcomes among Hispanic patients treated with Osimertinib is scarce. The objective of this study was to examine real-world effectiveness and safety of first-line Osimertinib in a cohort of Hispanic patients with NSCLC, emphasizing post-progression outcomes. MethodsThis is a multicenter, multinational, retrospective cohort study of Hispanic patients treated with Osimertinib as first-line for EGFR-mutated NSCLC. Patients with a confirmed diagnosis of metastatic EGFR-mutated NSCLC who received Osimertinib (80mg/day until evidence of disease progression or presence of intolerable adverse effects) were identified and included. NGS was performed in tumor samples or liquid biopsies among patients who had disease progression. The primary outcome was progression-free survival, and the secondary outcome was post-progression survival. ResultsA total of 94 patients from Mexico, Argentina, Costa Rica, Colombia, Panama, Chile and the USA were included, with a median age of 59 years. Identified mutations included EGFR Exon 19 deletions and EGFR pL858R point mutations. Median progression-free survival (PFS) was 14.4 months (95%CI 12.4–18.2 months). Lung/pleura and lymph nodes were the most common sites of progression. Median post-progression survival was 7.73 months (95%CI 4.07 months-Not reached). Factors which negatively affected PFS included presence of liver metastases at diagnosis and a tumor mutational burden > 5 mut/Mb. ConclusionTreatment with first line osimertinib represents an effective and safe option for Hispanic patients with metastatic NSCLC. Liver metastases and a higher tumor mutation burden were associated with a lower PFS. Despite effectiveness, different mechanisms of resistance were identified among the patients in this cohort, including mutations which can be targeted by other therapeutic options.

EPEN-17. Recurrent infratentorial ependymomas in children: a meta-analysis on molecular-based outcomes

Abstract The overall prognosis of infratentorial ependymoma differs based on molecular signature, however the impact of recurrence on prognosis remains poorly defined in the pediatric population. PubMed, Scopus, Embase, and Ovid were searched for publications on recurrent infratentorial ependymomas in patients under 25 years of age. Exclusion criteria were case series of less than 5 patients and studies that did not provide individualized patient data. Our search yielded 472 unique articles, of which 17 were included in the analysis. There was a total of 460 recurrent ependymomas reported, with 52.8% WHO grade II tumors and 47.2% grade III. The overall mortality for recurrent infratentorial ependymoma was 49.1% (226/460). The pooled median survival was 32.39 months after recurrence (95% CI: 23.45-41.33). Gross total resection was achieved in 237 (53.1%) patients at initial presentation. Raw mean survival post-recurrence was 32.9 months (SD: 11.2 months) for those who received GTR for their primary tumor versus 23.7 months (SD: 10.8 months) for those who received subtotal resection (STR) (p &amp;lt; 0.001). There was no difference in survival between those that received GTR (49.3 months, 95% CI: 32.3-66.3) versus STR (41.4 months, 95% CI: 11.6-71.2) of their recurrent tumor (p=0.610). In the studies that provided molecular classification, there were 169 PFA tumors (83.3%) and 34 PFB (16.6%), with 28 that demonstrated 1q gain. PFA-A tumors demonstrated worse post-progression survival (24.7 months, 95% CI: 15.3-34.0) compared to PF-B (48.0 months, 95% CI: 32.8-63.2) (p=0.0073). The average post-recurrence survival for tumors with 1q gain was 5.93 months (SD: 9.15). The overall mortality rate for recurrent infrantentorial ependymomas was found to be 49.8%, with a pooled median survival of 32.39 months. Almost 90% of recurrent infratentorial ependymomas were of the PFA molecular subtype, and those tumors that demonstrated 1q gain had a worse survival than those that did not.

Validity and efficiency of progression-free survival (PFS)-2 as a surrogate endpoint for overall survival (OS) in advanced cancer.

6518 Background: PFS is used widely as a primary endpoint in oncology trials and as a surrogate for OS. PFS-2, defined as time from randomization to progression on second line therapy, is potentially a more reliable surrogate than PFS but requires additional follow-up time. We evaluated the validity and efficiency of PFS-2 as a surrogate endpoint for OS and compared its performance with PFS. Methods: We performed an electronic search to identify randomized trials of advanced solid tumors reporting on PFS, PFS-2 and OS as pre-specified endpoints. We compared the correlations in the relative treatment effect for OS with PFS and PFS-2. We extracted data from Kaplan-Meier survival curves to create individual patient data to estimate time to statistical significance (TSS), defined as logrank P &lt; 0.05. We further computed the samples size (person-year follow-up) required to reach statistical significance and assessed for the effect of survival post-progression (SPP). If trials failed to reach statistical significance for a particular endpoint, the maximal follow-up time was used. Results: Our study consisted of 39 analysis units with 20714 patients. Correlations of the OS treatment effect with the PFS and PFS-2 treatment effects were r= 0.12 (95% CI 0.00-0.13) and r= 0.67 (95% CI 0.08-0.69) respectively. The median differences in TSS between OS with PFS, OS with PFS-2, and PFS2 with PFS were 8.7, 8.4, and 3.2 months respectively. For trials with a SPP &lt; 12 months, smaller differences in the median TSS as compared to SPP ≥12 months were seen. The median differences in follow-up required to reach statistical significance were 329, 151 and 122 person-years (PY) respectively. These differences were equivalent to a median 18.3% increase in sample size required for PFS-2 over PFS. The median increase in sample sizes were 18.2% and 22.3% for trials with SPP &lt; 12 and ≥12 months respectively. Conclusions: PFS-2 has a stronger correlation with OS benefit than PFS. When PFS-2 is used as primary endpoint, trials will require an additional median 3.2 months to achieve statistical significance, and an additional 18.3% increase of sample size over PFS. PFS-2 balances between improved correlation with OS but modest increase in follow-up time and sample size. PFS-2 should therefore be considered as a primary endpoint in future trials of advanced cancers.[Table: see text]

Bevacizumab Combined with Continuation of EGFR-TKIs in NSCLC Beyond Gradual Progression.

ObjectiveContinuation of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has shown potential in prolonging survival in patients with non-small cell lung cancer (NSCLC) harboring EGFR mutation who had gradual progression at initial targeting therapy. However, it remains unknown whether the combination of bevacizumab and continuation of EGFR-TKIs would benefit this subpopulation. This study retrospectively explored the effect of bevacizumab combined with EGFR-TKIs in NSCLC beyond gradual progression in the real-world setting.MethodsThe records of 48 patients were reviewed who received bevacizumab and continuation of EGFR-TKIs beyond gradual progression at initial targeting therapy. The response to the treatment and post progression survival (PPS) were reviewed and analyzed.ResultsThe median PPS was 11.4 months (95% CI 7.368–15.492) for all patients included at the median follow-up time of 17.3 months. The objective response rate (ORR) was 8.3%, and the disease control rate (DCR) was 86.1% (with 3 partial response and 28 stable disease) in 36 patients who were evaluable for response with at least one measurable lesion. Univariate Cox analysis showed that age <60, male sex, and EGFR exon19 deletion mutation were associated with longer PPS (P<0.05). Patients harboring EGFR exon19 deletion mutation had significantly longer PPS than those with EGFR exon21 L858R mutation, with an mPPS of 15.5 months and 5.7 months, respectively (HR=0.251, 95% CI 0.112–0.561, P=0.019). Multivariate Cox analysis indicated that age <60 and EGFR exon19 deletion mutation were associated with longer PPS (P<0.05).ConclusionContinuation of EGFR-TKI with the combination of bevacizumab is a reasonable strategy in NSCLC patients beyond gradual progression in previous EGFR-TKI treatment. Younger patients with EGFR exon19 deletion mutation may benefit more from the combination therapy.

P-56 Estimating endpoint correlation between surrogate measures and overall survival using reconstructed survival data: Case studies from adjuvant and metastatic gastric cancer trials

Validation of intermediate endpoints such as disease-free survival (DFS) and progression-free survival (PFS) as surrogate predictors for overall survival (OS) in randomized controlled trials (RCTs) requires establishing their association at the individual-level. In the absence of individual-level patient data (IPD), this study developed an analytical framework to estimate this association between DFS/PFS and OS using reported Kaplan-Meier (KM) curves from the RCTs and demonstrated its predictive performance in adjuvant and metastatic gastric cancer (GC) treatment settings. Assuming a three-state illness-death model for cancer survival, we developed a linear optimization model to elicit the underlying pre-progression death probability as well as post-progression survival (PPS) distribution using pseudo-patient level DFS/PFS and OS data reconstructed from the published KM curves. In the adjuvant setting, pre-progression death probability was bounded below by the cure rates which were estimated by fitting mixture cure models (MCMs) to the DFS data. In the MCMs, time-to-event outcomes for the uncured subpopulation were modeled using parametric survival functions suggested by National Institute for Health and Care Excellence (NICE) and non-disease-related mortality rates were derived from the age- and sex-adjusted local life-table data from World Health Organization. Reconstructed DFS/PFS distributions were extrapolated via parametric- and spline-based models suggested by NICE and adjusted with estimated background mortality rates whereas elicited PPS distributions were extrapolated assuming constant hazard rate over time. Estimated pre-progression death probabilities and modeled DFS/PFS/PPS distributions governed a Monte-Carlo simulation framework which generated paired pseudo pre- and post-progression data to predict Spearman’s rank and Pearson’s product moment correlation coefficients. Model performance was tested on two correlation meta-analyses in GC (14 RCTs with 3371 patients on adjuvant chemotherapy; 20 RCTs with 4069 patients on metastatic treatments) published in 2013 by the GASTRIC group. For each test case, model-predicted OS rates and Spearman rank correlation coefficients were compared against their reported counterparts and corresponding 95% CIs. Predicted OS curves laid within the 95% CIs of the reported OS KM-curves 96% and 100% of the time in the adjuvant and metastatic setting, respectively, where the average deviation between the restricted mean survival times under the model-predicted OS curves and the statistically best-fitting OS curves to the reported data was < 1% in both settings. Average deviation between the estimated and reported Spearman rank correlation coefficients was no more than 0.01 (reported: 0.97 [95% CI:0.97-0.98] vs. predicted: 0.96 [95% CI:0.96-0.96]) and 0.13 (reported: 0.85 [95% CI:0.85-0.85] vs. predicted: 0.72 [95% CI:0.71-0.72]) in both settings. Predicted Pearson correlation coefficients were 0.95 [95% CI:0.95-0.95] and 0.94 [95% CI:0.94-0.95] in the adjuvant and metastatic setting, respectively. Our study offers a useful approach for an indirect endpoint correlation assessment in the absence of IPD. Results indicate the model to be precise in adjuvant but conservative in metastatic GC setting which should be approached with caution due to independent simulation of paired DFS/PFS and PPS durations from the illness-death model and the lack of data-driven lower bounds on pre-progression death probability in the metastatic setting.

Dynamic changes in RAS gene status in circulating tumour DNA: a phase II trial of first-line FOLFOXIRI plus bevacizumab for RAS-mutant metastatic colorectal cancer (JACCRO CC-11)

BackgroundFew prospective studies have used liquid biopsy testing in RAS-mutant metastatic colorectal cancer (mCRC), and its clinical significance remains unknown. Therefore, this study aimed to carry out a biomarker analysis by liquid biopsy using updated data of the phase II trial of FOLFOXIRI plus bevacizumab as first-line chemotherapy for RAS-mutant mCRC.Materials and methodsA total of 64 patients who received modified FOLFOXIRI regimen (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, levofolinate 200 mg/m2, and fluorouracil 2400 mg/m2) plus bevacizumab biweekly were enrolled. The primary endpoint was the objective response rate (ORR). Plasma samples were collected at pre-treatment, 8 weeks after treatment, and progression in participants included in the biomarker study. The levels of circulating tumour DNA (ctDNA) and specific KRAS and NRAS variants were evaluated using real-time PCR assays.ResultsThere were 62 patients (median age: 62.5 years, 92% performance status 0, 27% right side) who were assessable for efficacy and 51 for biomarker analysis. ORR was 75.8% (95% confidence interval 65.1% to 86.5%). The median progression-free survival was 12.1 months, and the median overall survival (OS) was 30.2 months. In 78% of patients, RAS mutations disappeared in the ctDNA at 8 weeks after treatment; these patients tended to have better outcomes than those with RAS mutations. Interestingly, RAS mutations remained undetectable during progression in 62% of patients. Survival analysis indicated that the median OS from progression was significantly longer in patients with RAS mutation clearance than in those with RAS mutation in the ctDNA at disease progression (15.1 versus 7.3 months, hazard ratio: 0.21, P = 0.0046).ConclusionsOur biomarker study demonstrated no RAS mutations in ctDNA at disease progression in 62% of patients with RAS-mutant mCRC. Both OS and post-progression survival were better in patients with clearance of RAS mutations in ctDNA after triplet-based chemotherapy.

Identification of pretreatment genomic biomarkers and mechanisms of acquired resistance to first-line osimertinib in advanced EGFR-mutant lung cancers.

9100 Background: Despite its widespread use, few series explore genomic biomarkers that impact progression-free survival (PFS) for first line osimertinib use and how mechanisms of acquired resistance impact post-osimertinib progression survival. Methods: All pts treated with first line osimertinib at Memorial Sloan Kettering Cancer Center were identified; available pre-osimertinib and post-progression tumor samples underwent next-generation sequencing (NGS) using MSK-IMPACT. Real-world (rw)PFS was estimated with Kaplan-Meier methods from start of osimertinib to progression, defined using interpretation of imaging reports. Post-baseline factors were evaluated using time-dependent covariate Cox model. Results: We identified 331 pts, of which 67 had paired tumor samples and 28 had post-progression tumor samples that underwent MSK-IMPACT. Most pts with biopsies were women (68%), never smokers (83%) and did not have baseline brain metastases (56%). With median follow-up of 24 months (mo), median rwPFS was 14 mo (95% confidence interval (CI) 13 -17 mo, n = 331). EGFR driver alterations (n = 40 atypical, n = 108 L858R, n = 182 exon 19 deletion) were associated with distinct rwPFS (median 8 (95% CI 6-12), 14 (12-18) and 16 mo (13-21), respectively, p &lt; 0.001 logrank test). Pts with concurrent pre-treatment TP53 (14 mo,12-17) or TP53/RB1 (12 mo, 9-15) alterations had shorter median rwPFS compared to pts without these alterations (20 mo,16-24, p &lt; 0.001, logrank test). Fifty patients (53%) had an identified mechanism of resistance. Off target mechanisms (n = 9 MET amplification (amp), n = 3 HER2 amp, n = 3 PIK3CA mutations, n = 3 acquired fusions, n = 2 RB1 loss and n = 1 CCND1 amp, MYC amp, CDK4 amp, KRAS G12A, respectively) and histological transformation (n = 7 small cell, n = 5 squamous and n = 2 large cell neuroendocrine) were detected. On target acquired mechanisms were EGFR amplification (n = 7), and G724S (n = 2) and C797S (n = 3) mutations. Pts with an identified mechanism of resistance did not have improved post-progression survival (12 mo HR 1.6, p = 0.09), but receiving next line of therapy based on post-progression tumor biopsy results (including platinum-etoposide for transformation) did improve post-progression survival (12 mo HR 0.4, p = 0.01). Conclusions: Pts with atypical EGFR drivers or concurrent TP53+/- RB1 alterations have significantly shorter rwPFS on first line osimertinib, highlighting need for additional interventions for these patients. Given the high frequency of transformation and improvement in post-progression survival by tailoring next line of therapy to the identified mechanism, pts with EGFR-mutant lung cancer on first line osimertinib may benefit from tissue biopsies at progression. For pts without an identified resistance mechanism by NGS, additional methods of interrogating tumors at progression are needed.

Treatment with tebentafusp beyond radiographic progressive disease (PD) in metastatic uveal melanoma (mUM).

9585 Background: Tebentafusp (tebe) is the first T cell receptor therapeutic to demonstrate overall survival (OS) benefit in a randomized Phase 3 study vs investigator’s choice (IC) [ NCT03070392 ]. OS benefit was also observed in patients (pts) with best objective response (BOR) PD (HR 0.43), and in pts who had tumor growth ≥20% as best change in tumor size (HR 0.41), suggesting tebe-treated pts may exhibit atypical radiological responses and could benefit from treatment beyond radiographic progression (TBP), a well-established concept in immuno-oncology. Here we analyzed tumor kinetics and clinical benefit in pts treated with tebe beyond initial radiographic progression (TBP). Methods: 378 mUM pts were randomized 2:1 to tebe vs. IC. BOR was assessed by investigators using RECIST v1.1. TBP was permitted until: 1) additional ≥20% increase in tumor burden with absolute increase of ≥5 mm, or 2) unequivocal PD of non-target lesions; or 3) new non-measurable lesions. A Cox model adjusted for baseline covariates and for covariates at time of progression for TBP-eligible pts was used to compare survival post progression between those who did (TBP) and did not receive TBP (non-TBP). Stepwise selection of covariates (using p &lt; 0.1 as the entry and staying criterion) was applied. Analysis performed on data cut-off 13Oct2020. Results: 183 tebe pts were eligible for TBP per protocol; 60% (109/183) received TBP with median duration of 8 wks. 21% of all tebe doses were administered as TBP. The proportion of pts with new lesions at initial progression (44% vs 57%) and median time to initial progression (2.9 mo vs 2.9 mo) were similar between TBP and non-TBP pts. Pts receiving TBP were more likely to have favorable key prognostic factors at baseline or at time of progression. After adjusting for these differences, a numerical benefit in post-progression OS favoring TBP was observed (HR 0.67, 95% CI [0.38,1.19]). Serial review of radiographic time points identified initial progression of sum of target lesions followed by stabilization for &gt; 3 months after initial progression in some TBP pts. Safety profile during TBP was consistent with that expected for pts established on tebe and no pts experienced an AE leading to treatment discontinuation. Conclusions: An OS benefit observed for tebentafusp among mUM patients who have initial radiographic progression demonstrates that RECIST assessment underestimates benefit. In a post-hoc analysis of OS following initial radiographic progression, continued treatment with tebentafusp was associated with numerically longer OS after adjusting for key prognostic variables. Tebentafusp treatment beyond progression was tolerated without new safety signals and, in some patients, was associated with radiological stabilization of sum of target lesions for &gt; 3 months following the initial progression. Clinical trial information: NCT03070392.

The clinical relevance of tumor RAS/TP53 dual mutation in early and metastatic colorectal cancer (CRC).

3540 Background: The relevance of individual RAS (KRAS and NRAS) and TP53 mutations in CRC is well described, but the impact of the combination of both mutations together is less understood. RAS/TP53-mutant (mut) patients (pts) were selected in FOCUS 4-C for treatment with Adavosertib (Wee1 inhibitor) due to hypothesised sensitivity due to replication stress and loss of cell cycle checkpoint control. Initial analyses in CRC suggest that RAS/TP53-mut pts may be prognostically distinct from either mutation alone. Here we examine the impact of RAS/TP53-mut status in both early stage and metastatic CRC (mCRC). Methods: RAS and TP53 mutational status were assessed by whole gene targeted NGS or PCR in hotspot regions. Pts with RAS/TP53 status in the following studies were included after exclusion of BRAF-V600E mutants and MSI-H cases: for early-stage, QUASAR2 trial (N = 408) and an Australian community cohort (N = 654); for mCRC, FOCUS (N = 373) and FOCUS4 (N = 721). Biomarker prevalence, clinical characteristics and outcome data in the RAS/TP53-mut group were compared to pts not showing dual RAS/TP53-mut. Results: The prevalence of RAS/TP53-mut was greater in mCRC compared to early CRC (43.9% vs 25.4% respectively, p &lt; 0.001). In early-stage (II &amp; III) cohorts combined, RAS/TP53-mut pts were more likely to be female, have a right-sided primary tumour, and involved lymph nodes. In early CRC RAS/TP53-mut pts had worse outcome: DFS HR = 1.49[1.19-1.88], p = 0.001, and OS HR = 1.48[1.16-1.89], p = 0.001. In FOCUS, RAS/TP53-mut mCRC pts had inferior PFS with 1st line chemotherapy than not dual RAS/TP53-mut: 6.9 vs 8.6 months (HR = 1.44[1.17-1.79], p = 0.001), and also shorter post-progression survival (HR = 1.49, p = 0.001), and overall survival (14.9 vs 18.9 mths [HR = 1.60, p &lt; 0.0005]). Consistently, during 16 weeks of induction chemotherapy for mCRC pts in FOCUS4, 27.4% of RAS/TP53-mut pts had progressive disease, compared with 18.4% in not dual RAS/TP53-mut; PFS from study registration was reduced in RAS/TP53-mut (5.3 vs 6.1 mths;HR = 1.53[1.22-1.94],p &lt; 0.001), but no statistically significant difference in OS (13.6 vs 17.6 mths;HR = 1.27,p = 0.23). Outcomes by each of the four biomarker groups (RAS/TP53 dual mut; RASwt/TP53mut; RASmut/TP53 wt; RAS/TP53 dual wt) will be presented but in all cases the dual mut subgroup had the worst outcomes compared to the other three groups, marginally better than BRAF-V600E CRC. Conclusions: RAS/TP53 dual mutation status provides useful and readily available prognostic information in both early and mCRC, independent of MSI and BRAF status. It is associated with increased risk of recurrence in early CRC, and a higher risk of chemotherapy resistance and inferior outcomes in mCRC. Evaluation of treatment strategies in this sizeable patient group and further understanding of the underlying mechanism of poor outcomes are urgently required.

PCMT1 Is a Potential Prognostic Biomarker and Is Correlated with Immune Infiltrates in Breast Cancer.

Background Protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1) is involved in the occurrence and development of a variety of malignant tumors. However, the prognostic value of PCMT1 in breast cancer remains unclear. Methods Based on the Cancer Genome Atlas database, we assessed the correlation between the expression of PCMT1 and prognosis, immune invasion, and tumor mutation burden in a variety of cancers. The expression level, mutation, immune correlation, and coexpression of PCMT1 in breast cancer were studied using the following databases: UALCAN database, Human Protein Atlas database, cBioPortal database, TIMER database, and LinkedOmics database. Kaplan–Meier Plotter was used for survival analysis. Receiver operating characteristic (ROC) curves and nomograms were drawn using the R software package. P < 0.05 was considered statistically significant. Results Pancancer analysis showed that PCMT1 is highly expressed in a variety of cancers and is significantly related to the prognosis of a variety of cancers. PCMT1 is significantly related to the tumor mutation burden of a variety of cancers. PCMT1 is significantly high in breast cancer, and it is significantly related to the abundance of immune infiltration. Survival analysis revealed that high PCMT1 expression is significantly associated with shorter overall survival (OS), relapse-free survival (RFS), and postprogression survival (PPS) in breast cancer patients. ROC curves and nomograms verify the effectiveness of PCMT1 as a prognostic biomarker for breast cancer. Conclusions PCMT1 can be used as a potential prognostic biomarker of breast cancer, and it is significantly related to the abundance of breast cancer immune infiltration.

Progression-free survival at 3 years is a reliable surrogate for 5-year overall survival for patients suffering from locally advanced esophageal squamous cell carcinoma.

BackgroundDespite 3‐year survival being used as a primary endpoint in some randomized controlled trials (RCTs), limited evidence supports the use of intermediate endpoints to evaluate the effect of new therapies in esophageal squamous cell cancer (ESCC). This study aimed to systematically evaluate progression‐free survival at 3 years (3‐year PFS) and overall survival (OS) among patients with ESCC.MethodsWe identified 528 patients newly diagnosed with locally advanced ESCC who received definitive radiotherapy. OS was compared with an age‐ and sex‐matched general Chinese population using the standardized mortality ratio (SMR). Regression analysis was used to validate the correlation between PFS and OS using published data.ResultsThe annual risk of progression decreased to 11.5% after 3 years. Patients who did not achieve 3‐year PFS had a median postprogression survival (PPS) of 7.3 months, with a 5‐year OS rate of 9.6% and a SMR of 15.0 (95% confidence interval [CI], 12.9–17.5). Conversely, the SMR for patients who achieved 3‐year PFS was 0.9 (95% CI, 0.6–1.3). We observed a significant correlation between log hazard ratio (HR) (PFS) and log HR (OS) at the trial level (r = 0.89; 95% CI, 0.88–0.90). The strongest correlation was observed between 3‐year PFS and 5‐year OS in RCTs and retrospective studies.ConclusionsPatients exhibiting progression within 3 years experienced poor survival, whereas patients achieving 3‐year PFS had excellent outcomes. Our study supports 3‐year PFS as a reliable primary endpoint for study design and risk stratification in locally advanced ESCC.

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.

The clinicopathological and prognostic significance of PD-1 expression in cancers: A bioinformatics analysis

Background: Programmed cell death protein 1 (PD-1), which is encoded by PDCD1 gene, is a cell-surface protein of immunoglobin family. A number of published studies have reported the relationship between PD-1 expression and prognosis in cancers. The purpose of our study was to identify an independent prognostic marker. Methods: In the present study, we investigated the prognostic value of PD-1 mRNA expression through the Kaplan&amp;ndash;Meier plotter databases. Results: The expression of PD-1 mRNA was negatively related with the overall survival (OS) rate of gastric cancer, but positively associated with the OS rate of breast cancer, ovarian cancer and liver cancer (P &lt; 0.05). High PD-1 mRNA expression was linked to an improved relapse-free survival rate of breast cancer, ovarian cancer, and liver cancer (P &lt; 0.05). There was a negative correlation with post-progression survival in gastric cancer (P &lt; 0.05). Besides, there was a positive correlation with progression-free survival and disease specific survival in liver cancer. We also further evaluated the prognostic value of PD-1 in relation to different clinicopathological features of cancers. Conclusion: Our results showed that PD-1 expression might be a good marker for the prognosis of patients with cancers, which highlights new methods and ideas for preventive treatment.

Progression Patterns and Post-Progression Survival in Recurred Intrahepatic Cholangiocarcinoma Patients: A Novel Prognostic Nomogram Based on Multicenter Cohorts.

BackgroundThe post-progression survival (PPS) of recurred intrahepatic cholangiocarcinoma (iCCA) patients relates to the characteristics of tumor progression. Moreover, the prediction model of PPS in those patients has not been well established. This study aimed at developing a novel nomogram for predicting PPS in recurred iCCA patients.MethodClinical characteristics were retrospectively collected in 396 patients diagnosed with iCCA from cohorts of Sun Yat-sen University Cancer Center (SYSUCC) and the First Hospital of Dalian Medical University (FHDMU). The PPS in patients with different progression patterns was investigated. The nomogram of PPS was established with the Cox regression model in the primary cohort. Then the nomogram was verified in the external validation cohort.ResultsLiver progression was the commonest pattern (42.08%) in recurred iCCA patients, while patients with local LN progression had significantly better PPS than those with other patterns. The independent prognostic factors comprised elevated CEA levels, tumor differentiation, N stage 8th, adjuvant therapy, Local LN metastasis, Liver Metastasis only, and Multiple Metastasis. The nomogram constructed on these factors achieved satisfied C-indexes of 0.794 (95% CI 0.769–0.828) and 0.827 (0.779–0.876) for the training and validation cohorts, respectively. These values were significantly higher than those of the 8th TNM stage system (all p < 0.001). The recurred iCCA patients could be precisely classified into high- and low-risk groups according to the cutoff point of this nomogram (p < 0.01).ConclusionThe investigation of progression patterns and the development of this nomogram can offer new evidence to precisely postoperative and post-progression management of iCCA patients.

LINC00665 interacts with BACH1 to activate Wnt1 and mediates the M2 polarization of tumor-associated macrophages in GC

Gastric cancer (GC) remains one of the prevalent causes of cancer-related deaths globally. Long non-coding RNAs (lncRNAs) have been associated with different cancers. The polarization of macrophages towards the M2 (alternatively activated) phenotype promotes immunologic tolerance and can induce gastric tumorigenesis. Thus far, lncRNAs have been shown to modulate the differentiation of immune cells. Here, we investigated the biological effects of LINC00665 on the progression of GC and explored the mechanisms underlying its ability to mediate the polarization of macrophages towards the M2 phenotype. We report that the levels of LINC00665 were increased in GC tissues. Furthermore, this increase in LINC00665 expression could be associated with decreased overall survival (OS), progression-free survival (PFS), and post-progression survival (PPS). Using cell-based macrophage polarization models, we demonstrated that LINC00665 upregulation in GC cells facilitated the polarization of macrophages towards the M2 but not M1 (classically activated) phenotype. Furthermore, the loss of LINC00665 prevented the M2 polarization of macrophages. Mechanically, we identified that Wnt1 was the downstream target of LINC00665. Additionally, LINC00665 could directly interact with the transcription factor BTB domain and CNC homology 1 (BACH1). The interaction between LINC00665 and BACH1 resulted in the activation and binding of BACH1 to the Wnt1 promoters. Furthermore, BACH1 silencing could inhibit GC progression, which highlighted a crucial role for BACH1 in LINC00665-mediated Wnt1 activation. In addition, genetic Wnt1 overexpression effectively abolished the repression of Wnt signaling after BACH1 depletion and mediated GC development by supporting M2 macrophage polarization. In conclusion, we report that LINC00665 modulates M2 macrophage polarization and suggest that it may facilitate macrophage-dependent GC progression.

Predicting Long-Term Prognoses and Grading Platinum Sensitivity Using a Novel Progression-Free Interval Criterion in Ovarian Clear Cell Carcinoma: A Multi-Institutional Cohort Study.

Simple SummaryOvarian clear-cell carcinoma is a unique subtype of epithelial ovarian cancer. This collaborative study aimed to provide important information regarding patient demographics and treatment-associated prognostic factors in ovarian clear-cell carcinoma in Asia. Given the difference in prognoses between early- and advanced-stage cohorts, varying predictors between these two cohorts were clarified in separate analyses. Efforts should be made to promote early diagnosis and the inclusion of advanced-stage patients in clinical trials. Additionally, early recognition of poor responders to platinum-based chemotherapy and those with cancer progression occurring within seven months after completing primary chemotherapy should be emphasized in research and clinical settings. Our findings suggest that treatment selection for patients with platinum-resistant/refractory features (e.g., novel biomarkers) or relapsed disease should be based on the results of ongoing clinical trials for ovarian clear-cell carcinoma. Our results (if confirmed) will guide and inform treatment recommendations for patients at risk for poor prognosis.This large-scale study aimed to determine the long-term influences of potential prognostic predictors and progression-free interval (PFI) criteria for grading platinum-sensitivity in ovarian clear cell carcinoma (OCCC). We retrospectively reviewed the medical records of OCCC patients presenting at nine tertiary centres (1995–2015), and evaluated patient characteristics, therapeutic factors, clinical outcomes, and hazard ratios for disease progression and death. We enrolled 536 patients (median follow-up, 36.6 months) and developed newly defined distributions of PFIs (seven and 14 months) for grading platinum sensitivity. In the multivariate model, preoperative CA125 levels and chemo-response independently predicted early-stage progression-free survival (PFS) risk. Post-progression cytoreduction correlated with reduced mortality risk. No unfavourable outcomes were observed with respect to coexisting endometriosis, fertility-sparing strategies, or platinum-based regimens. A PFI of <7 months, the strongest predictor of both post-progression mortality and second relapse risks, correlated with chemo-resistance, advanced tumour stage, and shortened post-progression survival. Chemotherapy regimens commonly used in front-line or relapse settings were limited in improving prognoses, especially in the advanced-stage cohort. Clinical trials of novel targeted agents and/or innovative biomarkers for chemoresistance should be comprehensively investigated and offered early to advanced-stage patients or those with OCCC progression occurring within seven months after receiving chemotherapy.

CCNB1, Negatively Regulated by miR-559, Promotes the Proliferation, Migration, and Invasion of Ovarian Carcinoma Cells.

Cyclin B1 (CCNB1) is regarded as an oncogene in multiple tumors. This work aims to investigate the expression, function, and related mechanisms of CCNB1 in ovarian carcinoma (OC). Three microarray datasets (GSE14407, GSE18520, and GSE54388) were obtained from the Gene Expression Omnibus (GEO) database and screened for differentially expressed genes (DEGs) of OC tissues and normal ovarian tissues. CCNB1 expression in OC tissues and paracancerous tissues was detected by immunohistochemistry. Kaplan-Meier plotter database was utilized to analyze the correlation between CCNB1 expression and the prognosis of OC patients. After the loss-of-function and gain-of-function cell models were established, cell counting kit-8 (CCK-8), bromo-deoxyuridine (BrdU), and transwell experiments were employed to examine the proliferation, migration, and invasion of OC cells, respectively. The targeting relationship between miR-559 and CCNB1 was verified using the dual-luciferase reporter gene experiment. The expressions of CCNB1 mRNA and miR-559 were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Western blot was used to quantify the protein expression of CCNB1. In addition, xenograft nude mouse models were established to examine the effects of CCNB1 on lung metastasis in vivo. CCNB1 expression was markedly increased in OC tissues and cell lines. The overall survival, progression-free survival, and post-progression survival of OC patients with high CCNB1 expression were significantly shorter. OC cell proliferation, migration, and invasion were enhanced by CCNB1 overexpression while CCNB1 knockdown led to opposite effects. MiR-559 expression was remarkably reduced in OC tissues and cell lines, and miR-559 markedly suppressed the malignant characteristics of OC cells. Besides, miR-559 directly targeted the 3' UTR of CCNB1 mRNA and reduced CCNB1 expression at both the mRNA and protein levels. Overexpression of CCNB1 accelerated lung metastasis of OC cells in vivo. CCNB1, of which expression is modulated by miR-559, facilitates proliferation, migration, and invasion of OC cells, therefore, working as a potential therapeutic target of OC. This work provides new insights into the clinical diagnosis and treatment of OC.