Median TTF Research Articles

Benchmarking mismatch repair testing for patients with cancer receiving immunotherapy.

179 Background: Mismatch repair deficiency (MMR-D) serves as a theranostic marker for directing immune checkpoint inhibitor (ICI) treatment across various cancer stages and tumor types. The College of American Pathologists endorses immunohistochemistry (IHC) as the primary approach for assessing mismatch repair (MMR) testing in colorectal (CRC) and endometrial cancer (EC) patients. An alternative method involves genetic evaluation of microsatellite instability (MSI). Previous studies have shown that resistance to immune checkpoint inhibitors (ICIs) may occur due to inaccurate MSI or MMR IHC status determination. Accurate assessment of MMR status is critical for treatment decision-making. Methods: We hypothesized that tumor-only next generation sequencing (NGS) for MMR mutation signature assessment for identification of MMR-D tumors is more sensitive than MMR IHC testing. Using a standardized, clinically validated, tumor-only NGS mutation signature pipeline in place in the Oncopanel assay at DFCI/BWH, we compared the concordance in MMR determination between NGS and IHC. We then evaluated a subset of ICI-treated patients to assess the clinical implications of these findings. Results: 1655 colorectal cancer (CRC) and endometrial carcinoma (EC) patients who had both NGS MSI (NGSd = deficient or NGSp = proficient) and MMR IHC (IHC- = absent or IHC+ = intact) assays performed were assessed. Discordant NGSd/IHC+ results were identified in 1% of CRC and 5% of EC cases that were IHC+. Importantly, patients with discordant NGSd/IHC+ (median OS: not reached [NR], 95% CI, 9.9 months-NR; median TTF: 44.4 months, 95% CI, 4.1-NR) and concordant NGSd/IHC- results, showed a similar overall survival and time to treatment failure with ICI treatment (p=non-significant) which contrasted with results for patients with concordant NGSp/IHC+ results (median OS: 14.9 months, 95% CI, 7.3-24.6, p-value 0.0025 and < 0.0001; median TTF: 5.0 months, 95% CI, 3.2-7.3; p-value 0.0014 and < 0.0001). Patients with EC or CRC and discordant NGSd/IHC+ results had better survival when treated with ICI-based regimens, compared to those who received non-ICI treatments (p= 0.054 and 0.017). Conclusions: In 2022, 151,030 new CRC and 65,950 new EC cases were diagnosed in the USA. Extrapolating our findings to this larger population, use of NGS mutational signature analysis instead of IHC would amount to about 1510 additional MMR-D CRC cases and 3297 additional MMR-D endometrial cases identified each year for whom first-line ICI therapy is preferred. Our findings support revisiting guideline recommendations for diagnostic testing of MMR to incorporate both IHC and targeted NGS tumor panel testing using sensitive and specific mutation signature calling algorithms. Larger prospective studies are warranted to confirm these findings in patients with mCRC and mEC treated with ICIs. Evaluation of this approach in other cancer types is also warranted.

Machine learning (ML)-based quantification of tumor-infiltrating lymphocytes (TIL) and clinical outcomes of patients with melanoma treated with immune-checkpoint inhibitors (ICI).

9560 Background: TIL quantification has shown promising prognostic and predictive impact in various tumors treated with ICI. More recently, TIL therapy has become an emerging treatment agent for ICI-refractory melanoma. In this work, we studied the effect of intrinsic TILs on clinical outcomes of patients with melanoma treated with ICI and quantified its utility as a biomarker in combination with tumor mutational burden (TMB). Methods: We applied a previously developed ML model to process digital whole-slide images of hematoxylin and eosin slides to quantify TIL density (TIL/mm2) in 182 metastatic melanoma samples treated with ICI at the Dana-Farber Cancer Institute. All samples underwent next-generation targeted-panel sequencing and had available TMB data (mutations/megabase). Overall survival (OS) was calculated from the data of ICI initiation to the date of death. TTF was calculated from the data of ICI initiation to the date of next line treatment or death. Alive patients were censored at the date of last follow-up. Multivariable cox regression was used to estimate adjusted hazard ratios (adj-HR) and p-values (adj-p), with TMB, prior lines of treatment and regimen type (single vs. combination ICI) used as covariates. TMB-high (TMB-H) group was defined as samples with TMB≥10. TIL-high (TIL-H) group was defined as samples with TIL density higher than the median. Results: Of 182 patients, 60% (110/182) were male and the median age at ICI start was 65.5 years. 63% (115/182) of patients received single-agent ICI (anti-PD1 or anti-CTLA4). Of 182 tumor specimens assessed for TILs, 47 (25.8%) were obtained from the primary site. There was no difference in TIL density (medians 583 vs. 817 TILs/mm2, p=0.57; 709 TIL/mm2 for full cohort) or TMB (medians 11.4 vs 12.2 mutations/megabase) between primary and metastatic samples, respectively. Moreover, there was no correlation between TIL density and TMB (pearson’s correlation coefficient = 0.92, p=1) across all samples. Compared to patients in the TIL-low (TIL-L) category, patients in TIL-H had significantly longer median TTF (33.9 [15.9-NR] versus 13.0 [7.8-18.6] months, adj-HR: 0.53 (95% CI: 0.36-0.78); adj-P=0.0012), while there was no difference in OS (P=0.57). In fact, patients in the TMB-H/TIL-H group had the longest TTF, followed by TMB-H/TIL-L, TMB-L/TIL-H then TMB-L/TIL-L (table). Conclusions: Our results support the potential use of ML-based TIL scoring as a novel and independent biomarker to predict time to failure on ICI. There is ongoing effort to validate our findings in an external dataset. [Table: see text]

Abstract 935: The real-world data of the cancer genome profiling testing for pancreatic ductal adenocarcinoma from a nationwide database in Japan

Abstract Background: In Japan, which has a universal health insurance system, cancer genomic profiling (CGP) testing was approved by the authority in June 2019. 99.7% of CGP data under insurance coverage have been registered with a nationwide database; C-CAT (Center for Cancer Genomics and Advanced Therapeutics). This study aims to clarify the real-world data of CGP for pancreatic ductal adenocarcinoma (PDAC) in Japan with particular attention to KRAS mutation and homologous recombination deficiency (HRD) status. Method: 2568 PDAC patients enrolled in C-CAT from June 2019 to January 2022 were analyzed retrospectively. The clinical background, treatment outcomes and the detection rate of gene alterations such as Big4 genes (KRAS, TP53, SMAD4, CDKN2A) or other druggable genes, especially HRD genes, were evaluated. We defined it significant when genetic alterations are described as oncogenic/pathogenic in C-CAT report. Results: 85.7% and 14.3% of patients underwent tissue DNA sequence (FoundationOne (F1) CDx 62.9%, NCC OncoPanel 22.8%) and ctDNA assays (F1 Liquid), respectively. 70.3% of the analyzed tissue were obtained from the primary pancreatic lesions. Big4 genes mutations were most frequently prevalent such as KRAS (85.1%), TP53 (69.1%) and CDKN2A (35.4%). Big4 genes mutations were detected significantly more frequently in the tissue samples than in the liquid: KRAS (92.2% vs 42.1%) and TP53 (73.0% vs 45.6%). 16.1% of enrolled patients carried pathogenic variants related to HRD, such as ARID1A, BRCA2, ATM, PALB2 and BRCA1. Therapeutic agents were proposed in 27.6% of cases, the proportion of successfully treated patients eligible for targeted therapy was 2.6%. The median OS of KRAS-wild patients was prolonged than KRAS-mutated patients (65.4 vs 27.1 months, p<0.001). The median TTF of BRCA1/2 mutated patients who received FOLFIRINOX as a first line treatment was better than BRCA1/2 wild patients (9.3 vs 5.6 months, p=0.025). Conversely, there was no difference between HRD and non-HRD (6.9 vs 6.5 months, p=0.25). Conclusion: Detection rates of gene alteration vary widely between tissue and liquid samples. KRAS mutation is confirmed as a poor prognostic factor for PDAC and patients with BRCA1/2 mutation are sensitive to FOLFIRINOX. Further accumulation of cases will help us to elucidate the more details of the relationship between gene alteration and therapeutic efficacy. Citation Format: Toshifumi Doi, Takeshi Ishikawa, Tomoki Sakakida, Ryuichi Morita, Daiki Sone, Junichiro Itani, Seita Kataoka, Hayato Miyake, Masahiro Iwasaku, Yoshio Sogame, Hideyuki Konishi, Koichi Takayama, Yoshito Itoh. The real-world data of the cancer genome profiling testing for pancreatic ductal adenocarcinoma from a nationwide database in Japan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 935.

Abstract P4-01-31: High Incidence of Palbociclib Related Neutropenia in Asian Patients Associated with Genetic Polymorphisms

Abstract CDK4/6 inhibitors (CDK4/6i) is well established as the current standard of care for hormone positive (HR(+)) metastatic breast cancer (mBC), in combination with endocrine therapy. CDK4/6i extend a chemotherapy-free, progression free survival (PFS) that preserves quality of life in patients. The most common side effect of CDK4/6i is myelosuppression, with neutropenia the most prevalent adverse effect, especially for palbociclib and ribociclib. In PALOMA-2 and MONALEESA-2, where neutropenia was prevalent (any grade neutropenia 79.5%, grade 3/4 neutropenia 66.5% in PALOMA-2, and any grade neutropenia: 74.3%, grade 3/4 55.3% in MONALEESA-2), although febrile neutropenia seldom occurred (1.8%). Several studies have proposed different genetic factors predisposing to CDK4/6 inhibitor induced neutropenia, including Duffy antigen polymorphisms, ABCB1 and ERCC1 polymorphisms (ABCB1_rs1128503, ABCB1_rs1045642, ERCC1_rs11615, ERCC1_rs3212986), CDK6 polymorphisms, and others. Subgroup studies from the PALOMA trials have suggested that Asian patients receiving palbociclib have higher rates of neutropenia, although the exact explanation is unknown. We conducted a retrospective analysis of 102 Taiwanese patients who received palbociclib for HR(+) mBC at the Taipei Veterans General Hospital for the clinical features, incidence and time course of neutropenia were analyzed. Significant neutropenia incidence was observed (> 95% of all grade neutropenia, 74.5% grade 3/4 neutropenia). In addition, in our clinical cohort, one of the patients was a long term peritoneal dialysis patient newly diagnosed of HR(+) mBC and started on Palbociclib, initially 125mg, later decreased dosage to 100mg after neutropenia occurrence. By Liquid chromatography–mass spectrometry (LC–MS), we quantified the levels of palbociclib in her serum and peritoneal fluid at various time points, while on different dosage use. To our knowledge, this is the first pharmacokinetics analysis on a peritoneal dialysis patient receiving CDK4/6i. To investigate a possible genetic association for the high prevalence of neutropenia, we queried the Taiwan biobank, a nationwide biospecimen repository with 129,586 healthy individual genome wide DNA sequencing data deposited. We investigated the prevalence of the 4 SNPs previously reported to be related to neutropenia in the PALOMA studies. By comparing the Taiwan biobank data to SNP databases from different ethnicities, we observed interesting findings on ethnicity differences of SNP distribution and higher prevalence of neutropenia SNPs. Collectively, in this study we report real world data, biobank genome wide analysis, and a novel report of pharmacokinetic study in a peritoneal dialysis patient, providing novel insights into the real world use of palbociclib and CDKi. Table 1. Median TTF of each subsequent therapy after PAL+ET Characteristics of the clinical cohort treated with palbociclib at TVGH Citation Format: Kuan-Jung Huang, Ting-Hao Kuo, Ta-Chung Chao, Chun-Yu Liu, Yi-Fang Tsai, Chi-Cheng Huang, Ling-Ming Tseng, Cheng-Chih Richard Hsu, Jiun-I Lai. High Incidence of Palbociclib Related Neutropenia in Asian Patients Associated with Genetic Polymorphisms [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 P4-01-31.

Association between time-of-day of the immune checkpoint inhibitor (ICI) infusion and disease outcomes among patients with metastatic renal cell carcinoma (mRCC).

678 Background: Recent studies have suggested an association between the time-of-day of ICI infusions and disease outcomes, including progression free survival and overall survival, among patients with cancer. (Qian et al Lancet Oncology 2021). We sought to identify whether such an association exists in patients with mRCC receiving ICIs. Methods: Patients with mRCC treated with nivolumab alone, or in combination with ipilimumab, in either first- or second-line treatment were retrospectively identified. Patients who received <25% of infusions after 4:30 pm were assigned to the early time of infusion (TOI) sub-cohort while patients who received ≥ 25% of infusions after 4:30 pm were assigned to the late TOI sub-cohort. Objective response rate (ORR, per RECIST 1.1), time to treatment failure (TTF, defined as time from the date of first ICI infusion to time of treatment discontinuation), and overall survival (OS) were compared across the two groups using Cox proportional hazard models before and after adjustment for potential confounders (age, gender, line of treatment, IMDC risk, and histologic subtype). Results: A total of 145 mRCC pts (M:F,102:43) were included in the analysis. Median age was 64 (range 31-89) years, 81.4% had clear cell histology, and 75.9% had intermediate/poor risk disease. Early TOI sub-cohort included 110 (75.9%) patients while late TOI sub-cohort included 35 (24.1%) patients. Baseline characteristics were comparable across the two groups. Median OS for the entire cohort was 41.7 months (95% CI, 33.0 – Not reached [NR]), with a median TTF of 6.5 months (95% CI, 5.0 – 10.8). ORR was 32.7% in early TOI sub-group versus 25% in late TOI sub-group (p=0.60). Median TTF for the early TOI sub-cohort was 8.3 months (95% CI 6.0 – 12.6), as compared to 4.4 months (95% CI 2.1 - 10.8) among the late TOI group with a hazard ratio (HR) of 0.79 (95% CI, 0.50 – 1.25; p=0.32). Multivariate analysis showed a HR of 1.55 (95% CI, 0.98 – 2.57; p=0.06) after adjustment for potential confounders. The median OS was 46.3 months (95% CI, 32.2 – NR) in early TOI sub-cohort versus 41.7 months (95% CI, 16.7 – NR) in late TOI sub-group with a HR of 0.67 (95% CI 0.37 – 1.23; p=0.20) in univariate analyses and 0.61 (95% CI 0.33 – 1.15; p=0.13) in multivariate analyses. Conclusions: Our results demonstrated a numerical increase in ORR, TTF and OS with early TOI compared to late TOI, with the TTF difference approaching significance after adjustment for potential confounders. Larger randomized and controlled investigations are warranted to examine the impact of chronomodulation on the efficacy of ICIs in cancers, including mRCC.

Identification of a new prognostic score for patients with high-grade metastatic GEP-NEN treated with palliative chemotherapy

PurposeHigh-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN G3) are rare and heterogeneous malignancies with poor prognosis. Aim of this study was to develop prognosticators identifying those patients that derive the most benefit from currently available systemic therapies.MethodsThis retrospective analysis included 78 patients with metastatic GEP-NEN G3. For patients with imaging data available (n = 52), the overall response rate (ORR) and disease control rate (DCR) were evaluated according to the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). A Cox proportional hazard model was used to analyze the prognostic value of selected clinical and blood-based biomarkers. The impact of palliative chemotherapy regimens on time-to-treatment-failure (TTF) and overall survival (OS) was assessed.ResultsMedian OS of the study cohort was 9.0 months (95% CI 7.0–11.1). The majority of patients received first-line treatment with platinum plus etoposide (83.3%). The ORR and DCR of the RECIST-evaluable subgroup were 34.6% and 76.9%. Median TTF upon first-line treatment was 4.9 months (95% CI 3.4–6.4). Multivariate analysis identified the Eastern Cooperative Oncology Group performance status (ECOG PS), lactate dehydrogenase (LDH) and absolute lymphocyte count as independent prognostic factors. A prognostic score based on these parameters discriminated patients with favorable and unfavorable outcomes.ConclusionOutcomes of patients with GEP-NEN G3 are still limited. A new prognostic score identifying those patients benefitting from current platinum/etoposide-based chemotherapy protocols may help as stratification factor in future trial design.

Diabetes Mellitus and Other Predictors for the Successful Treatment of Metastatic Colorectal Cancer: A Retrospective Study.

Background and Objectives: In the last decades there has been an increasing body of research identifying the positive correlation between diabetes mellitus (DM) and solid malignancies, moreover, having shown DM as an independent risk factor for colorectal cancer (CRC). The aim of the present study was to assess the impact of DM on metastatic CRC (mCRC), and to identify possible predictive factors in the successful treatment of mCRC. Materials and Methods: 468 patients with mCRC were included in this retrospective, observational study. A total of 8669 oncological treatment cycles related to 988 distinct chemotherapy lines were analyzed. Data regarding lines of treatment and blood panel values were obtained from the Oncohelp Hospital database. Results: The presence of DM in male patients >70 years was a negative predictor (RR = 1.66 and a p = 0.05). DM seemed to have a detrimental effect in patients whose treatment included bevacizumab (median time to treatment failure -TTF- 94 days for DM+ cases compared to 114 days for DM-patients, p = 0.07). Analysis of treatments including bevacizumab based on DM status revealed lower values of mean TTF in DM+ female patients versus DM-(81.08 days versus 193.09 days, p < 0.001). It was also observed that DM+ patients had a higher mean TTF when undergoing anti-EGFR (epidermal growth factor) therapy (median TTF 143 days for DM+ patients versus 97.5 days for those without DM, p = 0.06). Conclusions: The favorable predictive factors identified were the inclusion of antiangiogenic agents, a higher hemoglobin value, a higher lymphocyte count, the inclusion of anti-EGFR treatment for DM+ patients, a higher creatinine, and a higher lymphocyte count in treatment lines that included anti-EGFR treatment. Unfavorable predictive factors were represented by the presence of DM in female patients undergoing antiangiogenic treatment, neutropenia in male patients, the association of oxaliplatin and antiangiogenic agents, and a higher monocyte count in the aforementioned treatment lines.

P-15 Histology classification highlights the difference in the effectiveness of S-1 over capecitabine when combined with cisplatin in patients with HER2-negative unresectable advanced or recurrent gastric cancer with measurable disease

As there is no clear preference between S-1 plus cisplatin (SP) and capecitabine plus cisplatin (XP) as first-line therapy for patients with HER2-negative unresectable advanced or recurrent gastric cancer with measurable disease, we performed an integrated analysis of three phase II randomized trials (HERBIS-2, HERBIS-4A, and XParTS II) with the use of individual participant data (IPD) from each trial. The aim of this trial was to investigate any differences in therapeutic efficacy between SP and XP for this subset, by focusing on the differences in histology. IPD from three randomized phase II trials were collected where patients received either SP [S-1 (40–60 mg twice daily for 21 days) plus cisplatin (60 mg/m2 on day 8), every 5 weeks] or XP [capecitabine (1000 mg/m2 twice daily for 14 days) plus cisplatin (80 mg/m2 on day 1), every 3 weeks]. Overall, SP (n=79) vs. XP (n=83) showed significantly better overall survival (median OS, 14.2 vs. 11.0 months; hazard ratio [HR], 0.704; P = 0.048) and time to treatment failure (median TTF, 4.7 vs. 3.8 months; HR, 0.664; P= 0.011) and a trend toward better progression-free survival (median PFS, 5.9 vs. 5.1 months; HR, 0.717; P = 0.052), whereas no difference in overall response rate (ORR, 47.5% vs. 50.6%). Despite no difference of ORR by histological classification, the differentiated tumors showed significantly better OS but not PFS or TTF of SP against XP, due to a deeper tumor shrinkage of SP over XPas demonstrated by the fact that cases achieved >60% reduction were significantly more common in SP than in XP (28.2% [11/39] vs. 6.7% [2/30]; P = 0.029, Fisher’s exact test). The undifferentiated tumors showed a consistent better trend of OS, PFS and TTF of SP vs. XP, likely as cases without tumor shrinkage tended to be less in SP than XP (2.6% [1/38] vs. 13.0% [6/46]; P=0.121, Fisher’s exact test). Our subgroup analysis further identified that a significant benefit of SP vs. XP was found in OS for differentiated tumors with a tumor reduction of 30% or more [SP, 23.7 months (95%CI, 13.2-NA) vs. XP, 11.7 months (95%CI, 7.8-19.6); HR of 0.339 (95 % CI 0.163–0.705), interaction P = 0.003], strongly suggesting that deeper tumor shrinkage by SP vs. XP contributed most to OS in the differentiated tumors. Our data showed that SP is superior to XP in this setting, but there is a qualitative difference between the effects of SP and XP, which depends on the histological type of the tumor. For the undifferentiated tumors, SP has fewer treatment failures than XP, reflecting better PFS, OS, and TTF in SP than XP. For the differentiated tumors, SP achieves deeper tumor shrinkage than XP, which contributes to longer OS, but not PFS or TTF. Further study is needed to determine whether these differences of S-1 vs.capecitabine are reproduced by the combination of oxaliplatin and immune-checkpoint inhibitors, the new standard of care for HER2-negative unresectable advanced or recurrent gastric cancer.

Determinants of the Cancer Drug Funding Process in Canada.

Background: Canada has a publicly funded healthcare system with a complex drug funding process. After Health Canada approval to market a drug, the pan-Canadian Oncology Drug Review (pCODR) (now renamed the CADTH reimbursement review) makes a non-binding funding recommendation to the Canadian provinces (except Quebec), which each then decide whether the drug will be publicly funded. We identified the determinants of funding in this process. Methods: We analyzed drugs for advanced lung (n = 15), breast (n = 8), colorectal (CRC) (n = 7), melanoma (n = 10), and neuroendocrine (NET) (n = 3) cancers undergoing the funding decision process from 2011 to 2019. Determinants of funding assessed in the model included list price, cancer type, drug class, and pCODR recommendation. The primary outcome was the correlation between list price and time to funding (TTF: Health Canada approval to first provincial funding). Secondary outcomes included an exploratory analysis of predictors of drug funding. Results: We analyzed 43 drugs: targeted agents 72%, immunotherapy 20%, chemotherapy 7%. A total of 72% were funded in at least one province. Median TTF was 379 days (IQR 203–601). Median list price (28-day course) was CAD 8213 (IQR CAD 5391–9445). Higher list price was not correlated with TTF (correlation coefficient −0.20, p = 0.28). There was no association between list price and pCODR recommendation or the decision to fund in at least one province. A positive pCODR recommendation correlated with the provinces’ funding decisions (p < 0.001), where 89% of drugs with a positive recommendation were funded and 100% of drugs with a negative recommendation were not funded. Tumor type was predictive of TTF (p < 0.001): CRC drugs were the slowest at a median of 2541 days (IQR 702–4379), and NETs were the quickest at a median of 0 days (IQR 0–502). Cancer type predicted decision to fund in at least one province (p = 0.005), with funding for 100% of NET drugs at the high end and 29% of CRC drugs at the low end. Drug class was predictive of TTF (p = 0.01): 465 days (IQR 245–702) for targeted agents, 443 days (IQR 298–587) for chemotherapy, and 339 days (IQR 164–446) for immunotherapy. Conclusions: Determinants of drug funding included cancer type, drug class, and pCODR recommendation but not list price. Factors other than cost were more heavily weighted in the funding decisions of cancer drugs in Canadian provinces.

Effectiveness of first-line therapy in patients with advanced non-clear renal cell carcinoma (nccRCC).

304 Background: Current treatment principles for advanced nccRCC have been largely extrapolated from guidelines for clear cell RCC. Given the emerging randomized data for select nccRCC subtypes, real-world outcomes for these patients are informative particularly in the contemporary checkpoint inhibitor era. Methods: We performed an analysis using the Canadian Kidney Cancer information system (CKCis), a prospective database involving 14 academic centers, on nccRCC patients undergoing first-line systemic therapy between January 2011 – December 2019. Treatment groups were defined as receipt of: vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGF-TKI), mammalian target of rapamycin inhibitors (mTORi), and PD-1/PD-L1 immune checkpoint inhibitors (ICI, mono- or combination therapy). Primary outcome was 1-yr overall survival (OS) rate. Secondary outcomes were median time to treatment failure ((TTF, months), defined as treatment discontinuation, change or death) and objective response rate (ORR, %). Results: We identified 265 nccRCC patients: 204 (77.0%) received VEGF-TKI, 19 (7.2%) received mTORi and 42 (15.8%) received ICI-based first-line therapy (Table). Overall, median age was 64 years, 75% were male, 84% were classified as IMDC intermediate/poor risk, and 16% underwent prior nephrectomy. Twenty-three percent of patients were enrolled in clinical trials. Patients received primarily sunitinib (81%) or pazopanib (15%) in the VEGF-TKI group (other: 4%), while mTORi-treated patients received temsirolimus (74%) or everolimus (26%). For the ICI-based treatment group, most patients received combination therapy as ipilimumab-nivolumab (71%) or pembrolizumab-axitinib (26%), with 3% receiving ICI monotherapy. 1-yr OS was 65.2% for VEGF-TKI, 57.9% for mTORi and 69.0% for ICI-treated patients. Median TTF was 3.3 for VEGF-TKI, 3.5 for mTORi and 7.1 mos for ICI-treated patients. ORR was 17%, 5%, and 37% respectively for the VEGF-TKI, mTORi and ICI-treated groups. Conclusions: We describe the effectiveness of first-line therapy for patients with nccRCC from a national database. This real-world data suggests an association between first-line ICI-based therapies and improved outcomes, albeit with cabozantinib not available for the indication during this time. Our data supports consensus recommendations for preferred use of ICI-based or VEGF-TKI over mTORi as first-line therapy in nccRCC.[Table: see text]

Effect of Spatially Distributed Sequential Stimulation on Fatigue in Functional Electrical Stimulation Rowing.

A critical limitation in clinical applications using functional electrical stimulation (FES) for rehabilitation exercises is the rapid onset of muscle fatigue. Spatially distributed sequential stimulation (SDSS) has been demonstrated to reduce muscle fatigue during FES compared to conventional single electrode stimulation (SES) in single joint movements. Here we investigated the fatigue reducing ability of SDSS in a clinical application, i.e., FES-rowing, in able-bodied (AB) participants. FES was delivered to the quadriceps and hamstring of 15 AB participants (five female, ten male) for fatiguing FES-rowing trials using SES and SDSS, participants rowed with voluntary arm effort while endeavoring to keep their legs relaxed. Fatigue was characterized by the time elapsed until a percent decrease occurred in power output (TTF), as well as the trial length indicating the time elapsed until the complete stop of rowing. Trial length was significantly longer in SDSS rowing than in SES (t-test, , d=0.71 ), with an average SDSS:SES trial length ratio of 1.31 ± 0.47. TTF SDSS was significantly longer than TTF SES with a median TTF SDSS :TTF SES ratio of 1.34 ranging from 1.03 to 5.41 (Wilcoxon Ranked Sum, , r=0.62 ). No rower experienced a decrease in TTF with SDSS. SDSS reduced fatigue during FES-rowing when compared to SES in AB individuals, resulting in a lengthened FES-rowing period by approximately 30%. Application of SDSS would increase the effectiveness of FES-rowing as rehabilitative exercise for individuals with paralyses.

Effects of Liver Metastases and Liver-Metastasis-Directed Radiotherapy on Response to Immunotherapy

Liver metastases (LM) are associated with diminished anti-tumor immunity and response to immune checkpoint blockade (ICB). In preclinical models, liver-metastasis-directed radiotherapy (LRT) restores sensitivity to ICB; however, there is limited human data supporting this hypothesis. We therefore examined the outcomes of patients with LM treated with LRT and ICB.We reviewed the records of patients who received LRT and anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy. Patients were classified as receiving LRT before ICB, concurrently with the start of ICB (within 21 days), or as salvage during ICB (> 21 days after initiation). Outcome measures included time to failure of ICB (TTF) and overall survival, both defined from the initiation of ICB. For patients who received RT before or concurrently with ICB, outcomes were further stratified by presence of active LM at the time of ICB initiation. Patients who received LRT during ICB were excluded from comparative analyses to avoid potential immortal time bias.We identified 41 patients who received both ICB and LRT. 27 (66%) patients were male. The median age at LRT was 57 (26 - 80). Patients received a median of 2 lines of systemic therapy (0-4) before ICB. Tumor types included colorectal cancer (n = 20), non-small cell lung cancer (n = 10), anal squamous cell carcinoma (n = 5), melanoma (n = 4), and bladder cancer (n = 2). 16 patients were treated with LRT before ICB, 9 of whom recurred in the liver and had active LM at the start of ICB. 12 patients received LRT concurrently with ICB initiation, and 13 patients received salvage LRT during ICB. 95% (39/41) of patients had disease involving at least 2 organs at the time of ICB. Among the 28 patients treated with LRT before or concurrently with ICB, the presence of active, untreated LM (n = 21) at the time of the ICB initiation was associated with shorter TTF (HR 6.0, 95% CI 1.7 - 21.0, P = 0.005) and overall survival (HR 5.4, 95% CI 1.2 - 23.8, P = 0.025). The median TTF for patients with treated LM at ICB (n = 7) was 874 days (95% CI 111 - NR) vs. 78 days (95% CI 54 - 126) for patients with active LM (n = 21). Patients treated with LRT concurrently with the start of ICB (n = 12) did not have improved TTF compared to patients with active, untreated LM at the time of ICB who had prior LRT (n = 9) (P = 0.41). Among 13 patients treated with salvage RT during ICB, the median time to subsequent treatment failure was 101 days (95% CI 61 - NR).This analysis suggests that patients with treated LM have improved TTF compared with patients with active LM at the time of ICB. This provides the first data in humans that treatment of LM may improve response to ICB and sheds light on the importance of LRT and ICB timing. Prospective studies to further investigate the use and timing of LRT and ICB are warranted.

A retrospective study on the efficacy and safety of sorafenib or lenvatinib combined with sintilimab in patients with advanced hepatocellular carcinoma.

e16127 Background: To evaluate the efficacy and safety of sorafenib or lenvatinib combined with sintilimab in patients with advanced hepatocellular carcinoma. Methods: This retrospective study included patients with advanced/metastatic hepatocellular carcinoma who received sintilimab (iv. 200 mg, Q3W) combined with sorafenib (oral, 400 mg twice-daily) (cohort A) or lenvatinib (oral, 12 mg/day for bodyweight≥60 kg or 8 mg/day for bodyweight &lt; 60 kg) (cohort B) as first line therapy between March 2019 to December 2020 in the 5th medical center of the PLA general hospital of China. The primary endpoint was Progression-Free Survival (PFS), and the secondary endpoints included the Objective Response Rate (ORR), Disease Control Rate (DCR), Overall Survival (OS), Time to Progression (TTP) and safety. Results: 45 patients were enrolled, of which 29 were in the cohort A and 16 were in the cohort B. Except for the extrahepatic metastasis (62.1% vs 25.0%, P= 0.029), there were no significant differences in age, gender, weight, ECOG performance status, Child-Pugh, BCLC staging, and the proportion of previous treatment regimens between the two cohorts. The mean (±SD) exposure cycles in the two cohorts were 7.2±6.7 vs 7.1±4.7 ( P= 0.584). The median PFS of cohort A (8.2 months, 95%CI 3.1-19.5) was longer than that of cohort B (5.2 months, 95%CI 2.0-10.8), but there was no significant difference (HR 0.55, 95%CI 0.24-1.29, P = 0.161). However, there was no significant difference between the two cohorts in ORR (24.1% vs 6.3%, P= 0.226), DCR (82.8% vs 75.0%, P= 0.700) and median TTF (8.2 vs 4.6months, HR 0.49, 95%CI 0.21- 1.10, P= 0.074). OS data were not yet mature. There was no significant difference in the incidence of all grades and grade 3-4 adverse events between the two cohorts. The most common grade 3-4 adverse events in the two cohorts were hand-foot syndrome (17.2%, 5/29) and lung infection (12.5%, 2/16). There was 1 patient (immune hepatitis) in cohort A and 2 patients (pulmonary infection) in cohort B leading to treatment interruption due to adverse events, and no deaths due to treatment. Conclusions: Sorafenib or lenvatinib combined with sintilimab showed a good efficacy and safety in patients with advanced hepatocellular carcinoma, the safety and tolerability profiles were consistent with those previously observed. Sorafenib plus sintilimab provided an improved PFS versus lenvatinib, which requires a large sample of randomized controlled trial to confirm.[Table: see text]

Treatment patterns following first-line pertuzumab + trastuzumab in patients with HER2+ metastatic breast cancer in the United States.

e18746 Background: Limited real-world data exists on the treatment of HER2+ metastatic breast cancer (mBC) following pertuzumab (P)+trastuzumab (T) based regimens in first-line (1L) setting. In the EMILIA trial, T-DM1 had higher median progression-free survival (mPFS) (9.6 months vs. 6.4 months) and median overall survival (mOS) (30.9 months vs. 25.1 months) than lapatinib plus capecitabine in patients previously treated with trastuzumab and a taxane. Real-world treatment effectiveness data following 1L P+T could complement clinical trial data to help inform understanding of unmet needs of HER2+ mBC patients requiring second-line (2L) treatment. Methods: IQVIA Oncology EMR (US) database was analyzed to identify adult patients with confirmed HER2+ mBC who were treated with a 1L P+T based regimen between Jan 2015-Sep 2019. An anti-HER2-based regimen might include hormonal therapy and/or chemotherapy. Eligible patients who had ≥60 days of follow-up since 1L P+T regimen initiation were included in outcomes assessment. Treatment discontinuation was defined as a treatment gap of at least 365 days, initiation of a new line of therapy, or death. Treatment failure was defined as the initiation of a new line of therapy or death. A new line of therapy was defined as the use of another anti-HER2 agent, switching to a different class of chemotherapy, or re-initiation of the same regimen after a gap of at least 365 days. Median duration of anti-HER2 regimen, median time to treatment failure (mTTF) and median overall survival (mOS) were estimated using Kaplan-Meier analysis. Results: A total of 710 patients were treated with a 1L P+T based regimen (median age: 57 years; 47% HR+, 26% HR- and 27% unknown HR status; 80% received a taxane). Median follow-up was 20.3 months. Median treatment duration for 1L P+T regimens was 15.3 months. A total of 302 patients (43%) discontinued 1L P+T treatment during the study, of which 222 patients received 2L therapy with a median follow-up of 9.6 months post 2L initiation. Among patients receiving 2L treatment, 214 (96%) received anti-HER2-based regimens. T-DM1 based regimens were most common (n = 159; 72%), followed by trastuzumab-based regimens (n = 29; 13%), lapatinib-based regimens (n = 13; 6%) and neratinib (n = 13; 6%). Overall, median 2L treatment duration was 5.9 months, mTTF was 8.6 months, and mOS was 25.4 months. For patients receiving T-DM1 as 2L therapy, median duration of T-DM1 treatment was 5.7 months, mTTF was 7.9 months, and mOS was 24.4 months. Conclusions: T-DM1 was the most common 2L treatment following 1L P+T based regimen for HER2+ mBC. Median TTF and mOS for T-DM1 in this study were numerically shorter than mPFS and mOS reported in the EMILIA trial, possibly due to the inclusion of a broader patient population beyond those studied in a clinical trial in the current study. There remains an unmet need of a more effective treatment for HER2+ mBC after 1L treatment.

Efficacy of anti-PD(L)1 therapy for patients (Pts) with advanced urothelial carcinoma (aUC) with primary resistance to platinum-based chemotherapy (PC).

e16515 Background: PC remains standard first-line (1L) therapy for aUC. Approximately 15% of pts exhibit primary resistance (P-R) to PC and ∼25% progress by 4 months. PD(L)1 inhibitors yield objective response rates (ORR) of ∼20% in pts with progression after PC; however, it is unclear if this benefit extends to pts with P-R to PC. We examined the efficacy of anti-PD(L)1 in pts with aUC who experienced P-R to 1L PC. Methods: We conducted a multi-institutional retrospective study of pts with aUC who experienced P-R to PC and were subsequently treated with single-agent anti-PD(L)1 therapy. Eligibility included pts with unresectable or metastatic disease diagnosed after January 1, 2017. P-R to PC was defined as radiographic progression by RECISTv1.1 within 12 weeks from initiation of PC. Pts who developed metastatic disease while receiving (neo)adjuvant PC were eligible. Clinicopathologic variables were collected. ORR to anti-PD(L)1 was the primary endpoint. Secondary endpoints included time to treatment failure (TTF, defined as time from start of anti-PD(L)1 therapy to next line of therapy, hospice or death) and overall survival (OS) were estimated using Kaplan-Meier method. Multivariate (MV) analysis using Cox regression evaluating factors associated with OS was performed. Results: Overall, 42 pts were included: 74% male, median age 65 (28-90); 79% ever smokers; 21% mixed histology; 31% received definitive locoregional therapy. Metastatic sites at diagnosis of aUC included: lymph node only (19%), liver (29%), bone (38%) and lung (33%). At diagnosis of aUC, ECOG PS was 0 in 26%, 1 in 52% and unknown in 21%. 1L PC included cisplatin (76%) and carboplatin (24%) based regimens. Anti-PD(L)1 was received either 2L (98%) or 3L (2%). Overall, ORR to anti-PD(L)1 was 17%: CR (2%), PR (14%), SD (14%), PD (57%) and unknown (12%). Of the 24 pts with PD as best response to anti-PD(L)1, only 9 (38%) received subsequent therapy. Overall, median TTF was 4.2 mo (95% CI 2.8-6.7 mo) and median OS was 7.4 mo (95% CI 4.2-11.1 mo). ORR in patients with a PDL1 combined positive score ≥ 10% (n=6) was 0%: 1 SD and 5 PD. MV analysis for OS from start of anti-PD(L)1 is shown (Table). Conclusions: P-R to PC portends a poor prognosis in pts with aUC. While a subset of patients may respond to anti-PD(L)1 therapy, the majority of pts do not derive benefit. Alternative agents, e.g. antibody drug conjugates and FGFR inhibitors, and combination-therapy should be investigated for this high risk population.[Table: see text]

Outcomes in men with metastatic castrate-resistant prostate cancer treated with early platinum-based chemotherapy following an unsatisfactory response to androgen receptor (AR) inhibition as part of the phase II dynamic allocation modular sequential (DynAMo) trial.

83 Background: Most prostate cancers are driven by the androgen receptor (AR) and have significant responses to AR inhibition. However, approximately 20-30% respond poorly to AR signaling inhibitors and have an atypical and virulent clinical course. Previous studies have shown that early declines in PSA and CTC on treatment are linked with “AR-responsiveness” in metastatic castration resistant prostate cancer (mCRPC). Few non-androgen directed therapies are approved for AR-unresponsive patients though combination cabazitaxel and carboplatin showed efficacy in this patient population in a phase I/II trial (Corn et al. Lancet Oncol, 2019). We hypothesized that early addition of chemotherapy in AR-unresponsive patients would improve outcomes. Methods: In a modular phase II trial (NCT02703623), men with mCRPC treated with abiraterone acetate plus prednisone and apalutamide were classified at week 8 as having a ‘satisfactory’ decline in PSA (≥ 50% from baseline) and CTC (≤5/7.5mL) or ‘unsatisfactory’. Patients with ‘unsatisfactory’ declines had carboplatin and cabazitaxel added to the AR inhibitors. Primary objectives included the estimation of the overall survival (OS) of patients in this cohort. Results: 198 men were registered. 59 (31.5%) of 187 evaluable had ‘unsatisfactory’ marker declines. Patients were primarily white/non-Hispanic men (81%) over the age of 60 (78%) with ECOG score of 0 (75%). Median baseline PSA and CTC were 11.3 ng/mL and 9.0 cells/mL respectively. Median follow-up was 31.7 months with median OS 19.2 months (95% CI 14.8-27.8). Median TTF was 9.0 months (6.9-11.0). Related adverse events included decreased WBC (39%; 15% G3+), anemia (56%; 7% G3+), and lymphopenia (59%; 8% G3+). There was one grade 5 sepsis of unknown attribution. Conclusions: Although early platinum-based chemotherapy offers a durable response in a subset of AR unresponsive patients, there were patients that continued to have rapid progression. We will present additional clinical and molecular data (IHC, RNA-seq, WES) in an attempt to further differentiate AR responders from AR non-responders. Clinical trial information: NCT02703623.

Real‐world efficacy of atezolizumab in non‐small cell lung cancer: A multicenter cohort study focused on performance status and retreatment after failure of anti‐PD‐1 antibody

BackgroundAtezolizumab is a programmed death‐ligand 1 (PD‐L1) targeted monoclonal antibody that inhibits PD‐L1 interacting with its receptors PD‐1 and B7‐1, thereby enhancing anticancer immunity. Some real‐world efficacy and safety studies of anti‐PD‐1 antibody have been previously reported. However, there have been no reports investigating the efficacy of atezolizumab monotherapy in clinical practice which have focused on performance status and previous anti‐PD‐1 antibody treatment.MethodsWe retrospectively reviewed consecutive advanced NSCLC patients who received atezolizumab monotherapy between April 2018 and February 2019 at eight institutions. A total of 152 patients with NSCLC were enrolled in this study.ResultsA total of 38 patients (25%) had already been treated with anti‐PD‐1 treatment (nivolumab or pembrolizumab) before atezolizumab. The median OS and TTF was 384 days (12.8 months) (95% confidence interval [CI]: 206–424), and 42 days (1.4 months) (95% CI: 27–56) in all patients, respectively.ECOG PS 0 had significantly longer OS (median OS; not reached, p < 0.0001) and TTF (median TTF; 63 days, p = 0.012) compared with PS 1 or 2–3. Most retreated patients were unable to continue atezolizumab for a longer period, but seven patients (18.4%) were able to continue atezolizumab over four months as an ICI retreatment.ConclusionsIn previously treated advanced NSCLC patients, atezolizumab monotherapy demonstrated good efficacy and safety regardless of heavily treated patients in real‐world clinical practice, and ECOG PS 0 was a favorable predictive factor. The efficacy of retreatment with atezolizumab was limited but was well tolerated in patients treated with prior anti‐PD‐1 antibody.

CTIM-16. INTERSTITIAL PHOTODYNAMIC THERAPY WITH 5-ALA FOR MALIGNANT GLIOMA RECURRENCES

Abstract Interstitial photodynamic therapy (iPDT) using 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PPIX) as a cytotoxic photosensitizer has been shown to be a feasible treatment option for malignant gliomas. We present outcome measures and a risk profile analysis of salvage iPDT in a large monocentric cohort with local tumor recurrence following standard therapy. This study included consecutive adult patients undergoing salvage iPDT for small, circumscribed, biopsy-proven malignant glioma recurrences not deemed eligible for safe complete resection of contrast enhancing tumor. A modified 3-D treatment-planning software was used to calculate the treatment-volume and the position of the stereotactic light diffusers within the lesion. Outcome measurements included estimated time-to-treatment-failure (TTF), post-recurrence survival (PRS) and the risk profile of iPDT. Prognostic factors were obtained from logistic regression models. The institutional review board approved the study. A total of 44 patients (median age: 49.4 years, range 33.4–87.0 years, 17 female) were included. Recurrent tumors included 37/44 glioblastomas WHO grade IV and 7/44 anaplastic astrocytomas WHO grade III. Thirty (68.2%) tumors were MGMT methylated. Median treatment volume was 3.3 ccm (range, 0.5–22.8 ccm). A median number of 4 (range: 3–8) laser fibers were used. Median illumination time was 60min (range: 60–167 min). Symptomatic edema (8/44) or intratumoral hemorrhagic imbibition (7/44) did not result in any permanent morbidity. Median TTF was 7.1 months and median PRS was 13.0 months. The 2- and 5-years PRS rates were 25.0% and 4.5%. Treatment response was heterogeneous and not significantly associated with patient characteristics, treatment-related factors or molecular markers. In conclusion, iPDT was associated with promising outcome measurements in local malignant glioma recurrences in highly selected patients. Transient neurologic deterioration did not lead to any permanent morbidity. The procedure deserves further prospective evaluation particularly to identify mechanisms of favorable treatment response and prognostic factors associated with long-term survival.

Cabazitaxel in patients aged ≥80 years with castration-resistant prostate cancer: Results of a post-marketing surveillance study in Japan

ObjectivesData on the safety and efficacy of cabazitaxel in patients aged ≥80 years with castration-resistant prostate cancer (CRPC) are limited. We report the safety (adverse drug reactions [ADRs]) and efficacy (overall survival [OS], time to treatment failure [TTF], and prostate-specific antigen [PSA] response rates) in patients aged <80 or ≥80 years treated with cabazitaxel for CRPC in clinical practice. Materials and methodsWe performed post-hoc subgroup analyses of a Japanese post-marketing surveillance study involving 662 patients with CRPC treated with cabazitaxel between September 2014 and June 2016. ResultsIn patients aged <80 (n = 610) and ≥80 years (n = 49), median PSA at baseline was 168.7 and 109.0 ng/mL, and 86.7% and 83.7% of patients were previously treated with enzalutamide and/or abiraterone. ADRs (all grade) occurred in 77.2% and 79.6% of patients aged <80 and ≥80 years, with grade three/worse ADRs in 61.8% and 63.3% of patients. Hematologic toxicities were the most common grade three/worse ADRs, including neutropenia, febrile neutropenia, and anemia in both subgroups. No specific ADRs were observed in patients aged ≥80 years. The PSA response and median OS and TTF were 28.3%, 292 days, and 116 days in patients aged ≥80 years, and 29.7%, 319 days, and 125 days in patients aged <80 years. ConclusionCabazitaxel could be a treatment option for CRPC in patients aged ≥80 years based on its safety and efficacy profiles. This is the first report to investigate the safety and efficacy of cabazitaxel in patients aged ≥80 years with CRPC.

Real-world utilization and safety of ipilimumab plus nivolumab (I+N) in metastatic renal cell carcinoma (mRCC) patients: Results from the Canadian Kidney Cancer Information System (CKCis).

633 Background: I+N is now standard of care for first line treatment of intermediate/poor risk mRCC patients (pts). Real world data is vital to understand drug usage, toxicity and outcomes in non-trial pts. This project describes the amount and tolerability of treatment delivered including discontinuation rates, reasons for discontinuation and outcomes from the CKCis database. Methods: Pts in CKCis, a prospective Canadian database from 15 academic centers, who received first line I+N were included. The number of doses of I+N, number of pts who received single-agent nivolumab (N) and duration of single agent N were determined. Reasons for treatment discontinuation, including the rate, type, and grade of toxicities were identified. Efficacy outcomes included time to failure (TTF – time to progression, death, or second line therapy), overall response rate (ORR) and overall survival (OS). Results: The cohort consists of 182 pts. Median age was 63 yrs, 71% had clear cell histology, 11% were on a clinical trial, the IMDC risk distribution was 5% good, 63% intermediate, 32% poor. Median follow up was 8.8 m. All 4 I+N doses were received by 30% of pts of which 78% went on to receive single-agent N. Less than 4 doses of I+N were received by 70% of pts of which 28% went on to receive single-agent N. The median time on single agent N was 5.7 m. In the entire cohort, 21% of patients discontinued therapy due to toxicity. The most common toxicity events were colitis (56% of all events), pneumonitis (19%), and hepatitis (8%). There were no toxicity-related deaths. Median OS has not been reached (22 events to date). Median TTF was 12.4 m. ORR was 32% (5% complete responses). 26% of pts received second line treatment, the most common being sunitinib in 79%. Conclusions: In this real world cohort, the majority of mRCC pts did not receive all 4 doses of I+N, contrasting with clinical trial reporting, yet many of these pts went on to receive single agent N. Discontinuation rates due to toxicity were similar to those reported in CheckMate 214. Further follow up is ongoing and efficacy outcomes analyzed on the basis of treatment quantity/duration will be presented.