Bone Mets Research Articles

Effect of tumor burden on survival in patients with stage IV EGFR-mutant NSCLC receiving osimertinib monotherapy.

8611 Background: Osimertinib (osi) has traditionally been given as monotherapy for patients (pts) with stage IV EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC), although acquired resistance remains a challenge. Recent data from the FLAURA2 study demonstrated a progression free survival (PFS) benefit of approximately 9 months (mos) when osi is combined with platinum-pemetrexed chemotherapy. Despite this improvement, combination therapy is associated with higher rates of adverse events, making it challenging to decide which pts should receive TKI + chemo vs TKI monotherapy. Tumor burden (TB) in pts with stage IV EGFRm NSCLC, which may be associated with risk of developing resistant clones on TKI monotherapy, and its association with clinical outcomes has not been examined. Methods: Retrospective, single institution manual case review of pts who received osi monotherapy. Primary objectives were PFS (i.e., oligoprogression requiring local therapy, disease progression (PD) with osi discontinuation, or death) and overall survival (OS) related to extent of TB. Those who did not receive osi monotherapy for stage IV EGFRm NSCLC or discontinued osi for reasons other than PD were excluded. Demographics, comorbidities, performance status, PD-L1 expression, histology, EGFRm subtype, prior TKI use, total number of visceral tumors (TTn), and total number/sites of metastatic disease (MDn) collected for analysis. Extent of TB categorized by TTn (1-4, 5-9, ≥10) and MDn (1-2, 3-4, ≥5). PFS and OS estimated by Kaplan-Meier method and compared using log-rank test. Results: 325 pts eligible for analysis. Median follow-up time was 22.7 mos. Median PFS (mPFS) for the overall cohort was 16.3 mos (95% CI; 13.7 - 18.9) and median OS (mOS) was 31.1 mos (95% CI; 27.4 - 39.3). Pts with a TTn of 1-4 had significantly better mPFS compared to those with a TTn of 5-9 and ≥10 (mPFS: 21.5 vs 16.3 vs 13.4 mos, respectively; P = 0.001). Pts with a TTn ≥10 had significantly worse mOS compared to those with a TTn of 5-9 and 1-4 (23.7 vs 35.1 vs 57.7 mos, respectively; P < 0.0001). Similarly, pts with a MDn of 1-2 had significantly better mPFS and mOS compared to those with a MDn of 3-4 and ≥5 (mPFS: 21.6 vs 11.4 vs 9.0 mos, respectively [P < 0.0001]; mOS: 44.3 vs 20.8 vs 22.4, respectively [P < 0.0001]). Pts with liver and bone mets had significantly worse mPFS and mOS, whereas those with lung and brain mets had worse mOS without affecting PFS. Conclusions: The extent of baseline TB, categorized by TTn and MDn, impacts both PFS and OS in pts with stage IV EGFRm NSCLC treated with osi monotherapy. Pts with “low-TB” (i.e., TTn 1-4, MDn 1-2) appear to have a survival advantage compared to those with “intermediate- or high-TB” (i.e., TTn 5-9 and ≥10, MDn 3-4 and ≥5) and may derive less benefit from the addition of chemotherapy to osi. Prospective, matched real-world treatment cohorts are warranted to optimize treatment strategies for this patient population.

Abstract PO4-27-08: A Phase II Multi-Institutional Study of Concurrent Radiotherapy, Palbociclib, and HormoneTherapy for Treatment of Bone Metastasis in Breast Cancer Patients

Abstract Background: This Phase II study aimed to determine the efficacy and safety of administering palliative radiotherapy (RT) to bone metastases (mets) in patients (pts) receiving concurrent palbociclib and hormone therapy (HT) for hormone receptor positive, Her2/neu negative breast cancer. The primary endpoint was response rate 3 months after RT. Methods: Pts with painful bone mets or asymptomatic bone mets with risk for impending clinical event were treated with RT to 30 Gy in 10 fractions or 20 Gy in 5 fractions with concurrent palbociclib and HT. Change in maximum pain score on the Brief Pain Inventory was used to assess pain response 3 months post RT relative to baseline. Among pts with asymptomatic bone lesions, response was defined as prevention of a clinical event (e.g., bone fracture) without evidence of local tumor growth on surveillance imaging. Patient reported outcomes (PROs) of fatigue, depression, anxiety, and quality of life were collected. Blood-based biomarkers were examined to determine their relationship with response and PROs. Using a non-inferiority study design, a sample size of at least 33 pts was needed to achieve 80% power to detect a non-inferiority proportion of 60% using a one-sided binomial test and assuming a Type I error of 0.05. Results: Among 38 patients enrolled, 79% had painful bone mets. 35 pts completed baseline and 3-month post RT assessments. 61% and 37% of pts received aromatase inhibitors and fulvestrant, respectively, with palbociclib. Median age was 60 years (31-83) and 25% of pts were non-Hispanic Black. The majority (72%) of pts received 5 fraction RT and 69% received RT to one bone region. 29 patients (83%) were responders [95% CI: 66%-93%, p=.003]. Median progression free survival (PFS) was 30.4 months (1.3 - 44.0). Three-year PFS and overall survival were 45.6% and 67.2%, respectively. Grade 3 neutropenia developed in 4 (11%), 4 (11%), and 7 (20%) pts at end of RT, 1 month, and 3 months post RT, respectively. No pts developed Grade 4 neutropenia. One patient developed Grade 3 gastrointestinal toxicity during RT, another developed Grade 3 dyspnea 1 month post XRT, and another developed a bone fracture 6 months after RT. >While patient reported measures of fatigue, depression, and overall quality of life did not significantly change during or after RT relative to baseline, pain scores (i.e., BPI pain severity and interference, BM22 pain characteristics and pain site subscales, EORTC C15 pain) significantly decreased 3 months post XRT relative to baseline. Heightened inflammatory marker levels (e.g., TNFRII, IL1ra, CRP, TNF alpha) were significantly associated with worse symptoms of fatigue (MFI) and depression (HADS), increased pain interference (BPI), and lower overall quality of life (SF-36), controlling for age and time using mixed effect models. Patients with improved pain symptoms and lower pain scores had significantly lower inflammatory marker levels relative to baseline (e.g., interleukin-6). Conclusions: Our study demonstrated high rates of response to concurrent RT with palbociclib and HT with acceptable levels of toxicity. These results suggest that RT to bone mets effectively alleviates pain in patients taking palbociclib and pain response to treatment is associated with decreased inflammatory markers. RT may be given to pts receiving palbociclib and HT for breast cancer. Clinical Trial Identification: NCT03691493 Citation Format: Mylin Torres, Jolinta Lin, Sarah Friend, Canhua Xiao, Yichun Cao, Shannon Kahn, Karen Godette, Sheela Hanasoge, David Yu, Tony Eng, Matthew Cheney, Nancy Wiggers, Andrew Pippas, Keerthi Gogineni, Jane Meisel, David Schuster, Aditya Bardia, Andrew Miller, Jennifer Felger, Jeffrey Switchenko, Amelia Zelnak, Kevin Kalinsky, Manali Bhave. A Phase II Multi-Institutional Study of Concurrent Radiotherapy, Palbociclib, and HormoneTherapy for Treatment of Bone Metastasis in Breast Cancer Patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-27-08.

Abstract 7582: Descriptive analysis of patients with mCRPC and liver metastases receiving alpha and beta PSMA targeted radionuclide therapy (PSMA-TRT)

Abstract Introduction: Predictors of outcomes after PSMA-TRT are still being established. Liver metastases (mets) have been associated with poor response. Mutations in genes encoding DNA damage repair (DDR) and TP53 affect radiosensitivity. Here we describe a cohort of patients with mCRPC and liver metastases treated on clinical trials of PSMA-TRT. Methods: 39 patients with liver mets were enrolled on phase I/II PSMA-TRT studies between Jan 2006 to Apr 2022. Patients received alpha therapy (225Ac-J591), beta therapy (fractionated 177Lu-PSMA-617, single-dose and fractionated 177Lu-J591) or a combination of both (225Ac-591 and 177Lu-PSMA-I&T). All patients included in this analysis had CT imaging; patients enrolled after 2017 had PSMA-PET imaging. 15 patients also had genomic analysis completed. Results: Median age was 69 (range 55-93), PSA 85.7 (2.45-9614). 39 (100%) bone mets, 33 (84.6%) LN, 9 (23.1%) lung. 22 (56.4%) greater than 1 ARPI, 23 (59.0%) greater thanc 1 chemo, 13 (33.3%) sip-T, 7 (17.9%) Ra-223, 4 (10.2%) prior TRT (with concurrent liver mets). Of the 19 with both CT and PSMA PET, 18 (94.7%) were identified on PSMA PET (including 8 PET only), 10 (55.6%) on CT (1 CT only, i.e. non-PSMA PET avid). Median whole body PSMA-imaging score (PSMA-IS) was 4 (range 1-4), with 7 (17.9%) 1-2 and 32 (82.1%) 3-4. 9 (23.0%) received alpha-TRT, 26 (66.7%) beta-TRT, and 4 (10.3%) combo-TRT. Somatic or germline analysis was completed in 15 (38.5%) of 39 patients. 8 (53.3%) had mutations in DNA repair pathways (3 in BRCA2, 3 in CHEK 2, 1 in FANC, 1 in MSH2). 7 (46.7%) had mutations in TP53. 31 patients (79.5%) had PSA decline, with 15 (38.5%) achieving PSA 50. 26 (66.7%) had baseline CTC measured; 19 (73.0%) had detectable CTC at baseline. Of these 19, 3 (15.8%) converted to undetectable after therapy and 2 (10.5%) converted to favorable CTC. PSA50 rate in alpha-TRT was 4 (44.4%), beta-TRT 8 (30.7%), combo-TRT 3 (75%). PSA50 in patients with PSMA-IS 1-2 was 1 (14.2%) compared to 14 (43.9%) in PSMA-IS 3-4. 3 (37.5%) of 8 patients with mutDDR achieved PSA50, compared to 3 (42.9%) with mutTP53. Conclusions: This dataset adds to the collective literature of two subgroups of patients with mCRPC receiving TRT: those with liver disease and those with mutations in DNA repair pathways. The results of this study suggest higher rates of response in patients receiving alpha therapy, either alone or in combination with beta therapy, and in patients with high radiotracer uptake on PSMA-PET, based on PSMA-imaging score of 3 or 4. Genomic alterations in DRR proteins did not have clear implications. Citation Format: Samuel Ruder, Michael Sun, Andres Ricaurte Fajardo, Jones Nauseef, Zachary Davidson, Joseph Thomas, Sandra Huicochea Castellanos, Ana Molina, Cora Sternberg, Amie Patel, Escarleth Fernandez, Sarah Yuan, Edward Fung, Vasilios Avlonitis, Elisabeth O'Dwyer, David Nanus, Joseph Osborne, Neil Bander, Scott Tagawa. Descriptive analysis of patients with mCRPC and liver metastases receiving alpha and beta PSMA targeted radionuclide therapy (PSMA-TRT) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7582.

Outcomes in patients (pts) with advanced urothelial carcinoma (aUC) treated with enfortumab vedotin (EV) after switch maintenance avelumab (MAv) in the UNITE study.

537 Background: MAv is approved in pts with aUC without progression (PD) on 1L platinum-based therapy (PBT). As pts in the pivotal EV trials had not received MAv after PBT, data on outcomes with EV post-MAv are limited. We examined outcomes with EV post-MAv in the multicenter retrospective UNITE study. We hypothesized that outcomes would be similar to published EV data. Methods: Pts who received sequential PBT, MAv, then EV monotherapy were included. Investigator-assessed observed response rate (ORR) was assessed for evaluable pts with scans after ≥ 1 cycle EV using χ2 test and logistic regression. Progression-free and overall survival (PFS, OS) were measured from EV start and assessed using ΚΜ method and Cox proportional hazards model. Results: Among 633 pts at 16 US sites, 49 received PBT and MAv then EV. Median age 72; 63% men; 96% Caucasian; 82% ECOG PS 0/1, 71% lower tract tumor; 65% pure urothelial histology; 71% visceral or bone mets; 33% Bellmunt score (BS) 2-3. In terms of PBT, 67% had cisplatin-based (cis); 26% carboplatin-based (carbo); 6% both cis- and carbo-based therapy. Best response to PBT was CR/PR/SD for 12% / 59% / 29% pts, respectively. Median time from PBT start to EV start was 8.5 months (mo) (3.9-21.2). Median follow up from EV start was 8.5 mo (95%CI 6.7-15.0). ORR to EV was 54%; median PFS and OS were 7.0 mo (95%CI 5.8-13.3) and 13.3 mo (95%CI 10.8-NR). Median PFS2 measured from PBT start until PD after starting EV or death was 17.5 mo (95%CI 15.2-22.5). Median OS from PBT start was 22.5 mo (95%CI 18.6-NR); 29% of pts remained on EV at data cutoff; 43% received subsequent therapy (Tx) after EV with median time to next therapy 6.4 mo (1.8-15.9). Outcomes did not differ among subgroups, except for improved PFS and OS in pts with BS 0-1 vs BS 2-3 (Table). Conclusions: Pts with aUC treated with EV after MAv had outcomes consistent with data for EV in PBT- and checkpoint inhibitor-refractory aUC. These data support the use of EV as third-line Tx after progression on MAv but should be validated in larger cohorts. [Table: see text]

Impact of squamous histology on outcomes with enfortumab vedotin in patients with advanced urothelial carcinoma: Analysis of the UNITE study.

651 Background: Squamous histology (SH) is the most common variant of Urothelial Carcinoma (UC) and is associated with lower response rates to chemotherapy. The impact of SH on outcomes with enfortumab vedotin (EV) is less defined. We hypothesized that increased SH component would correlate with inferior outcomes with EV treatment. Methods: UNITE is a multi-institutional retrospective study in pts advanced UC (aUC) treated with targeted agents. In this analysis, we compared EV monotherapy outcomes in pts with pure UC (pUC) and pts with urothelial predominant histology (UCP) [<50% SH], SH-predominant [50-99% SH] and pure SH (pSH) [100% SH] respectively. We also compared pSH to UCP and SHP. Observed Response Rate (ORR) was compared in evaluable pts with scans after ≥1 cycle of EV using Chi-squared test. Progression-free survival (PFS) and overall survival (OS) from EV start were assessed and compared using the KM method and Cox proportional hazard test. Results: This analysis included 460 pts from 17 US sites treated with EV monotherapy. 366 pts had pUC and 94 pts had SH component (including pSH). In the overall cohort, median age was 70, 73% men, 88% Caucasian, 73% ECOG PS 0-1, 67% lower tract tumor, 30% liver mets, 38% bone mets, 65% had ≥ 2 prior therapy lines. There were no significant differences in baseline clinical characteristics between pts with pUC vs SH component except for higher incidence of liver mets in pts with pUC (32% vs 20%; p = 0.02). Among all 460 pts, median follow up was 20.7 mos from EV start, ORR was 51%, mPFS and mOS were 5.8 mos (95% CI: 5.3-6.4) and 12.7 mos (95% CI: 11.5-14.3). Among 94 pts with SH component, 70 were UCP, 17 SHP and 7 pSH. Inferior outcomes were noted in pts with pSH relative to pts with pUC and pts with UCP (Table). No differences in outcomes were seen across other cross-group comparisons. Conclusions: These hypothesis-generating findings suggest that SH component may impact outcomes with EV treatment in pts with aUC. A subset of pts with SH-predominant histology can have robust responses and outcomes with EV treatment, but larger studies and further biomarker data are needed to determine pts most likely to benefit. Patients with pSH are shown to have worse outcomes with EV, but further studies with a larger sample size are needed to validate our findings and define the role of EV for this rare and biologically distinct entity. [Table: see text]

Outcomes with sacituzumab govitecan (SG) in patients (pts) with advanced urothelial carcinoma (aUC) and variant histologies (VH): Analysis of the UNITE study.

667 Background: SG is approved in pts with aUC refractory to platinum-based chemotherapy (PBT) and checkpoint inhibitor therapy (CPI). Data on SG outcomes in pts with subtype/variant histologies (VH) are limited. We examined SG-treated pts in the UNITE study and hypothesized that outcomes would be similar between pts with pure urothelial histology (pUC) and any VH component. Methods: UNITE is a multi-site retrospective study of pts with aUC treated (Tx) with targeted agents, such as enfortumab vedotin (EV) and SG. Pts who received SG monotherapy were included in this analysis. Observed response rate (ORR) was assessed by investigators at each site for evaluable pts with scans after ≥ 1 SG cycle using χ2 and logistic regression. Progression-free and overall survival (PFS, OS) from SG start were assessed using KM method and Cox proportional hazards model. Results: Among 633 total pts in UNITE, 116 received SG monotherapy at 11 US sites. Median age was 70; 79 (68%) male; 97 (84%) Caucasian; 86 (74%) ECOG PS 0/1; 84 (72%) lower tract tumor; 90 (78%) visceral or bone mets; 48 (41%) Bellmunt score ≥2; 72 pts (62%) had pUC and 44 (38%) VH, including 33 (28%) with UC predominant (<50% VH) and 11 (9%) with variant predominant (≥50% VH). For prior therapy, 109 pts (94%) received >2 prior lines; 75 (65%) PBT; 102 (88%) CPI; 109 (94%) EV. Median time from metastatic diagnosis to SG start was 18.6 months (mo) (0.9-84.5). Median follow up from SG start was 10.6 mo (8.5-15.4). Median time on SG was 1.6 mo (0.2-14.7). ORR to SG was 24% (20/84); median PFS and OS from SG start were 3.7 mo (95% CI 3.0-4.6) and 6.7 mo (95% CI 5.3-10.8). VH (n ≥1) included: squamous (SQH) (19, 16%), micropapillary (9, 8%), plasmacytoid (8, 7%), adenocarcinoma (3, 3%), neuroendocrine (NE) (2, 2%). In evaluable pts with VH, ORRs: squamous (3/14), micropapillary (1/4), plasmacytoid (0/6), adenocarcinoma (2/3), NE (1/2). No significant differences were observed in outcomes between pUC and any VH or pUC and SQH (Table). Conclusions: Pts with aUC treated with SG appear to have similar clinical outcomes between pUC and any VH. Responses to SG are observed across different VH. Limitations include low power, tumor heterogeneity, lack of central pathology/scan review, selection and confounding biases. These hypothesis-generating findings suggest activity of SG post-PBT, CPI, and EV in pts with VH, but should be validated in larger cohorts with adequate sample size of specific VH and longer follow up. [Table: see text]

Mature results of a phase 2 pilot study of radium-223 and radiotherapy in untreated hormone-naïve men with oligometastatic prostate cancer to bone.

160 Background: We hypothesized that treatment with Radium-223 (Ra223) and to ≤5 sites of bony metastases could safely delay the time to start androgen deprivation therapy (ADT) and maintain quality of life (QoL). Methods: 20 men previously treated with surgery, radiation, or both for M0 PCa later developed ≤5 bone-only mets were eligible for this prospective trial. Inclusion: testosterone ≥ 100 ng/dL and mets on conventional bone scan, validated by a CT, MRI, or PET/CT. Exclusion: LHRH therapies after initial treatment or N1 disease at diagnosis of bone mets. Therapy was 6 cycles of Ra223 and SBRT (30 Gy in 5 fractions between cycles 1-2). Bone scan was performed at baseline and q3 months. PSA was evaluated monthly during the Ra223 course and q3 months after. Therapeutic effectiveness was defined as ≥20% of patients meeting the primary endpoint of freedom from ADT (FFAdt) use at 15 months. Discontinuation of study therapy occurred if: PSA rise > 10% if baseline PSA >20ng/ml, PSA>20 if baseline PSA <20 ng/ml, radiographic progression or a skeletal-related event (SRE). All endpoints were timed from the Cycle 1 radium date. Patients were followed for 2 years. Clinically significant changes in patient-reported outcome (PRO) measures were defined as >1/2 standard deviation from the mean baseline value and were censored after the time of ADT use. Continuous and categorical covariates were compared using the Wilcoxon rank sum and Pearson’s Chi2 tests and univariate Cox regression. Statistical significance was considered at P<0.05. Results: The median number of Ra223 cycles was 6. 6 patients had <6 cycles (range 2-5) due to progression. FFAdt at 15 and 24 months was 50.0% and 40.0%, respectively (p<0.001). Median time to ADT was 15 months. 11 (55%) and 5 (25%) patients had a PSA decline exceeding 50% and 90%, respectively. Two patients had undetectable (PSA<0.01) at 2 years. There were no significant changes from baseline in any PRO QoL domain (physical functioning, anxiety, depression, fatigue, satisfaction with participation in social roles, sleep disturbance, and pain interference). There were 2 patients with Grade 3 SREs (bone fracture, pain). Grade 2+ events attributed as possible or likely to Ra-223 were seen in 4 patients (bone pain, fatigue, fracture, decreased WBC count, and other). Grade 2+ events attributed as possible or likely to EBRT were seen in 2 patients, including fatigue and other pain. No differences were noted for age, baseline PSA, days from primary treatment, NCCN risk group, TNM stage, ISUP grade group, BMI, or # of lesions in those who met or failed the primary endpoint (all p>0.05). Conclusions: In this prospective pilot study, the first-line use of Ra223 and SBRT to conventionally imaged oligomets in hormone-naïve men resulted in a significant delay in ADT use compared to historical control. The therapy is well tolerated, maintains QoL, and may result in undetectable PSA. Clinical trial information: NCT03304418 .

SAT572 Concomitant Metastatic Hurthle Cell Carcinoma And Rectal Cancer, Challenges In Diagnosis And Management

Abstract Disclosure: D. Khurram: None. R. Pansare: None. S.L. Mokshagundam: None. Hurthle cell carcinomas (HCC) are aggressive tumors and account for 5% of follicular cell thyroid malignancies. Tumor size, extra-thyroid extension and distant metastases indicate poor prognosis. 20-30% of HCCs have mets at initial diagnosis, frequent sites being lungs and bones. Metastatic HCCs are exceedingly difficult to manage. Detecting two primary cancers concomitantly is uncommon and poses additional challenges in diagnosis and management. We present an interesting case of HCC with mets to the manubrium, vertebrae, lungs and concomitant rectal adenocarcinoma. A 69-year-old male had MRI spine for back pain which showed multiple lytic osseous lesions within T3 and L1 vertebrae. Further imaging revealed a large lesion in the manubrium. Manubrial mass biopsy was positive for poorly differentiated carcinoma, immunohistochemical staining for CAM5.2, cytokeratin, CD 138, CD56 and TTF-1 (weak). He underwent 6 cycles of palliative chemotherapy with carboplatin and Taxol for carcinoma of unknown origin. PET scan following chemotherapy showed a large heterogenous thyroid mass with intense FDG uptake, along with a suspicious rectal mass. Left thyroid nodule FNA reported Bethesda IV follicular neoplasm, Hurthle cell type. Rectal mass biopsy reported moderately differentiated adenocarcinoma. Histology after total thyroidectomy showed unifocal oncocytic HCC, with lymphovascular invasion but no extrathyroidal extension. Molecular markers showed low TMB, stable microsatellite status, negative PDL-1, negative NTRK fusion and positive ATM E839. He received suppressive dose levothyroxine. Radio-iodine ablation was postponed owing to prioritization of radiation therapy for rectal cancer. Thyroglobulin level increased from 53 ng/ML to 216 ng/ML. He received 149 milli Curies of I131 after Thyrogen stimulation. There was mild radioiodine uptake in the thyroid bed, but the metastatic lesions were not radioiodine avid. Follow-up scans showed multiple bilateral pulmonary nodules with worsening osseous mets. Endoscopic biopsy was consistent with HCC, TTF-1 and PAX8 positive. He was started on Lenvatinib but developed diarrhea, hence switched to Pembrolizumab. Thyroglobulin level improved on Pembrolizumab but was complicated by adrenal insufficiency. For rectal cancer, he received radiation therapy and capecitabine. Our case is interesting for several reasons. Firstly, although bone mets are commonly seen in HCC, manubrial mets, especially as the presenting feature is rare. Secondly, concomitant rectal cancer delayed the treatment of the thyroid cancer. Thirdly, there is no major consensus regarding management of HCC, especially metastatic HCC. HCCs are often not radioactive iodine avid. Combination therapy with Lenvatinib and Pembrolizumab is currently under trial for aggressive thyroid malignancy. It will be interesting to follow the clinical outcomes in this individual. Presentation: Saturday, June 17, 2023

SAT631 EPAS1 Mutations In Three Adjacent Nucleotides Resulting In Different Phenotypes

Abstract Disclosure: M. Alswailem: None. B. Alghamdi: None. L.A. Alobaid: None. H. Al-Hindi: None. M. Aldawish: None. O. Alsagheir: None. A.S. Alzahrani: None. EPAS1 (HIF2a) mutations have been described in patients (pts) with paragangliomas (PGL) in association with cyanotic congenital heart disease (CHD), polycythemia and some additional tumors. Here, we present 3 cases of PGL with closely located EPAS1 mutations. Despite the common gene location, their manifestations are different. 1. A 14-year-old girl found at age 9 years (yrs) to have polycythemia (Hb 177-195 g/l) and hypertension. At age 14 years, she was diagnosed to have multiple mid abdomenal and the urinary bladder PGLs. U. noremetanephrine was 35.8 umol/day (0-3.43). No evidence of somatostatinoma so far. Family hx is negative for PGL and WES revealed no germline mutations in PGL-associated genes. Tumor testing revealed a novel heterozygous EPAS1 variant (c.1589C>T, p.A530V). 2. A 32-yr-old woman has a complex cyanotic CHD diagnosed since birth. She underwent five cardiac surgeries between 1993 and 2015. In 2011, she was diagnosed with two abdominal PGLs. She underwent surgery and remained free of disease until 2019 when she developed recurrence with metastases (mets) to the liver and spine. She received external beam radiotherapy to the spine. Currently PGL mets remained stable. WES was negative for any germline mutation but tumor testing revealed a heterozygous EPAS1 mutation (c.1591C>T, p.P531S). 3. A 55-yr-old man diagnosed to have an upper abdominal PGL with lung and bone metastases at the age of 9 yrs. Biopsy from a right femoral met confirmed the diagnosis of bone mets. He underwent four abdominal surgeries between 1978-2008 and received MIBG Tx 6 times with a cumulative dose is 586 mCi. His last surgery in 2008 revealed PGLs but also a non-functioning Pancreatic neuroendocrine tumor (pNET). PGL mets remained stable over the last 15 yrs. WES revealed no germline mutation in any of the known PGL genes but tumor testing revealed an EPAS1 mutation (c.1592C>A, p.P531H). Discussion:EPAS1 mutations are very rare. In this series, we present 3 pts with EPAS1 mutations in 3 adjacent nucleotides (c.1589, 1591, 1592) in 2 adjacent codons (p.530-531). These mutations are located in a domain that is important for recognition by propyl hydroxylases that normally lead to inactivation and proteasomal degradation of HIF2a (EPAS1). Despite the common location, the manifestations are quite different. Although all of them developed PGL at a young age, Pt # 1 had severe polycythemia, Pt#2 had complex CHD, and pt#3 had pNET. The first two patients had extensive mets but these mets have a smoldering course, especially in pt#3 who has been living with these mets for 44 yrs! Since EPAS1 mutations are usually postzygotic, as suggested by its involvement of more than one organ, it is possible that the variable presentations of these same domain adjacently located mutations is related to the timing of their post zygotic development. Another possibility is that the variable expression of the mutated EPAS1 in different tissues Presentation: Saturday, June 17, 2023

Abstract B037: Elevated mitochondrial activity is a targetable signature of prostate cancer bone metastases

Abstract Prostate cancer (PCa) patients’ 5-year survival is only ~30% when metastases develop. Most PCa metastases happen in bone. We seek to identify gene signatures unique for bone-metastatic PCa cells and explore potential drug candidates to specifically target PCa bone metastases (bone met). Using public RNA-Seq datasets, we defined differentially expressed genes (DE) intrinsic to PCa bone met by analyzing the DE between bone mets (MET500) and primary tumors (TCGA) and filtering out the genes shown as the DE between normal bone marrow and prostate (GTex). Similarly, we got DE intrinsic to liver met. These two intrinsic DE were further compared and functional annotation for bone met only DE was performed. We found that the bone met only up-regulated DE were significantly enriched for mitochondrial OXPHOS and electron transport chain (ETC). In contrast, no mitochondria-related terms were enriched in PCa liver met, PCa lymph node met or breast cancer bone met, suggesting unique elevated mitochondrial activities in PCa bone met. We further performed RNA-Seq analyses and determined the DE unique in intratibial xenografts (mimicking bone mets), compared to C4-2B PCa primary tumors, i.e., orthotopic or subcutaneous xenografts. OXPHOS was also positively enriched in the intratibial DE, suggesting that pre-clinical animal models recapitulate functional signatures of PCa patients and can be used for drug testing. Therefore, we hypothesized that inhibiting mitochondrial OXPHOS or ETC complex blocks PCa bone metastases. Excitingly, we found that mitochondrial ETC complex I inhibitor, IACS-010759, showed high potency and specificity in suppressing PCa cell growth without affecting osteoblasts in vitro, and significantly inhibited metastatic development of PCa cells in vivo. In summary, elevated mitochondrial activity appears to be a unique signature and phenotype for PCa bone met and mitochondria-interrupting drugs selectively suppress the growth of PCa cells without affecting normal cells in the bone microenvironment such as osteoblasts. Blocking mitochondria hyperactivation is a potential approach against PCa bone met. Citation Format: Shang Su, Ke Liu, Jing Xing, Yawei Zhao, Ruihua Liu, Bin Chen, Xiaohong Li. Elevated mitochondrial activity is a targetable signature of prostate cancer bone metastases [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B037.

Bone biomarkers and subsequent survival in men with bone-metastatic hormone sensitive prostate cancer (HSPC): Results from the phase III SWOG S1216 trial of androgen deprivation +/- orteronel.

5048 Background: We previously reported that circulating serum biomarkers of bone metabolism were significantly associated with overall survival (OS) in men with advanced prostate cancer, either in the hormone sensitive (Lara, et al. ASCO 2022) or castration resistant state (Lara, et al. JNCI 2016). In S1216, we showed that elevated bone biomarkers were significantly associated with an increased risk of death in HSPC regardless of bone metastases (mets). We also identified three risk groups (low, intermediate, and poor) with differential OS outcomes (median OS: 8.2, 5.1, and 2.1 years, respectively) based on combinations of bone biomarkers in these patients. Here we report the association of bone biomarkers with OS in men with HSPC and documented skeletal mets as part of a planned analysis of S1216. Methods: Bone resorption [C-telopeptide (CTx) and Pyridinoline (PYD)] and bone formation markers [C-terminal collagen propeptide (CICP) and bone alkaline phosphatase (BAP)] were assessed from patient sera. Patients were randomly divided into training (n=238) and validation (n=475) sets. In the training set, recursive partitioning that maximizes discrimination of OS was used to identify the dichotomous cut-point for each biomarker and for a combination of biomarker split points to define prognostic groups. In the validation set, Cox proportional hazards models were used to assess the impact of biomarkers on OS, adjusted for patient and tumor characteristics. Results: Of 1,279 men in S1216, 713 had both baseline bone mets and evaluable bone biomarkers. Patient characteristics were similar between the overall population and the subset with bone mets. Elevated levels of CICP, CTX, and PYD were strongly prognostic for OS, but not for BAP. Hazard ratios (95% CI) for OS adjusted for treatment arm and baseline clinical variables were: BAP – 1.31 (0.93, 1.84), p=0.12; CICP – 1.58 (1.09, 2.29), p<0.02; CTx – 1.55 (1.12, 2.15), p=0.008; and PYD – 1.66 (1.27, 2.217), p=0.0002. There was no evidence of interaction between elevated biomarkers and treatment (all p>0.2). Recursive partitioning algorithms identified four groups of patients with differential OS outcomes based on bone biomarkers, adjusted for baseline clinical variables, with median OS ranging from 2.3 years (highest risk group) to 7.5 years (lowest risk group). Conclusions: In this subset analysis of men with HSPC and bone mets in S1216, elevated serum markers of bone metabolism were significantly associated with worse OS. Bone biomarker levels alone and in combination with patient and tumor characteristics identify unique subsets of men with differential OS outcomes. Clinical trial information: NCT01809691 .

Racial disparities in the prevalence of extrathoracic metastases in lung cancer patients and survival: A SEER database study (2010–2019).

e20630 Background: Metastatic disease at the time of lung cancer diagnosis influences therapy choice and prognosis. Metastasis to the brain, bones, and liver may lead to higher morbidity. Differences in the prevalence of metastatic sites among patients (pts) of White (W) and Black (B) race and their association with overall survival need further elucidation. Methods: Utilizing the SEER database from 2010-2019, we identified W and B pts with metastatic small cell (SCLC), squamous cell (SQ-NSCLC), and adenocarcinoma (AD-NSCLC). Only pts with bone, brain, or liver metastasis (mets) at diagnosis were included. Metastatic site prevalence rates were determined. Cox proportional hazard ratios for survival were calculated while controlling for gender, ethnicity, other metastatic sites, chemotherapy, and radiation. Results: Total of 338,411 pts, 11.4% of B race. In SCLC, B pts had a higher prevalence of brain mets, while W pts demonstrated a higher prevalence of bone and liver mets. Survival between W and B pts with SCLC was comparable except for modest superior survival in B pts with liver mets. In SQ-NSCLC, metastatic disease for the 3 sites of interest was more prevalent in B pts, most notably in brain. However, survival did not differ. In AD-NSCLC, B pts were more likely to present with brain and liver mets. B pts with bone mets had inferior survival. Conclusions: Significant differences in patterns of mets at the time of lung cancer diagnosis between W and B pts exist. B pts with SCLC and liver mets had longer survival. Interestingly, B pts with bone mets and SQ-NSCLC had better survival while those with AD-NSCLC fared worse. Multiple factors, including socioeconomic, environmental/smoking patterns and access to healthcare, may have contributed. Further studies are needed. [Table: see text]

Retreatment with nivolumab and ipilimumab with or without chemotherapy in patients with metastatic non-small cell lung cancer after progression on immune checkpoint inhibitor therapy.

e21192 Background: The advent of immune checkpoint inhibitor (ICI) has revolutionized the therapeutic arsenal for metastatic non-small cell lung cancer. However, better therapeutic options after a progression on frontline ICIs are urgently needed and remain to be defined. ICI retreatment (rt) may constitute a rational therapeutic alternative in these patients. However prospective studies evaluating such opportunity are still lacking. Methods: We retrospectively collected data from 30 metastatic NSCLC patients (pts) having progressed on ICI (anti-PD-1, anti-PD-L1 or anti-PD-1/anti-CTLA4 combined or not with histologydriven chemotherapy) who were retreated by double-agent ICI (ipilimumab and nivolumab) combined or not with histology-driven ChT in order to evaluate rt overall survival (OS) and rt progression-free-survival (PFS). The rt PFS was calculated from rt ICI initiation to death, last follow-up or disease progression. An assessment of correlation between certain clinical variables like sex, age, smoking history and others; and survival variables was performed. Results: The median age of the 30 pts included in the analysis was 64 years (63% of pts were < 70 years old and 37% ≥ 70 years old) and 53% (n = 16) of the pts were male. Most suffered from a non-sq NSCLC (73%), with bone mets (66%), and were current or former smokers (90%). Median OS and median PFS in the whole group were 9 months (m) [95% confidence interval (CI): 5.7 - 14] and 2.5 m [95% CI: 2 - 4.6] respectively. Retreatment PFS was higher in pts having received dual ICI combined with ChT than dual ICI only [95% CI: 4.3 (3.7 – 6) versus 2.1 (1.5 – 2.9) m; hazard ratio (HR): 0.51 (0.24 – 1.10); p – value (p) = 0.085]. Retreatment OS and PFS were numerically higher in pts having received single- or double- ICI as prior therapy compared to ICI plus ChT [9.6 (6.4 – not reached) m versus 8.4 (3.7 – 13.5) m; HR: 0.53 (0.22 – 1.29), p = 0.15], and [4.2 (2.2 – not reached) m versus 2.4 (2 – 4.5 m); HR: 0.56 (0.25 – 1.24); p = 0.14), respectively], regardless of the rt. When we assessed the correlation between prior therapy and rt, we found the association of ChT to dual-ICI after prior single- or dual-ICI as first line treatment leads to a significantly higher PFS [4.5 (4 – NR) m versus 2.5 (1.6 – NR) m] compared to pts having received first ChT plus ICI then dual-ICI alone as second line treatment [HR 0.35 (95% CI: 0.13 – 0.93); p: 0.03]. The trend in OS benefit probably also favored ChT with dual-ICI as rt after prior single- or dual-ICI (HR 0.55; p = 0.23). Binary variables such as sex, histology, PD-L1 expression, smoking history, therapeutic discontinuation interval (TDI), baseline derived neutrophil-to-lymphocyte ratio dNLR) and baseline absolute lymphocyte counts (ALC) influenced positively the PFS in pts receiving dual ICI combined with ChT [ sex HR: 0.28; non-squamous histology HR: 0.26; PDL1 expression HR:0.22; former smoker HR: 0.23; never-smoker HR: 0.40; TDI less than 30 days HR: 0.09; high (≥ 3) dNLR HR: 0.22; and low (<1000) ALC HR: 0.37]. Conclusions: Patients previously treated by ICI could be retreated by ICI combined with histology-driven chemotherapy in an individual approach, under certain circumstances, which are yet to be formally evaluated and determined.

Outcomes with immune checkpoint inhibitors (ICI) in patients (pts) with MTAP alterations (alt) in advanced urothelial carcinoma (aUC).

4574 Background: MTAP loss of function alt in aUC has been associated with poor prognosis. MTAP is an enzyme involved in the adenine salvage pathway and deficiency of the protein leads to susceptibility to antifolate agents, e.g., pemetrexed. MTAP loss has also been correlated with immunosuppressive tumor microenvironment, inducing a “cold tumor” that may be less responsive to ICI. Response and outcomes to ICI in pts with MTAP altered aUC need further assessment. We hypothesized that pts with MTAP altered aUC would have lower response and shorter survival on ICI. Methods: We used our database from 26 centers (US/Europe) of pts with aUC treated with ICI. We included pts with available NGS data who received ICI for aUC. We excluded pts with pure non-UC, treated with adjuvant ICI, ICI combinations, or on clinical trials. Outcomes (observed response rate [ORR], progression free survival [PFS] and overall survival [OS]) were compared in pts who received either 1st line [1L] or 2nd line and beyond [2+L] ICI with and without MTAP alt. We compared ORR using logistic regression; PFS and OS were compared using Kaplan-Meier and Cox proportional hazards. We separately describe outcomes in pts with MTAP alt who received avelumab switch maintenance. Results: 211 pts from 8 centers met inclusion criteria with available MTAP alt status; 174 received ICI as distinct aUC treatment line (16% had MTAP alt; n=28) either in 1L or 2+L setting; 37 pts received avelumab switch maintenance (19% had MTAP alt; n=7). Pts with known MTAP status were 72% men, 91% White, 72% pure UC, 25% upper tract UC, 64% ECOG PS 0-1, 56% visceral mets, 18% bone mets, 15% liver mets. Median follow up from starting ICI was 44 months [mo] (IQR 29-51). ORR to ICI (1L + 2+L) in pts with MTAP alt was 25% (95%CI 10-47) vs 47% (95%CI 39-55%) in pts without MTAP alt [OR 3.11 (95%CI 1.15-7.82)]. PFS for pts with MTAP alt was not significantly different vs pts without MTAP alt (median 3 vs 6 mo, respectively: HR 1.46 [95%CI 0.91-2.35]). OS was similar between groups (median 14 vs 15 mo, respectively: HR 0.93 [95%CI 0.53-1.63]). Table describes outcomes by ICI treatment line (1L, 2+L, maintenance) in pts with and without MTAP alt. Conclusions: In pts with aUC receiving ICI, the presence of MTAP alt was significantly associated with lower ORR and a trend towards shorter PFS compared to absence of MTAP alt. Limitations include retrospective nature, small sample size, selection/confounding biases, lack of randomization and central scan review. Findings need external validation and might inform discussion on the optimal therapy sequence in aUC. [Table: see text]

Enfortumab vedotin (EV) outcomes with and without immediate prior immune checkpoint inhibitor (ICI) in patients (pts) with advanced urothelial carcinoma (aUC).

514 Background: EV is FDA-approved in pts with aUC and ≥1 prior therapy line. Data from EV-103 trial indicate robust response to first-line EV/pembrolizumab, suggesting potentially at least additive treatment effect with EV/ICI combination. Given the long half-life of ICIs, pts who start EV treatment immediately after ICI may potentially derive benefit from that therapy sequence. We hypothesized that the last systemic therapy prior to EV would impact outcomes, as pts treated with ICI immediately prior to EV would have superior outcomes relative to pts treated with chemotherapy (chemo). Methods: UNITE is a retrospective study of pts treated with EV at 16 US sites. Pt characteristics and outcomes were abstracted from EMR review at each site. Observed response was determined by investigators for evaluable pts with scans following ≥1 EV dose. Pts treated with EV monotherapy were divided into two groups based on whether they received chemo or ICI as the line of therapy immediately prior to EV, regardless of other therapy received. Chi-squared test was used to assess differences in pt characteristics and ORR while log-rank tests were used for OS and PFS measured from EV start. Results: Among 325 pts treated with EV monotherapy, 247 had chemo or ICI as immediate prior treatment, with 186 pts receiving ICI (Group A) and 61 pts receiving platinum-based chemo (Group B). In 247-pt cohort, ORR to EV was 52% and mPFS and mOS were 6 and 13 mos. Group B pts were younger, had more bone mets and higher Bellmunt risk factors, but were otherwise similar to Group A (Table). Most pts had both prior chemo and ICI in both group A (58%) and group B (84%). Group A pts had shorter time from last treatment (median 1.2 vs 3.2 mo, p<0.01), lower ORR to immediate prior treatment (16% vs 37%, p<0.01) and fewer prior therapy lines (mean 1.9 vs 2.6, p<0.01). Group A had superior ORR (58% vs 37%, p=0.02), mPFS (6.9 vs 4.8 mo, p=0.02) and mOS (15.2 vs 8.8 mo, p=0.01) from EV start vs Group B. Conclusions: Pts with aUC treated with EV had superior outcomes if they received ICI instead of chemo as immediate prior treatment, suggesting the hypothesis that this may represent an optimal therapy sequence or combination. These data need external validation as limitations include retrospective design, lack of randomization, and selection and confounding biases. [Table: see text]

Initial results of a phase 2 pilot study of radium-223 and radiotherapy in untreated hormone-naïve men with oligometastatic prostate cancer to bone.

156 Background: We hypothesized that treatment with Radium-223 (Ra223) and to ≤5 sites of bony metastases (mets) could safely delay the time to start androgen deprivation therapy (ADT) and maintain quality of life (QoL). Methods: 20 men previously treated with surgery, radiation, or both for M0 PCa later developed ≤5 bone-only mets were eligible for this prospective trial. Inclusion: testosterone ≥ 100 ng/dL and mets on conventional bone scan, validated by a CT, MRI, or PET/CT. Exclusion: LHRH therapies after initial treatment, or N1 disease at diagnosis of bone mets. Therapy was 6 cycles of Ra223 and SBRT (30 Gy in 5 fractions between cycles 1-2). Bone scan was performed at baseline and q3 months. PSA was evaluated monthly during the Ra223 course, and q3 months after. Therapeutic effectiveness was defined as ≥20% of patients meeting the primary endpoint of freedom from ADT (FFAdt) use at 15 months. Discontinuation of study therapy occurred if: PSA rise > 10% if baseline PSA >20ng/ml, PSA>20 if baseline PSA <20 ng/ml, radiographic progression or a skeletal-related event (SRE). All endpoints were timed from the Cycle 1 radium date. Patients were followed for 2 years. Clinically significant changes in patient-reported outcome (PRO) measures were defined as >1/2 standard deviation from the mean baseline value and were censored after the time of ADT use. Continuous and categorical covariates were compared using the Wilcoxon rank sum and Pearson’s Chi2 tests, respectively, and univariate Cox regression. Statistical significance was considered at P<0.05. Results: The median number of Ra223 cycles was 6. 6 patients had <6 cycles (range 2-5) due to progression. FFAdt at 15 and 24 Months was 49.5% and 38.5%, respectively (p<0.001). The median time to ADT was 14.8 months. There were no significant changes from baseline in any PRO QoL domain (physical functioning, anxiety, depression, fatigue, satisfaction with participation in social roles, sleep disturbance, and pain interference). There were 2 patients with Grade 3 SREs (bone fracture, pain). Grade 2+ events attributed as possible or likely to Ra-223 were seen in 4 patients (bone pain, fatigue, fracture, decreased WBC count, and other). Grade 2+ events attributed as possible or likely to EBRT were seen in 2 patients and included fatigue and other pain. were noted for age, baseline PSA, days from primary treatment, NCCN risk group, TNM stage, ISUP grade group, BMI, or # of lesions in those who met or failed the primary endpoint (all p>0.05). Conclusions: First-line use of Ra223 and SBRT to oligomets in hormone-naïve men in this prospective pilot study resulted in a significant delay in ADT use compared to historical control, is well tolerated, and maintains QoL. Clinical trial information: NCT03304418 .

Impact of Facility Case Volume on Radiation Schema and Outcomes in Palliative Radiation of Osseous Metastases

<h3>Purpose/Objective(s)</h3> To compare how facility volume impacts palliative RT practices in patients with osseous metastases, radiation schema used, and outcomes of the applied therapies by analyzing the percentage of remaining life spent receiving RT (PRLSRT) and RT completion rates. <h3>Materials/Methods</h3> A retrospective analysis was conducted using the National Cancer Database (2010-2016). Facilities were grouped and analyzed according to case volume of patients treated with palliative RT for bone mets. Facilities were grouped by case volume (<10, 10-24, 25-49, 50-74, 75-99, 100-149, ≥150). Patterns of palliative RT schemes (extended fractionation (>10 fx), hypofractionation (5 or fewer), and single fraction (8 Gy)) and outcomes were evaluated for facilities based on case volume. PRLSRT and course completion rates were calculated. <h3>Results</h3> 52,864 patient cases from 1,312 facilities were included. Higher facility case volume was associated with facility type (Academic > Comprehensive Community > Integrated Network > Community Cancer Program), higher population areas, higher distance traveled for treatment, lower comorbidity, younger age, and private insurance. Higher volume facilities were associated with the use of higher dose per fraction, resulting in increased use of single fraction, hypofractionation, and less use of extended fractionation regimens (see Table 1). The use of shorter courses at high volume centers resulted in increased radiation completion rates, and remaining life spent receiving radiation. <h3>Conclusion</h3> For palliative treatment of osseous metastases, facilities with higher case volumes favor shorter courses of RT and have better outcomes measured by PRLSRT and higher rates of treatment completion. It should be considered whether facility volume and experience influence the adoption of hypofractionation for palliative treatment of bone mets and how to improve adoption of shorter courses among all volume facilities.

252P Real-world progression-free survival (rwPFS) and time to next line of therapy (TTNT) as intermediate endpoints for survival in metastatic breast cancer: A real-world experience

Real-world progression-free survival (rwPFS) and time to next line of therapy (TTNT) are two endpoints of clinical interest in patients with metastatic breast cancer (MBC). Their validation as intermediate endpoints for overall survival (OS), in a real-world setting, remains not fully established. We conducted a retrospective cohort study using the nationwide US Electronic Health Record-derived de-identified Flatiron Health database. The study population included pts diagnosed with MBC from Jan 1, 2011 through Feb 30, 2021. Kendall tau correlation between each surrogate endpoint (rwPFS and TTNT) and OS was evaluated using the Hougaard copula model. Kendall’s tau (τ) was calculated in the full cohort, and within each subgroup of metastatic disease, based on their prognostic significance, as defined by the occurrence of bone metastases (mets) only (subgroup 1), non-hepatic visceral mets +/- bone mets (subgroup 2), liver mets +/- other visceral and/or bone mets (subgroup 3), and one or more brain mets +/- other types of metastasis (subgroup 4). This work was supported by the imCORE network. Overall, 9,733 patients with MBC were included. Median age was 63 years (IQR: 54-72). Regarding sites of metastatic disease, subgroup 2 was most highly represented (n=4,188; 43.0%), followed by subgroup 1 (n=2,601; 26.7%), subgroup 3 (n=2,306; 23.7%) and subgroup 4 (n=638; 6.6%). Median OS in the overall population was 32.4 mos (95%CI: 31.2-33.3). Median rwPFS was 11.5 mos (95%CI: 11.1-11.9), and median TTNT was 11.1 mos (95%CI: 10.7-11.5). In the full cohort, the correlation of rwPFS with OS was 0.54, while that of TTNT with OS was 0.47 (Table).Table: 252PMedian OS, rwPFS and TTNT and Kendall tau correlation of each pair of evaluated endpoints.Overall Population (n=9,733)Subgroup 1 (n=2,601)Subgroup 2 (n=4,188)Subgroup 3 (n=2,306)Subgroup 4 (n=638)Median OS, months (95%CI)32.4 (31.2-33.3)44.3 (42.2-46.9)32.7 (31.0-34.0)22.6 (21.3-24.4)16.6 (14.8-19.7)Median rwPFS, months (95%CI)11.5 (11.1-11.9)18.5 (16.9-19.4)11.9 (11.4-12.7)8.2 (7.7-8.9)5.9 (4.9-6.7)Median TTNT, months (95%CI)11.1 (10.7-11.5)16.2 (15.1-17.9)11.3 (10.6-12.0)8.7 (8.2-9.2)6.7 (5.7-7.6)rwPFS-OS Correlation: τ (95%CI)0.54 (0.53-0.56)0.47 (0.45-0.50)0.54 (0.52-0.56)0.57 (0.55-0.59)0.60 (0.56-0.64)TTNT-OS Correlation: τ (95%CI)0.47 (0.46-0.48)0.37 (0.34-0.40)0.45 (0.43-0.46)0.54 (0.52-0.56)0.58 (0.55-0.62) Open table in a new tab Real-world PFS (rwPFS) and TTNT may represent meaningful intermediate endpoints for OS in patients with MBC overall, and within different disease subgroups.

1040P Nivolumab or atezolizumab in the second-line treatment of advanced non-small-cell lung cancer? Prognostic index based on real-world data

The efficacy of nivolumab and atezolizumab in NSCLC was documented in prospective trials. We aimed to confirm the benefits and indicate prognostic factors in daily practice. This study was a retrospective analysis of patients (pts) treated in the daily practice in Poland. The median of progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The log-rank test was used for comparisons. Cox regression analysis was used for multivariate analyses. SASS v.27.0 software was used. A total of 260 pts (ECOG 0-1) were qualified to nivolumab (134 pts) or atezolizumab (126 pts). 18% of pts ended the treatment before radiological assessment. At landmark time-points of 12 and 24 months 31 % and 9 % pts remained alive. Median PFS and OS were 3 (95% CI 2.57-3.42) and 10 months (95%CI 8.03-11.96) for overall population. For atezo and nivo mPFS were 3 vs 3 months (p=0.175), mOS - 8 vs 14 months (p<0,018). In a univariate analysis for all pts, sum of measurable lesions (SML) >100.5 mm (p<0.001), liver mets (p=0.024), bone mets (p<0.001), short response for chemo (<4 mths) (p<0.001), BMI <25.6 (p=0.039), platelets (PLT) >281.5 G/l (p <0.007), a neutrophil-to-lymphocyte ratio >3.68 (p = 0.0001), platelet-to-lymphocyte ratio >182.9 (p<0.001) and LIPI 2 score (p=0.028) had a negative impact on OS. Other factors were less relevant. In a multivariate analysis SML >100.5mm (p=0.007; HR=1.003, 95% CI 1.001- 1.005), PLT>281,5 G/l (p<0.001; HR=1.003, 95%CI 1.001-1.003) and bone mets (p<0.004; HR=1.58, 95% CI 1.04-2.38) were independent negative prognostic factors for OS. Drug type was not shown to affect OS. Based on analyses, a prognostic index was constructed with formula: PI = 0.002 x (Platelets) + 0.003 x (Bones) - 0.725 x (SML). After estimating regression coefficients for individual variables, points were assigned to them to obtain three prognostic groups. Median OS differed significantly-16 (95%CI 13.3-18.7), 7 (95% CI 4.83-9.17) and 4 months (95%CI 2.88-5.13), respectively. Nivolumab and atezolizumab produced similar clinical benefit, but the treatment outcomes were worse than in clinical trials. Prognostic indices may help to indicate subgroups likely to benefit.

O005 Evaluation of occludin, a tight junction transmembrane protein in human lung cancer and its potential role in metastatic disease

Abstract Introduction Tight junctions (TJs) maintain cell adhesion. Modulation can promote cell dissociation/motility/ metastasis. Occludin is a transmembrane protein within TJs and may play a role in TJ modulation. The aim of this research was to identify the expression of Occludin in human lung cancer and its effect in cell motility/dissociation. Methods qPCR was used to quantify Occludin transcripts in a human lung cancer cohort (n=80) (Peking University Cancer Hospital Research Ethics Committee). In vitro experiments on A549/COR-L23 lung cancer cell lines included immunofluorescence staining, cell attachment/migration using ECIS Z-Theta. Cells were treated with Hepatocyte Growth Factor (HGF, 50ng/μl) and/or cell migration inhibitors N-WASPi (Wiskostatin) and ROCKi (Y-27632). Results qPCR analysis revealed reduced expression of Occludin in patients with metastasis (no bone mets 21.7+/- 12 v bone mets 3.23+/- 3 (p=0.42) v boneActv 0.263+/-0.096 (p=0.077). A549 cells showed a similar cell migration pattern with HGF, ROCKi/HGF+ROCKi. In COR-L23, HGF increased cell migration; ROCKi/HGF+ROCKi showed suppression. N-WASPi/HGF+N-WASPi prevented all cell migration. Immunofluorescence demonstrated that HGF caused loss of Occludin from cell-to-cell membranes with single cells and increased pseudopodia in COR-L23 and A549. Conclusion This preliminary study suggests an association between Occludin and bone metastasis in lung cancer. HGF promoted Occludin loss from cell membranes, cell dissociation and increased pseudopodia/increased cell motility. This suggests that loss of Occludin from cell membranes is linked to reduced TJ function leading to cell dissociation/increased motility. NWASPi may provide pharmacological value in future lung carcinoma treatment.