Overall Survival Benefit In Patients Research Articles

P12.10.A VASCULOGENIC MIMICRY OCCURS IN PRIMARY AND RECURRENT GLIOBLASTOMA AND IS NOT ASSOCIATED WITH PSMA EXPRESSION

Abstract BACKGROUND Glioblastomas are highly vascular tumours that overexpress vascular endothelial growth factor (VEGF), however the anti-VEGF antibody bevacizumab has not demonstrated significant overall survival benefit for patients. Vasculogenic mimicry (VM), the ability of tumour cells to form functional microvasculature lacking an endothelial lining, may compensate for insufficient or inhibited angiogenesis. VM has been reported in primary glioblastoma tissue, but not investigated at progression in recurrent tumours. Prostate specific membrane antigen (PSMA) is expressed in abnormal vessels within primary glioblastoma tumours. We aimed to determine whether VM occurs in primary and recurrent glioblastoma tumours and whether VM vessels also express PSMA. MATERIAL AND METHODS Thirty-five matched pairs of primary and recurrent formalin-fixed paraffin-embedded glioblastoma tissue were immunohistochemically labelled for the endothelial cell marker CD34 and PSMA, and counterstained with periodic acid-Schiff (PAS). Vascular structures were categorised as endothelial vessels (CD34+/PAS+) or VM (CD34-/PAS+). Vessels were counted in ten regions within each tumour and a vessel density/mm2 for each vessel category was determined. RESULTS Data are expressed as median values. Endothelial vessels accounted for most blood vessels observed. There was a significant decrease in endothelial vessel density in recurrent (41.34 vessels/mm2) compared to primary (86.98 vessels/mm2) glioblastomas (p <0.001). VM was observed in 15/35 primary tumours (42.86%) and 10/35 recurrent tumours (28.57%). VM accounted for only a small proportion of the overall vasculature and VM density was not different between the primary and recurrent groups (p = 0.266). Kaplan-Meier analyses with log rank tests indicated that VM-tumours had longer median OS time than VM+ tumours, regardless of whether VM status was determined based on the primary or recurrent tumour. However, there was no significant difference in survival distribution between VM+ and VM-tumours (primary χ2(1) = 0.381, p = 0.537; recurrent χ2(1) = 3.552, p = 0.059). PSMA is expressed in endothelia lined vessels based on serial section labelling for PSMA and CD34. PSMA expression significantly decreased in recurrent (median H-score = 0.22) compared to primary (median H-score = 0.44) tumours (one-tailed p = 0.031; n = 32) mirroring the CD34+ vessel density. CONCLUSION VM contributes to a relatively small proportion of the overall vasculature in glioblastoma tumours and was not associated with OS nor the expression of PMSA. Since VM- tumours had longer OS than VM+ tumours, assessment of VM in recurrent tumours in a larger cohort may determine if there is a clinical significance for VM in recurrent glioblastoma.

Early-Stage Breast Cancer, EGFR-Mutated NSCLC, and High-Risk Melanoma: 2023 ASCO Annual Meeting Highlights for the Advanced Practitioner

Lisa Kottschade, APRN, MSN, CNP, FAPO, of Mayo Clinic, discusses encouraging results of a trial examining adjuvant ribociclib plus estrogen therapy in patients with stage II or III HR+/HER2− early breast cancer. She also discusses the use of the novel mRNA-4157 vaccine in combination with pembrolizumab as adjuvant therapy for resected high-risk melanoma. Finally, she analyzes the overall survival data reported in the ADAURA trial, which demonstrated a statistically significant disease-free and overall survival benefit for patients with EGFR-mutated stage IB to IIIA non–small cell lung cancer.

Prognostic value of cranial radiotherapy and optimal timing stratified by lung-molGPA for NSCLC patients with brain metastases.

The updated Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (lung-molGPA) index provide more accurate survival prediction for patients diagnose with advanced non-small cell lung cancer (NSCLC) with brain metastases (BM). Given that the value of cranial radiotherapy (CRT) is still controversial for NSCLC patients with BM, this retrospective study aimed to evaluate the value of CRT and optimal timing in NSCLC patients with initial BM after stratified with lung-molGPA index. This study screened NSCLC patients with initial BM in our cancer center from February 2012 to July 2018. The prognosis value of CRT and optimal timing was evaluated with Kaplan-Meier survival analysis and the patients were classified into lung-molGPA0-2 and lung-molGPA2.5-4 group. Upfront CRT was defined as received CRT within 3months after initial diagnosis and without BM progression, other CRT was classified into deferred CRT. Overall, 288 patients were enrolled in our study, 156 patients received CRT. The median follow-up time was 47months. In the entire cohort, the median PFS and OS were 9.2 and 17.0months, respectively. In the lung-molGPA2.5-4 group, CRT can bring significantly overall survival benefit for NSCLC patients with initial BM (HR: 0.48, 95% CI: 0.34-0.68, P < 0.0001), and the upfront CRT can further expand this survival benefits compared with deferred CRT (HR: 0.49, 95% CI: 0.27-0.89, P = 0.0026). But this phenomenon was not observed in lung-molGPA0-2 group patients. Upfront CRT could bring significantly overall survival benefit for these patients with lung-molGPA2.5-4 but not for patients with lung-molGPA0-2.

Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR-mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC).

LBA3 Background: Osimertinib is a third-generation, central nervous system (CNS) active EGFR-TKI, that potently and selectively inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations. In the primary analysis from the Phase III ADAURA study (NCT02511106), adjuvant osimertinib demonstrated a clinically meaningful, statistically significant, and practice-changing disease-free survival (DFS) benefit vs placebo in patients with completely resected EGFRm (ex19del/L858R) NSCLC ± adjuvant chemotherapy. In an updated DFS analysis, with 2 years additional follow-up, DFS and CNS DFS benefit with adjuvant osimertinib were sustained (stage II–IIIA DFS hazard ratio [HR] 0.23; 95% confidence interval [CI] 0.18, 0.30; stage IB–IIIA DFS HR 0.27; 95% CI 0.21, 0.34; stage II–IIIA CNS DFS HR 0.24; 95% CI 0.14, 0.42), with a tolerable safety profile observed over the extended treatment duration. Here, we report the planned final overall survival (OS) analysis from ADAURA. Methods: Eligible patients (aged ≥18 years [≥20 in Japan and Taiwan], WHO PS 0/1 with completely resected EGFRm (ex19del/L858R) stage IB, II or IIIA [AJCC/UICC 7th edition] NSCLC; adjuvant chemotherapy allowed) were randomized 1:1 to osimertinib 80 mg once daily or placebo until disease recurrence, treatment completion (3 years), or a discontinuation criterion was met. The primary endpoint was investigator-assessed DFS in stage II–IIIA. Key secondary endpoints: DFS in stage IB–IIIA, OS and safety. Data cut-off: January 27, 2023. Results: Globally, 682 patients were randomized; osimertinib n=339, placebo n=343. Adjuvant osimertinib significantly improved OS vs placebo. In patients with stage II–IIIA disease, OS HR was 0.49 (95% CI 0.33, 0.73; p=0.0004; 100/470 events, 21% maturity); 5-year OS rate was 85% with osimertinib vs 73% with placebo. Median follow-up for OS in stage II–IIIA was 59.9 months (osimertinib) and 56.2 months (placebo). In the overall population (stage IB–IIIA), OS HR was 0.49 (95% CI 0.34, 0.70; p&lt;0.0001; 124/682 events, 18% maturity); 5-year OS rate was 88% with osimertinib vs 78% with placebo, with a median follow-up for OS of 60.4 months (osimertinib) and 59.4 months (placebo). Median OS was not reached in either population or treatment group. Conclusions: Adjuvant osimertinib demonstrated an unprecedented, highly statistically significant and clinically meaningful OS benefit in patients with EGFRm stage IB–IIIA NSCLC after complete tumor resection, with or without adjuvant chemotherapy. ADAURA is the first global Phase III study to demonstrate a statistically significant DFS and OS benefit with targeted treatment for patients with EGFRm stage IB–IIIA NSCLC. Clinical trial information: NCT02511106 .

Understanding the activity of antibody–drug conjugates in primary and secondary brain tumours

Antibody-drug conjugates (ADCs), a class of targeted cancer therapeutics combining monoclonal antibodies with a cytotoxic payload via a chemical linker, have already been approved for the treatment of several cancer types, with extensive clinical development of novel constructs ongoing. Primary and secondary brain tumours are associated with high mortality and morbidity, necessitating novel treatment approaches. Pharmacotherapy of brain tumours can be limited by restricted drug delivery across the blood-brain or blood-tumour barrier, although data from phase II studies of the HER2-targeted ADC trastuzumab deruxtecan indicate clinically relevant intracranial activity in patients with brain metastases from HER2+ breast cancer. However, depatuxizumab mafodotin, an ADC targeting wild-type EGFR and EGFR variant III, did not provide a definitive overall survival benefit in patients with newly diagnosed or recurrent EGFR-amplified glioblastoma in phase II and III trials, despite objective radiological responses in some patients. In this Review, we summarize the available data on the central nervous system activity of ADCs from trials involving patients with primary and secondary brain tumours and discuss their clinical implications. Furthermore, we explore pharmacological determinants of intracranial activity and discuss the optimal design of clinical trials to facilitate development of ADCs for the treatment of gliomas and brain metastases.

Survival Analysis of 1140 Patients with Biliary Cancer and Benefit from Concurrent Renin-Angiotensin Antagonists, Statins, or Aspirin with Systemic Therapy.

Patients with advanced biliary tract cancers (BTCs) have poor prognoses and limited therapeutic options. Renin-angiotensin antagonists (ACE-I/ARBs), statins, and aspirin may have potential anti-tumorigenic effects and decrease mortality per retrospective analyses in some solid tumors. To evaluate the efficacy of ACE-Is/ARBs, statins, and/or aspirin concurrent to first-line systemic therapy in patients with advanced or metastatic BTC. Adult patients at University of Michigan with pathologic confirmation of BTC between January 2010 and December 2020 were included in this retrospective analysis. Of 1140 patients who met eligibility, a total of 509 patients received one or more concomitant medication(s) of interest in conjunction with systemic therapy for advanced cancer. In the total cohort, the overall survival for locally advanced patients (N = 305) was 16.3 months (95% CI: 12.1-18.6), and metastatic patients (N = 512) 8.6 months (95% CI: 7.6-9.5); P < .0001. Within this concomitant medication cohort, patients with locally advanced stage (n = 132) experienced significantly longer progression-free survival (9.8 vs 4.5; P < 0.0001), and overall survival (17.4 vs 10.6; P < 0.0001) than those with metastatic (n = 297) cancer, respectively. Patients who received ACE-Is/ARBs, statins, and/or aspirin (n = 245) versus not (n = 264) concurrent with systemic anti-cancer therapy did not experience improved progression-free (5.5 vs 5.5 months; hazard ratio (HR) 1.1; P = 0.51), or overall survival (12.3 vs 12.6 months; HR 1.1; P = 0.18), respectively. In contrast to prior studies, no progression free or overall survival benefit in patients with advanced BTC from concurrent use of ACE-I/ARBs, statin, and/or aspirin with systemic therapy was observed when assessed by BTC subtype or specific systemic therapy regimen.

Abstract PD17-12: Primary efficacy and safety results from the AMALEE trial evaluating 600 mg vs 400 mg starting doses of first-line ribociclib in patients with HR+/HER2− advanced breast cancer

Abstract Background: In the Phase III MONALEESA (ML)-2, -3 and -7 trials, a 600 mg dose of ribociclib (RIB) demonstrated significant overall survival benefit in patients (pts) with HR+/HER2− advanced breast cancer (ABC) but was associated with QTcF (&amp;gt;480 ms, 3%-7%) and neutropenia (G3/4, 57%-64%) adverse events (AEs) which were managed by dose reductions. The Phase II AMALEE study was performed as a postmarketing commitment to assess whether reducing the starting dose of RIB from the recommended dose (3 wk on, 1 wk off) of 600 mg/day to 400 mg/day decreases QTcF prolongation without compromising the efficacy of first-line RIB in pts with HR+/HER2− ABC. Here, we present efficacy and safety results from the primary analysis of AMALEE. Methods: AMALEE is a randomized Phase II open-label study including pre- and postmenopausal pts with HR+/HER2− ABC with no prior therapy for ABC. Pts received RIB 400 mg + nonsteroidal aromatase inhibitor (NSAI) or RIB 600 mg + NSAI. The primary endpoint is to determine whether overall response rate (ORR) in the 400 mg arm is noninferior to the 600 mg arm. The key secondary endpoint is QTcF prolongation at cycle 1, day 15 (C1D15) 2 hours post dose. Additional endpoints included safety, progression-free survival (PFS), duration of response (DOR), time to response (TTR), and pharmacokinetics. Results: A total of 376 pts were randomized 1:1 to receive RIB at either 400 mg or 600 mg doses. Baseline (BL) characteristics and prior antineoplastic therapy were balanced across treatment (tx) arms. At the time of the data cutoff (June 11, 2021), median follow-up was 14.9 mo (min, 6.1; max, 23.8), and all pts had been treated for ≥6 months from randomization or had discontinued study tx. ORR for RIB was 41.5% (95% CI, 34.4-48.7) with 400 mg vs 45.3% (95% CI, 38.1-52.6) with 600 mg (ORR ratio for RIB 400 mg vs 600 mg, 0.921 [90% CI, 0.757-1.121]). The lower 90% CI boundary did not meet the prespecified noninferiority (NI) margin of 0.814. Results for ORR by subgroups were consistent with the overall analysis set. RIB plasma exposure was lower at 400 mg than 600 mg; the geometric mean Cmax and AUC0-24h at C1D15 were approximately 28% and 43% lower in the 400 mg than the 600 mg arm (Cmax 1080 vs 1500 ng/mL and AUC0-24h 16400 vs 28600 ng × h/mL). This study met the key secondary endpoint, change in QTcF at C1D15 in the RIB 400 mg group with a 90% CI upper boundary of &amp;lt; 20 ms. Mean change in QTcF from BL to C1D15 2 hours post dose was lower in the 400 mg (12.5 ms, 90% CI, 10.9-14.1) than the 600 mg arm (19.7 ms, 90% CI, 17.4-22.0). QTcF ≥501 ms occurred in 1.6% of pts in the 400 mg arm vs 0.5% in the 600 mg arm. Rates of G3/4 neutropenia were lower in the 400 mg (31.4%) than the 600 mg arm (46.3%). Other safety results were consistent with those previously reported for RIB in the ML trials. Median duration of exposure to RIB was 8.0 mo (min, 0.1; max, 23.7) in the 400 mg arm vs 8.8 mo (min, 0.5; max, 20.8) in the 600 mg arm. Dose reductions of RIB were more frequent in the 600 mg group with 30.5% vs 13.8% of pts requiring 1 dose reduction in the 600 mg and 400 mg groups, respectively. Dose reductions were primarily attributable to AEs, with neutropenia being the most frequently reported AE requiring a dose modification. Rates of discontinuation due to AEs were similar in the 400 mg vs 600 mg arms (8.5% vs 9.6%). PFS, DOR, and TTR data are currently immature. Conclusions: RIB at the 400 mg dose shows a better safety profile vs 600 mg in terms of key AEs that are RIB concentration dependent (neutropenia and QTcF prolongation). ORR was 3.8% lower with 400 mg than 600 mg. The lower 90% CI boundary of the ORR ratio did not meet the NI margin, thus this study was unable to demonstrate statistical NI of the 400 mg vs 600 mg dose of RIB using ORR as the endpoint. Updated results with additional follow-up and the clinically relevant endpoint PFS will be presented at the congress. Citation Format: Fatima Cardoso, William Jacot, Sherko Küemmel, Sudeep Gupta, Rama Balaraman, Liudmila Lebedeva, Yan Ji, Aparna Lakshmanan, Khalid Amin, Zheng Li, Joseph Sparano. Primary efficacy and safety results from the AMALEE trial evaluating 600 mg vs 400 mg starting doses of first-line ribociclib in patients with HR+/HER2− advanced breast cancer [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 PD17-12.

Role of Immunotherapy in Breast Cancer.

The advent of immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized the treatment of solid tumor malignancies. In breast cancer, the most robust data to date for ICI exist for triple-negative breast cancer (TNBC). Preclinical studies suggested increased antitumoral immune response in patients with TNBC undergoing ICI treatment. Early clinical trials investigated the use of ICI monotherapy in patients with metastatic TNBC with promising results, particularly in the first-line setting and for those patients whose tumors had high programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) expression. Subsequent trials evaluated the use of ICI in combination with conventional chemotherapy to enhance the host immune response. Pembrolizumab combined with chemotherapy in the KEYNOTE-355 study resulted in improved progression-free survival and overall survival benefits for patients with PD-L1 combined positive score > 10 metastatic TNBC. In early-stage disease, two phase III trials demonstrated increased rates of pathologic complete response at the time of surgery with the addition of neoadjuvant ICI to standard chemotherapy. The large KEYNOTE-522 trial showed improved event-free survival with neoadjuvant and adjuvant ICI. Several biomarkers have been identified, which may be predictive of response to ICI therapy including PD-1/PD-L1 expression, tumor mutational burden, tumor-infiltrating lymphocytes, and multigene assays capturing favorable immune cell signatures. For hormone receptor-positive and human epidermal growth factor receptor-positive breast cancer, there are ongoing studies evaluating ICI therapy in combination with chemotherapy and targeted agents. Finally, across all subtypes, several novel immunotherapeutic agents are under investigation including novel ICIs, cancer vaccines, adoptive cellular therapy, and oncolytic viruses.

Tebentafusp: a first-in-class treatment for metastatic uveal melanoma.

Tebentafusp is a first-in-class immunotherapy agent that comprises an engineered T-cell receptor targeting a gp100 epitope presented by human leukocyte antigen-A*02:01 cells, fused to an anti-CD3 single-chain variable fragment. Tebentafusp is both the first bispecific T-cell engager to show efficacy in the treatment of advanced solid cancer and the first anti-cancer treatment to demonstrate an overall survival benefit in patients with uveal melanoma (UM). This review article will focus on the clinical development of tebentafusp, the mechanism of action and resultant evolution of the management of advanced UM.

Phase I prospective trial of TAS-102 (trifluridine and tipiracil) and radioembolization with 90Y resin microspheres for chemo-refractory colorectal liver metastases

BackgroundExtrahepatic disease progression limits clinical efficacy of Yttrium-90 (90Y) radioembolization (TARE) for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). Trifluridine and tipiracil (TAS-102) has overall survival benefit for patients with refractory mCRC and may be a radiosensitizer.MethodsSequential lobar TARE using 90Y resin microspheres in combination with TAS-102 in 28-day cycles were used to treat adult patients with bilobar liver-dominant chemo-refractory mCRC according to 3 + 3 dose escalation design with a 12-patient dose expansion cohort. Study objectives were to establish safety and determine maximum tolerated dose (MTD) of TAS-102 in combination with TARE.ResultsA total of 21 patients (14 women, 7 men) with median age of 60 years were enrolled. No dose limiting toxicities were observed. Treatment related severe adverse events included cytopenias (10 patients, 48%) and radioembolization-induced liver disease (2 patients, 10%). Disease control rate in the liver lobes treated with TARE was 100%. Best observed radiographic responses were partial response for 4 patients (19%) and stable disease for 12 patients (57%).ConclusionsThe combination of TAS-102 and TARE for patients with liver-dominant mCRC is safe and consistently achieves disease control within the liver.Trial registrationClinicalTrials.gov identifier NCT02602327 (first posted 11/11/2015).

Economic evaluation of tislelizumab versus chemotherapy as second-line treatment for advanced or metastatic esophageal squamous cell carcinoma in China.

Background and purpose: The latest RATIONALE-302 trial (NCT03430843) showed that tislelizumab therapy significantly improved overall survival benefits for patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) compared with traditional chemotherapy. This study aimed to compare the cost-effectiveness of tislelizumab versus chemotherapy as a second-line treatment for advanced or metastatic ESCC in China. Methods: A partitioned survival model was developed to predict patients' lifetime quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER) from the Chinese healthcare payers' perspective. We extracted efficacy and safety data from the RATIONALE-302 trial and the local cost and resource use data from online databases and published studies. One-way sensitivity analysis (OWSA) and probabilistic sensitivity analysis (PSA) were performed to explore model uncertainty. Results: Compared with chemotherapy, tislelizumab generated a higher cost (US$ 10211.78 vs. US$ 7294.72) but yielded more QALY (0.78 vs. 0.51 QALYs). The ICER for tislelizumab was US$11073.85 per QALY gained. The PSA results indicated that the probability of tislelizumab being economical was 76% under a willingness-to-pay (WTP) threshold of 1.5 times per capita GDP ($17915) in China. Conclusion: Tislelizumab could be a promising cost-effective strategy as the second-line treatment for patients with ESCC compared with chemotherapy in the Chinese setting.

Immune-mediated pneumonitis: A clinical conundrum in a patient with stage IV lung adenocarcinoma with a dramatic and durable response to checkpoint inhibitor case report

Immune checkpoint blockade with pembrolizumab has demonstrated both progression-free survival and overall survival benefit for patients with NSCLC regardless of PD-L1 expression. However, immune-related adverse events, and in particular checkpoint inhibitor pneumonitis (CIP), are common and can complicate the treatment course, duration of response, as well as overall survival. Here we present a patient with stage IV lung adenocarcinoma who experienced a dramatic response following treatment with pembrolizumab, followed by the development of biopsy-proven organizing pneumonia and immune-mediated pneumonitis requiring early treatment discontinuation. The patient has now achieved a near-complete response over 13 months after treatment discontinuation, highlighting the importance of early recognition and management of immune-related adverse events as well as the possibility of durable response despite treatment discontinuation.

Cardiac resynchronisation therapy and implantable cardioverter-defibrillator in non-ischaemic systolic heart failure: extended follow-up of the DANISH trial

Abstract Background In the Danish Study to Assess the Efficacy of Implantable Cardioverter-Defibrillators [ICDs] in Patients with Non-ischaemic Systolic Heart Failure on Mortality (DANISH) trial, ICD implantation did not provide an overall survival benefit in patients with non-ischaemic systolic heart failure. A high proportion of patients in the DANISH trial received a cardiac resynchronisation therapy (CRT) device, which improves the prognosis in patients with heart failure. Therefore, it is of interest to examine whether the effect of ICD implantation in patients with non-ischaemic systolic heart failure is modified by CRT. Purpose Adding 4 years of additional follow-up to the DANISH trial, we examined the effect of ICD implantation according to status with respect to CRT implantation at baseline. Methods In the DANISH trial, 556 patients with non-ischaemic systolic heart failure were randomised to receive an ICD and 560 to receive usual clinical care (control). Patients fulfilling indications for a CRT device received a CRT-defibrillator (if randomised to ICD arm) or CRT-pacemaker (if randomised to control arm). In the ICD group, 322 patients (57.9%) received a CRT device; in the control group, 323 patients (57.7%) received a CRT device. In this extended follow-up study, patients were followed until May 18, 2020. The primary outcome was death from any cause; secondary outcomes were cardiovascular death and sudden cardiovascular death. Results During a median follow-up of 9.5 years, the ICD group did not have significantly lower all-cause mortality compared with the control group (hazard ratio [HR] 0.89 [95% CI, 0.74–1.08]). The results were independent of whether the patient received a CRT device at randomisation (patients with a CRT device: HR 0.92 [95% CI, 0.72–1.18]; patients without a CRT device: HR 0.86 [95% CI, 0.64–1.14]; P for interaction, 0.72). Similarly, ICD implantation did not reduce rates of cardiovascular death overall (HR 0.87 [95% CI, 0.70–1.09]), and this association was not modified by CRT (patients with a CRT device: HR 0.89 [95% CI, 0.66–1.19]; patients without a CRT device: HR 0.85 [95% CI, 0.60–1.20]; P for interaction, 0.86). The ICD group had significantly lower rates of sudden cardiovascular death in the overall population (HR, 0.60 [95% CI, 0.40–0.92]), and this association was not modified by CRT (patients with a CRT device: HR 0.69 [95% CI, 0.40–1.21]; patients without a CRT device: HR 0.51 [95% CI, 0.26–0.97]; P for interaction, 0.47). See Figure 1 for all results. Conclusions In this extended follow-up study of the DANISH trial, the effect of ICD implantation in patients with non-ischaemic systolic heart failure was not modified by CRT. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The DANISH trial was supported by unrestricted grants from Medtronic, St Jude Medical, Tryg Fonden, and the Danish Heart Foundation. No further funding was obtained for this follow-up study.

Early-stage gastric and gastroesophageal junction cancer: Is there a survival benefit to neoadjuvant therapy?

BackgroundSeveral randomized controlled trials have evaluated the efficacy of neoadjuvant chemotherapy in the management of resectable gastric cancer. Most patients in these studies had node-positive disease or more advanced T stage. The benefit of neoadjuvant therapy in patients with early-stage gastric cancer remains unclear. MethodsWe queried the National Cancer Data Base to identify patients presenting with clinical stage IB gastric adenocarcinoma between 2006 and 2015. Multivariable logistic regression was used to identify factors associated with receipt of neoadjuvant therapy. Patients undergoing neoadjuvant therapy were 1:1 propensity matched for age, year of diagnosis, Charlson index, insurance, tumor location, tumor grade, surgical approach, lymph nodes examined, and receipt of adjuvant therapy. Log rank testing was used to evaluate differences in overall survival between matched cohorts. ResultsA total of 1,258 patients met the inclusion criteria; 402 (32%) received neoadjuvant therapy. On multivariable logistic regression, increasing age (odds ratio 0.52, 95% confidence interval 0.34–0.80) was associated with reduced adjusted odds of undergoing neoadjuvant therapy, whereas proximal tumor location (odds ratio 3.67, 95% confidence interval 2.71–4.99) and poorly differentiated histology (odds ratio 1.78, 95% confidence interval 1.00–3.16) were associated with an increased adjusted odds of undergoing neoadjuvant therapy. A total of 271 patients undergoing neoadjuvant therapy were successfully matched to 271 patients undergoing upfront resection. There was no statistically significant difference in 5-year overall survival (58.8% vs 50.3%, P = .512) between matched cohorts. ConclusionNeoadjuvant therapy does not appear to be associated with an overall survival benefit in patients with stage IB stage gastric cancer.

Impact of adjuvant chemotherapy on the overall survival of patients with advanced stage low-grade serous ovarian carcinoma (130)

<b>Objectives:</b> Low-grade serous ovarian carcinoma (LGSOC) is a rare, relatively chemo-resistant histologic subtype of ovarian carcinoma. The impact of adjuvant chemotherapy on the survival of patients with the advanced-stage disease is not well defined. We aimed to utilize a large hospital-based database and investigate the survival of patients who did and did not receive adjuvant chemotherapy. <b>Methods:</b> Patients diagnosed between 2010-2015 with FIGO stage II-IV low-grade serous ovarian carcinoma who underwent primary debulking surgery with known residual disease status and had at least one month of follow-up were identified. Adjuvant chemotherapy or hormonal treatment was defined as receipt of chemotherapy or hormonal treatment within six months from surgery. Clinical-pathologic and demographic characteristics were compared with the Chi-square test. Overall survival was evaluated following the generation of Kaplan-Meier curves and compared with the log-rank test. A Cox model was constructed to control for a priori selected confounders. <b>Results:</b> A total of 618 patients with stage II-IV LGSOC were identified; 501 (81.1%) patients received adjuvant chemotherapy while 117 (18.9%) patients did not. In the present cohort, hormonal therapy was rarely administered (<i>n</i>=22, 3.6%). There were no differences between the two treatment groups in terms of age, presence of comorbid conditions, type of treatment facility, and insurance status. In the present cohort, the rate of CGR was 67.8%; 66.1%, and 75.2% among patients who did and did not receive adjuvant chemotherapy (p=0.057). The rate of adjuvant chemotherapy use was 67.4% for patients with stage II disease compared to 83.2% and 86.5% for those with stage III and IV disease, respectively. The median follow-up duration of the present cohort was 47.97 months. There was no difference in OS between patients who did and did not receive adjuvant chemotherapy (p=0.78); 4-year OS were 77.5% and 76.1%, respectively. Following stratification by residual disease status, adjuvant chemotherapy was not associated with a survival benefit for patients who achieved CGR (p=0.60; 4-year OS rates 85.5% and 79.5%, respectively) or had the gross residual disease (p=0.85; 4-year OS rates 63.1% and 66.3%, respectively). After controlling for patient age, presence of medical comorbid conditions, disease stage, and residual disease status, administration of adjuvant chemotherapy was not associated with better overall survival (HR: 0.87, 95% CI: 0.55-1.38). On the contrary, the presence of gross residual disease (HR: 2.25, 95% CI: 1.58, 3.21) was associated with worse overall survival. <b>Conclusions:</b> Adjuvant chemotherapy may not be associated with an overall survival benefit for patients with advanced-stage LGSOC.

A phase 2, randomized, open-label, multicenter study of sintilimab and anlotinib in combination with gemcitabine plus cisplatin (GemCis) as first-line therapy in patients (pts) with advanced biliary tract cancer (BTC): SAGC.

4100 Background: BTC has a higher incidence in China rather than worldwide, with extremely poor prognosis, and the efficacy of standard first-line therapy (GemCis) is rather limited. TOPAZ-1 study suggested immunotherapy + GemCis as first line in advanced BTC significantly improved OS and PFS vs placebo + GemCis with manageable safety, but the median OS was just 12.8 months. SAGC is the first randomized controlled phase 2 trial to evaluate first-line immunotherapy + antiangiogenic targeted drug + GemCis in advanced BTC. Methods: In this randomized controlled study, pts previously untreated for unresectable locally advanced, recurrent, or metastatic BTC were randomized 1:1 to receive sintilimab (200mg every 3 weeks [Q3W]) and anlotinib (10mg po qd, Days 1-14 Q3W) in combination with GemCis (Gem 1000 mg/m2 and Cis 25 mg/m2 on Days 1 and 8 Q3W) for up to 8 cycles, followed by sintilimab (200mg every 3 weeks [Q3W]) and anlotinib (10mg po qd, Days 1-14 Q3W) or GemCis (Gem 1000 mg/m2 and Cis 25 mg/m2 on Days 1 and 8 Q3W) for up to 8 cycles until disease progression or unacceptable toxicity. The primary objective was to assess the 1-year overall survival (OS). Secondary endpoints included OS, progression-free survival (PFS), objective response rate (ORR), and safety. Results: At data cutoff for this interim analysis (11 November, 2021), 48 pts were randomized to sintilimab + anlotinib + GemCis (n=26) or GemCis (n=22). The primary objective was not meet: the 1-year OS was 52.5% with sintilimab + anlotinib + GemCis and 36.3% with GemCis (p=0.437), but there was a trend of nominal OS benefit in patients treated with sintilimab + anlotinib + GemCis. PFS was significantly improved with sintilimab + anlotinib + GemCis vs GemCis (6.4m vs 5m; p=0.014). ORR was 37.5% with sintilimab + anlotinib + GemCis and 26.7% with GemCis. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 69.2% of pts receiving sintilimab + anlotinib + GemCis and38.7% of pts receiving GemCis. TRAEs led to discontinuation of any study medication in 7.7% of pts receiving sintilimab + anlotinib + GemCis and 9.1% of pts receiving GemCis. Conclusions: In pts with advanced BTC, sintilimab + anlotinib + GemCis could improve OS and PFS vs GemCis with manageable safety, indicating sintilimab + anlotinib + GemCis may be a new first-line standard of care regimen. Research Sponsor: Innoventbio Biologics, Inc, Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Clinical trial information: NCT04300959.

The optimal therapy strategy for epidermal growth factor receptor-mutated non-small cell lung cancer patients with brain metastasis: A real-world study from Taiwan.

BackgroundThe treatment options for epidermal growth factor receptor (EGFR)‐mutated non‐small cell lung cancer (NSCLC) with brain metastases (BMs) include EGFR‐tyrosine kinase inhibitors (TKIs), stereotactic radiosurgery (SRS), whole‐brain radiotherapy, brain surgery, and antiangiogenesis therapy. As treatment options evolve, redefining optimal treatment strategies to improve survival are crucial.MethodsA total of 150 EGFR‐mutant NSCLC patients with BMs who received first‐ or second‐generation EGFR‐TKIs as first‐line treatment between January 2012 and October 2019 were included in this analysis.ResultsAfter multivariate analysis, patients with the graded prognostic assessment for lung cancer using molecular markers (Lung‐mol GPA) ≥3 (hazard ratio [HR]: 0.538, 95% confidence interval [CI]: 0.35–0.83), who received afatinib or erlotinib as first‐line treatment (HR: 0.521, 95% CI: 0.33–0.82), underwent SRS therapy (HR: 0.531, 95% CI: 0.32–0.87), or were sequentially treated with osimertinib (HR: 0.400, 95% CI: 0.23–0.71) were associated with improved overall survival (OS). Furthermore, SRS plus EGFR‐TKI provided more OS benefits in patients with Lung‐mol GPA ≥3 compared with EGFR‐TKI alone in our patient cohort (44.9 vs. 26.7 months, p = 0.005). The OS in patients who received sequential osimertinib therapy was significantly longer than those without osimertinib treatment (43.5 vs. 24.3 months, p < 0.001), regardless of T790 mutation status (positive vs. negative vs. unknown: 40.4 vs. 54.6 vs.43.4 months, p = 0.227).ConclusionsThe study demonstrated that EGFR‐mutant NSCLC patients with BMs could be precisely treated with SRS according to Lung‐mol GPA ≥3. Sequential osimertinib was associated with prolonged survival, regardless of T790M status.

HHLA2 Immune Checkpoint Is a Novel Prognostic Predictor in Hepatocellular Carcinoma

Immunotherapy targeting PD-1/PD-L1 had low response rates and limited overall survival benefits in patients with hepatocellular carcinoma (HCC). We characterized the expression pattern and clinical significance of B7 family immune checkpoint proteins HHLA2, PD-L1, and B7-H4 in HCC. Immunohistochemistry for HHLA2, PD-L1, B7-H4, CD3, and CD8 was performed on tissue microarray slides from 103 surgically resected HCC specimens. Positive HHLA2 was detected in 63 (61.2%) cases, with 50 cases showing low expression and 13 cases showing high expression. Positive PD-L1 (combined positive score [CPS] ≥1) was detected in 27 (26.2%) cases, with the majority showing low expression (CPS <10) (n = 25) and only 2 cases showing high expression (CPS ≥10). The coexpression of PD-L1 and HHLA2 was observed in 17 (16.5%) cases. B7-H4 expression was detected in only one (1.0%) case. HHLA2-positive cases had significantly better survival than HHLA2-negative cases (P = .042). Positive HHLA2 correlated with higher density of CD8+ intratumoral lymphocytes (P = .015). The subgroup with both HHLA2 expression and high CD8+ cell density exhibited the most favorable prognosis (P = .036). HHLA2 is frequently expressed in HCC. Positive HHLA2 correlates with higher CD8+ cell density and favorable prognosis. HHLA2 may be considered a potential therapeutic immune target in HCC.

Significance of upfront cytoreductive nephrectomy stratified by IMDC risk for metastatic renal cell carcinoma in targeted therapy era – a multi-institutional retrospective study

BackgroundThis retrospective multicenter study aimed to evaluate the survival benefit of upfront cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (RCC) patients stratified by International Metastatic RCC Database Consortium (IMDC) risk criteria.MethodsWe reviewed the medical records in the Michinoku Database between 2008 and 2019. Patients who received upfront CN, systemic therapy without CN (no CN) and CN after drug therapy (deferred CN) were analyzed. To exclude selection bias due to patient characteristics, baseline clinical data were adjusted by inverse probability of treatment weighting (IPTW). Overall survival (OS) was compared between upfront CN and non-upfront CN (no CN plus deferred CN). Associations between time-varying covariates including systemic therapies and OS stratified by IMDC risk criteria were analyzed by IPTW-adjusted Cox regression method.ResultsOf 259 patients who fulfilled the selection criteria, 107 were classified in upfront CN and 152 in non-upfront CN group. After IPTW-adjusted analysis, upfront CN showed survival benefit compared to non-upfront CN in patients with IMDC intermediate risk (median OS: 52.5 versus 31.3 months, p < 0.01) and in patients with IMDC poor risk (27.2 versus 11.4 months, p < 0.01). In IPTW-adjusted Cox regression analysis of time-varying covariates, upfront CN was independently associated with OS benefit in patients with IMDC intermediate risk (hazard ratio 0.52, 95% confidence interval 0.29–0.93, p = 0.03) and in patients with IMDC poor risk (0.26, 0.11–0.59, p < 0.01).ConclusionsUpfront CN may confer survival benefit in RCC patients with IMDC intermediate and poor risk.

Association between Timing and Duration of Adjuvant Chemotherapy and Colorectal Cancer Survival in Korea, 2011-2014: A Nationwide Study based on the Health Insurance Review and Assessment Service Database.

Background: Population-based analyses of the treatment outcomes of colorectal cancer (CRC) in Asian countries are limited. Therefore, we conducted a nationwide study to assess the relationship between the timing and duration of adjuvant chemotherapy (AC) and survival in patients with CRC in South Korea.Methods: Data on AC from the Health Insurance Review and Assessment Service Database (HIRA) were analyzed, and the survival of patients who underwent curative-intent surgical resection for CRC between 2011 and 2014 was investigated.Results: From the HIRA data, 45,992 patients with stage II-III CRC were identified. Chemotherapy regimens were administered as follows: 10,640 (23.3%) received 5-fluorouracil and leucovorin/capecitabine (FL/CAP), 13,083 (28.7%) received FL/CAP plus oxaliplatin (FOLFOX/CAPOX), 299 (0.7%) received uracil and tegafur/doxifluridine (UFT/D), and 21,570 (47.3%) underwent surgery alone. Patients who did not receive AC had worse survival than those who received AC in both the colon and rectum groups (HR, 1.96, 95% CI, 1.85-2.07 and HR, 2.18, 95% CI, 2.01-2.37, respectively). Regarding patients with stage II-III CRC, AC initiation ≥ 2 months after surgery was associated with a significant decrease in overall survival (OS) (FL/CAP: HR, 1.82; 95% CI, 1.53-2.17 and FOLFOX/CAPOX: HR, 2.92; 95% CI, 2.47-3.45); however, the effects of UFT/D regimens were not statistically significant. For patients with stage II-III colon cancer, AC <3 months had lower OS (FL/CAP: HR, 3.72, 95% CI, 2.80-4.94; FOLFOX/CAPOX: HR, 2.15, 95% CI, 1.87-2.47; and UFT/D: HR, 1.74, 95% CI, 0.56-5.41). In terms of patients with stage II-III rectal cancer, AC <3 months, regardless of chemotherapy regimens, had a significant lower survival (FL/CAP: HR, 1.91, 95% CI, 1.66-2.20; FOLFOX/CAPOX: HR, 2.20, 95% CI, 1.75-2.77; and UFT/D: HR, 3.71, 95% CI, 1.45-9.44).Conclusions: Postoperative time to initiation and duration of AC were associated with survival. Based on our results, initiating AC within 2 months after surgery and administering AC for >3 months can potentially have an OS benefit in patients with stage II-III CRC.