Subsequent Lines Of Treatment Research Articles

Safety and toxicity of cabozantinib monotherapy in patients with advanced renal cell carcinoma: a Russian multicenter observational study

Aim. To assess the safety and to analyze an influence of cabozantinib monotherapy toxicity on treatment efficacy in unselected Russian patients with metastatic renal cell carcinoma (mRCC).
 Materials and methods. Medical data of 92 patients with verified mRCC were included in the study. The median age of the patients was 56 (1979) years, most of them - 60 (65.2%) were of male gender. Twenty five (27.2%) persons had Eastern Cooperative Oncology Group performance status (ECOG PS). At the time of cabozantinib monotherapy start 5 (5.4%) patients had favorable, 54 (58.7%) intermediate, and 33 (35.9%) unfavorable prognosis by International Metastatic Renal Cancer Database Consortium (IMDC) model. Eighty-three (90.2%) patients were pretreated, including 76 (82.6%) patients who previously received anti-angiogenic agents. All patients were administered with cabozantinib monotherapy (60 mg/day); dose adjustment was performed according to the instruction.
 Results. Adverse events (AEs) were reported in 81 (88.0%) of 92 patients; 30 (32.6%) AEs were grade 34. Toxicity-related dose reduction of cabozantinib was required in 28 (30.4%), treatment interruption in 15 (16.3%), and discontinuation in 2 (2.2%) patients. The most common AEs were hypertension (69 patients, 75.0%), asthenia (47 patients, 51.1%), diarrhea (43 patients, 46.7%), and palmar-plantar erythrodysesthesia (43 patients, 46.7%). The most common severe AEs were: arterial hypertension (17 patients, 18.5%), diarrhea (6 patients, 6.5%), and palmar-plantar erythrodysesthesia (2 patients, 2.2%). The most frequent laboratory abnormalities during therapy were elevated serum transaminases (33 patients, 35.9%), anemia (13 patients, 14.1%), and thrombocytopenia (10 patients, 10.9%). No previously unreported AEs or laboratory abnormalities were observed. There was a significant increase in progression-free survival (hazard ratio 2.5; 95% confidence interval 1.05.9; p=0.046) and overall survival (hazard ratio 3.0; 95% confidence interval 1.28.3; p0.025) in patients with treatment-related arterial hypertension.
 Conclusion. The observational study confirmed the acceptable safety profile of cabozantinib in the first and subsequent lines of treatment in mRCC patients. No new safety signals were identified. Treatment-related arterial hypertension may be a favorable predictor of survival.

Помалидомид в терапии рецидивирующей/рефрактерной множественной миеломы

Pomalidomide is a third-generation immunomodulatory drug (IMiD) that has taken an important place in the management of relapsed/refractory multiple myeloma (RRMM) including in patients with resistance to lenalidomide (R). Synergism of antitumor activity was obtained by combining pomalidomide with dexamethasone (Pd), proteasome inhibitors (PIs), and monoclonal antibodies directed against CD38 and SLAMF7 receptors. The dose-limiting toxicity of pomalidomide is neutropenia (4860% grade 3 for a dose of 4 mg/day). Overcoming resistance to lenalidomide is seen as a key benefit of pomalidomide in the development of triplets that can be used in 2nd and subsequent lines of RRMM treatment. In OPTIMISMM study (phase III), 70% of patients were lenalidomide resistant. Randomization was performed on VPd (bortezomib-Pd) and Vd (bortezomib, dexamethasone) therapy. Vd as control was implemented in two related phases III trials ENDEAVOR (carfilzomib, dexamethasone) and CASTOR (daratumumab-Vd). For patients with resistance to lenalidomide, the median progression-free survival (PFS) was 9.5 mon for VPd in OPTIMISMM; 9.3 mon in CASTOR (resistant to R 21%) for DVd, and 9.3 mon in ENDEAVOR (21%) for Kd - 8.6 mon. The ICARIA-MM study (phase 3; resistance to R 94%) demonstrated the benefit of incorporating isutaximab into the triplet (median PFS 11.1 and 5.9 mon for Isa-Pd and Pd respectively; p0.0001). Similar data were obtained in the ELOQUENT-3 study (phase II; resistance to R - 90%) for elotuzumab (10.3 and 4.7 mon for EPd and Pd respectively; p=0.008). In the APOLLO study (phase III; resistance - 80%), the efficacy of the triplet with daratumumab was confirmed (12.4 and 6.9 mon for DPd and Pd respectively; p = 0.0018). In the present review, the focus is on the consideration of treatment regimens that are of relevance to Russian clinical practice.

Cost-effectiveness analysis of trastuzumab deruxtecan in patients with HER2-low advanced breast cancer based on DESTINY-Breast04.

Breast cancer is a rapidly raising healthcare problem worldwide. DESTINY-Breast04 demonstrated that trastuzumab deruxtecan (T-Dxd) had a survival advantage comparing to the physician's choice of chemotherapy for patients with HER2-low metastatic breast cancer. But at the same time, this expensive novel treatment also brought an economic burden. This study assessed the cost-effectiveness of T-Dxd based on results of DESTINY-Breast04 from the perspective of Chinese healthcare system. A three-state partitioned-survival model [progression-free survival (PFS), progressive disease (PD) and death] based on data from DESTINY-Breast04 and Chinese healthcare system was used to estimate the incremental cost-effectiveness ratio (ICER) of T-Dxd vs. the physician's choice of chemotherapy for HER2-low metastatic breast cancer. Costs, quality-adjusted life-years (QALYs) and the ICER in terms of 2022 US$ per QALY gained were calculated for both hormone receptor-positive cohort and all patients. One-way and probabilistic sensitivity analyses were performed to assess the model robustness. Compared with the physician's choice of chemotherapy, T-Dxd increased costs by $104,168.30, while gaining 0.31 QALYs, resulting in an ICER of $336,026.77 per QALY in all patients. The costs of T-Dxd and the utility of PFS were the crucial factors in determining the ICER. In the hormone receptor-positive cohort, the ICER was lower than that in all patients, with the ICER of $274,905.72 per QALY. The ICER was much higher than the commonly accepted willingness-to-pay threshold ($357,96.83 per QALY). T-Dxd as second- or subsequent-line treatment is not a cost-effective treatment option for HER2-low metastatic breast cancer from the perspective of the Chinese healthcare system.

Panitumumab plus trifluridine/tipiracil as anti-EGFR rechallenge therapy in patients with refractory RAS wild-type metastatic colorectal cancer: Overall survival and subgroup analysis of the randomized phase II VELO trial.

The randomized phase II VELO trial showed that the addition of panitumumab to trifluridine/tipiracil significantly improves progression-free survival (PFS) as compared to trifluridine/tipiracil in third-line therapy in patients with refractory RAS wild-type (WT) metastatic colorectal cancer (mCRC). With longer follow-up, final overall survival results and posttreatment subgroup analysis are presented. Sixty-two patients with refractory RAS WT mCRC were randomly assigned to receive, as third-line therapy, trifluridine/tipiracil alone (arm A) or in combination with panitumumab (arm B). Primary endpoint was PFS; secondary endpoints included overall survival (OS) and overall response rate (ORR). Median OS was 13.1 months (95% CI 9.5-16.7) in arm A compared to 11.6 months (95% CI 6.3-17.0) in arm B (HR: 0.96, 95% CI 0.54-1.71, P = .9). To evaluate the impact of subsequent lines of treatment, subgroup analysis was performed for the 24/30 patients in arm A, that received fourth-line therapy after disease progression. Median PFS was 4.1 months (95% CI 1.44-6.83) for 17 patients treated with anti-EGFR rechallenge as compared to 3.0 months (95% CI 1.61-4.31) for seven patients that received other therapies (HR: 0.29, 95% CI 0.10-0.85, P = .024). Median OS from the start of fourth-line treatment was 13.6 months (95% CI 7.2-20), and 5.1 months (95% CI 1.8-8.3) for patients treated with anti-EGFR rechallenge vs other therapies, respectively (HR: 0.30, 95% CI 0.11-0.81, P = .019). Final results of the VELO trial support the role of anti-EGFR rechallenge in the continuum of care of patients with RAS/BRAF WT mCRC.

Real-world outcomes of long-term efficacy of T-DM1 after discontinuation due to limiting toxicity in patients with HER2-positive metastatic breast cancer.

e13034 Background: Antibody-drug conjugates (ADC) are widely used in the treatment of breast cancer (BC). In our service, we observed that a significant number of patients (pts) with HER2-positive metastatic breast cancer (MBC) treated with T-DM1 had long-lasting response and survival rates, even after discontinuing T-DM1 due to limiting toxicity. However, data are scarce regarding its long-term benefit. We performed a retrospective study to evaluate the long-term efficacy of T-DM1 in the treatment of HER2-positive MBC. Methods: Medical records of pts with HER2-positive MBC treated with T-DM1 between September 2013 and January 2023 were reviewed. We analyzed data in the overall population and in the subgroup of pts who discontinued T-DM1 due to only limiting toxicity and did not have disease progression or death for at least 12 months, without receiving other subsequent lines of treatment. The primary endpoints were progression-free survival (PFS) and overall survival (OS) from the start of the treatment with T-DM1 to disease progression or death for the overall population, and from the time of T-DM1 discontinuation to disease progression or death for the aforementioned subgroup. Secondary endpoints were objective response rate (ORR) and toxicity. Results: A total of 73 pts were included. In the overall population, ORR was 82.6%, median PFS was 12.7 months (CI95% 8-16) and median OS was 53.9 months (CI95% 34-73). 10 (13.6%) pts had T-DM1 discontinued due to only limiting toxicity and had no disease progression or death for at least 12 months. In this specific subgroup, 2 pts received T-DM1 as first line, 6 pts as second line, and 2 as third or more lines. At the start of T-DM1, 5 pts had visceral metastasis (3 liver, 2 lung), and 2 had only leptomeningeal involvement. Median age was 57 years (IQR 49-70) and median T-DM1 duration was 30 months (IQR 12-45). At the time of T-DM1 discontinuation, 9 pts presented complete response (CR) and 1 presented partial response (PR). 5 pts maintained CR, with no evidence of disease progression or death throughout the analyzed period. The PFS of these 5 pts, from the time of T-DM1 discontinuation to the last evaluation, was 35.6, 37.9, 40.5, 42.7 and 68.5 months. In the entire subgroup, median PFS was 22.5 months, 5-year OS was 66.7% and median OS was not reached. The adverse events that led to the T-DM1 discontinuation were thrombocytopenia (10%), nausea, vomiting and fatigue (10%), pneumonitis (20%), hepatic pseudocirrhosis (20%) and peripheral neuropathy (40%). Conclusions: Our experience suggests that pts with HER2-positive MBC who had T-DM1 discontinued due to limiting toxicity may derive long-term benefit. Further prospective studies are warranted to evaluate our findings, also including other ADC.

Real world assessment of clinical benefit with consolidation durvalumab following chemoradiotherapy in stage III unresectable non-small cell lung cancer.

e18853 Background: The phase III PACIFIC trial compared the efficacy of consolidation durvalumab to placebo in newly diagnosed, unresectable stage III non-small cell lung cancer (NSCLC) who had not progressed after chemoradiotherapy (CRT). With a median follow-up of 34.2 months, the median progression free survival (PFS) was 16.9 months (13.0-23.9) compared to 5.6 months (4.6-7.7) for placebo (HR = 0.55, 95% CI,0.45-0.68). We report a real-world study that utilizes surrogate endpoints to assess duration of clinical benefit with consolidation durvalumab. Methods: OncoHealth, a digital health company, conducted a retrospective observational real-world study to assess time to treatment failure in patients with unresectable Stage III NSCLC who received consolidation durvalumab after completion of CRT between June 2018-June 2021. Data sources included electronic medical records (EMR) submitted with prior authorization (PA) requests to OncoHealth and medical claims data. With a data cut-off of 12/22/2022, real-world Time to Progression (rwTTP), and real-world Time to Next Treatment (rwTTNT) were evaluated to assess time to treatment failure. All end points were measured from durvalumab administration dates, rwTTP spanned until earliest date of clinician-assessed progression, and rwTTNT spanned until initiation of subsequent treatment. Results: Total of 281 patients with unresectable Stage III NSCLC who received durvalumab after completion of definitive CRT were identified. Median age was 71 years (range: 53 to 88), 57% male, 53% former smokers, 47% Stage IIIA, 52% non-squamous histology and 98% received concomitant platinum-based chemotherapy prior to durvalumab. Median time between completing CRT and initiating durvalumab was 41 days. With a cutoff date of 12/22/2022, and a median follow up of 28.4 months, 34% (n = 95) experienced disease progression. Sites of progression included lung, lymph nodes, adrenal, liver, bone and brain. The median rwTTP was 10.6 months (range: 2.0-38.1 months) and median rwTTNT was 12.4 months (range: 2.5-39.6 months). Conclusions: In this real-world study, the patient and disease characteristics available in EMR were comparable to those reported in the PACIFIC trial. The rwTTP and rwTTNT reported here suggest treatment failure occurred within one year of exposure to durvalumab and subsequent line of treatment was initiated shortly thereafter. Variables such as co-morbidities, performance status, treatment compliance, change of payers and barriers to treatment in real world will be further explored.

Updated analysis of real-world treatment outcomes of first-line axitinib plus pembrolizumab in patients with advanced renal cell carcinoma in the United States.

e16553 Background: The combination of axitinib plus pembrolizumab (AXI+PEM) is a standard of care in the first-line (1L) treatment of patients with advanced clear cell renal cell carcinoma (ccRCC). Previous analyses described the demographic and clinical characteristics, as well as outcomes of patients receiving 1L AXI+PEM in a real-world setting. We report updated data with longer follow-up for this cohort. Methods: Electronic medical record data from the Flatiron Health, nationwide de-identified Database (280 cancer clinics across 800 sites in the US) were used to select patients with confirmed Stage IV/metastatic RCC and who initiated 1L AXI+PEM on or after 1/1/2018 to 7/31/2022. Analyses included best overall response to 1L therapy; real-world progression-free survival (rwPFS) and overall survival (rwOS) are reported as patients without a clinical event (rwPFS; progression/death; rwOS; death) at landmark time periods (3, 6, 9, 12, 18 and 24 months); denominators include censored patients. Other data are reported as medians (min, max) unless otherwise noted. Results: Three hundred and forty patients received 1L AXI+PEM, with an extended mean follow-up of 19.2 (0.1–41.6) months. Most patients were male (69.1%) and mean age of 64.1 (21.0–83.0) years. At diagnosis, 56.5% of patients had Stage IV RCC and 78.2% of patients had clear cell histology. IMDC Risk Score was favorable, intermediate, and poor in 24 (6.8%), 123 (34.4%), and 78 (22.1%) patients, respectively (unknown = 125 (36.8%)). At the time of analysis, 192 patients (56.5%) received only 1L therapy with AXI+PEM, while 148 patients (43.5%) received ≥1 subsequent line of treatment. Vascular endothelial growth factor receptor (VEGF-R) inhibitors were the most commonly used second-line (2L) treatment (109 patients, 73.6%), with cabozantinib being the most frequently used VEGF-R inhibitor (84 patients, 77.1%). Median rwPFS was 8.6 (CI: 7.2-9.7) months with 15.0% of patients achieving rwPFS at 2 years. Median rwOS was 29.4 (CI: 24.2-37.3) months with 38.5% of patients alive at 2 years. Best overall response rate to 1L was 54.1% (complete or partial response observed in 184/340 patients). 51.5% of patients required a dose hold, of which 58.3% required it due to an adverse event. Conclusions: This updated analysis supports the use of 1L AXI+PEM in patients with advanced RCC across all IMDC risk groups, providing further understanding of the clinical outcomes and treatment patterns of patients with advanced RCC in the US. [Table: see text]

Evaluating racial disparities for patients with advanced hepatocellular carcinoma (HCC) receiving first line immunotherapy within an equal access system.

4109 Background: The incidence and mortality of HCC are increasing in the USA. HCC disparities have been reported across the entirety of the cancer timeline, from screening to local and systemic treatment and liver transplant. We aim to analyze the clinical characteristics, outcomes, and racial disparities in patients with advanced HCC receiving first-line Atezolizumab plus Bevacizumab (A+B) in the Veterans Health Administration (VHA) – the only health care system in the USA that provides equal access to all patients. Methods: Patients were followed from their A+B initiation date through the earliest of the last VHA visit, loss to follow-up, death, or end of study on Jan 31, 2023. Structured electronic health record and chart review data were retrospectively collected to determine patient baseline characteristics, including self-reported race, number of A+B doses, treatment response, subsequent line of treatment, length of follow-up, and overall survival (OS). The Chi-Squared test was used to compare rates, and Mann-Whitney test was used to compare medians. Results: Three hundred twenty-five patients were included. 64% were non-Hispanic White (NHW), and 36% were all other (AO) ethnicities or races combined (26% Black, 8% Hispanic, 2% Asian or Indigenous). The median age for each cohort was similar (66 years for AO vs. 68 for NHW), and ECOG performance was <1 in nearly 90% of each cohort. Viral hepatitis accounted for 70% and 48% of AO and NHW, respectively (p=0.0001). Despite clinical differences in OS and progression free survival (PFS), they were not statistically significant. Conclusions: Our VHA real-world data shows that despite having statistically significant etiologies, there was no statistically significant difference in the PFS and OS of patients with advanced HCC receiving first-line A+B in an equal access care system. This study supports our group’s findings in other malignant cohorts within VHA where equal healthcare access can mitigate other socio-demographic and biological factors. [Table: see text]

Shifting perspectives on the value of non-OS endpoints and PROs: Considerations across stakeholder groups to support oncology HTA decision-making.

e13646 Background: The ability of novel cancer drugs to extend patients’ overall survival (OS) has been key to determining their approval and access conditions. However, in some disease settings, OS can have limitations: delayed access due to the time required to collect mature OS data; confounding from subsequent treatment lines; and poor ability to reflect value beyond survival. Stakeholders such as regulators and physicians increasingly recognise the value of non-OS endpoints as surrogates for OS. In addition, non-OS endpoints and patient reported outcomes (PROs) may have stand-alone value, e.g., in capturing disease burden. However, stakeholders are misaligned on the benefits of non-OS endpoints and PROs due to differences in underlying value drivers. Methods: This study investigates stakeholder perceptions of non-OS endpoints and PROs, based on 76 semi-structured interviews with physicians, patients, patient advocacy groups (PAGs), regulators and health economists in 7 key markets (U.S., Canada, Japan, UK, France, Germany and Italy), 3 roundtable discussions and a literature review. Results: Non-OS endpoints address some concerns with OS as they can be captured earlier in trials and may act as surrogates of OS; show reduced susceptibility to confounding; and better reflect the value to patients beyond survival. However, the value perception of non-OS endpoints and PROs varies across stakeholders: 1) Patients / PAGs value non-OS endpoints as they capture outcomes beyond mortality, e.g., the avoidance of surgery and PROs such as pain. 2) Physicians acknowledge the scientific and clinical trial limitations of relying primarily on OS, but note that OS limitations vary by cancer type / stage. 3) Regulators are accepting of non-OS endpoints, providing accelerated / conditional approvals when they are used as surrogates for OS or when they have standalone value, and increasingly expect PROs in submission dossiers. 4) Payers are uncertain, as without appropriate validation, drugs approved based on non-OS endpoints risk additional treatment burden and cost to healthcare systems without patient benefit. The limited alignment in value perception among stakeholders is further complicated as this may shift during the course of the disease – e.g., patients at early stages may value treatments which prolong survival but may place more emphasis on quality of life and freedom from progression as the disease advances. Conclusions: The value of non-OS endpoints and PROs is increasingly recognised, particularly by physicians and regulators; payers, however, can be less accepting, driven largely by uncertainties around their value, as surrogates or as stand-alone measures of benefit. Stakeholders must align on the value of non-OS endpoints and PROs, ensuring they are fit for purpose for each cancer type / stage, to improve their acceptance and advance patient access to novel therapies.

Profile of toxicities and quality of life in long-term survivors treated with immunotherapy: A prospective cross sectional trial.

6569 Background: Long-term cancer survivors (LTS) patients (pts) treated with immunotherapy (IT) represent a relatively new population whose characteristics, such as long-term toxicities, quality of life (QoL), and financial toxicities, need to be elucidated in a real-world setting. The aim of this study is to evaluate long-term toxicities in patients free of disease progression and treated with IT. Methods: This is a cross-sectional, multicentric study, involving ten Italian centres. Pts should have started IT (as monotherapy or combination, either in curative or adjuvant setting) more than 2 years before accrual and they needed to be progression free at last follow up (fup). Subjects who discontinued IT for disease progression or who started any subsequent line of systemic treatment were excluded. We retrieved baseline demographic and clinical characteristics of the pts, as well as haematological and biochemical exams at the start of IT (baseline) and at the last fup. We also assessed the patient's toxicities (according to CTCAE v5.0) at last fup and we submitted to each patient three questionnaires: PRO-CTCAE (selection of questions), EORTC QLQ C30, and FITALY (for financial toxicities), which were analysed according to subdomains. Results: We enrolled 141 LTS pts treated with IT from 2013 to 2022. Median age was 69 years (35-88), most were male (72%), and still receiving IT at time of last fup (72%). Primary tumour was in lung (43%), genito-urinary tract (26%), or melanoma (14%). IT included pembrolizumab and nivolumab in 40% and 32% of cases, respectively. The median global health status of QoL was 83 (IQR 25). Any toxicities > G2 negatively impacted on individual functional scales (physical, p=0.02; role, p= 0.06; and social p=0.08). A higher baseline Charlson Comorbidity Index was associated with worse global health status (p=0.02) at last fup. Most frequent low grade adverse events were fatigue, dyspnoea, and insomnia; younger age (< 65 years) was associated with higher pain (p=0.04). PRO-CTCAE questionnaires showed that the prevalent complained symptoms were rheumatological and cutaneous, regardless of tumor site. The most affected domain of financial toxicities was financial stress, including costs for out of pocket medications and transports. Pts with melanoma (p=0.01), with skin toxicities (p=0.04), and younger than 65 years (p=0.01) were at higher risk of financial toxicities (global score). Conclusions: Overall QoL is well preserved in LTS treated with IT. At long term fup, the pts complained mostly about rheumatological and skin adverse events. Financial stress due to out of pocket costs was the most affected financial toxicity domain. Baseline comorbidities predicted a worse long-term global health status, while young age, skin toxicities and melanoma predicted higher financial toxicities.

Final survival analysis of the phase III OVHIPEC-1 trial of hyperthermic intraperitoneal chemotherapy in ovarian cancer after ten year follow-up.

5509 Background: The randomized, phase 3 OVHIPEC-1 trial (NCT00426257) investigated the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery in patients with stage III epithelial ovarian cancer who were ineligible for primary cytoreduction. OVHIPEC-1 previously demonstrated improved recurrence-free and overall survival after 4.7 years of follow-up. Here, we report the final survival outcomes after ten years of follow-up. In addition, we report new data on the subsequent anti-cancer treatments given after disease progression. Methods: Patients were randomized to receive interval cytoreductive surgery with or without HIPEC, after receiving three cycles of neo-adjuvant carboplatin and paclitaxel. Randomization was performed at the time of surgery when either complete (no visible disease) or optimal cytoreduction (residual tumor measuring <10mm in diameter) was anticipated. All patients received an additional three cycles of adjuvant systemic chemotherapy. We analyzed survival according to the intention-to-treat principle using stratified log-rank tests and Kaplan-Meier methods. Subsequent lines of therapy were compared between arms. Results: At a median follow-up of 10.1 years, 114 of 123 patients (92.7%) who underwent surgery alone and 109 of 122 patients (89.3%) who had surgery-plus-HIPEC experienced recurrence, progression, or death from any cause. Median recurrence-free survival was 10.7 months in the surgery group compared to 14.3 months in the surgery-plus-HIPEC group (HR, 0.63; 95% confidence interval [CI], 0.48-0.83; stratified P<0.001). One hundred and eight patients (87.8%) in the surgery group have died as compared to 100 patients (82.0%) in the surgery-plus-HIPEC group. Median overall survival was 33.3 versus 44.9 months (HR, 0.70; 95% CI, 0.53-0.92; stratified P=0.011), respectively. Subsequent anti-cancer therapies, including chemotherapy (platinum and non-platinum based), secondary surgery, poly (ADP-ribose) polymerase (PARP) inhibitors and bevacizumab, were received by 104 patients (84.6%) in the surgery group and 100 patients (82.0%) in the surgery-plus-HIPEC group. The median number of subsequent systemic treatment lines was 2 (IQR 1-3) in both arms. Conclusions: This study provides the first long-term survival analysis of HIPEC in ovarian cancer and confirms the benefit of HIPEC in patients with primary stage III epithelial ovarian cancer undergoing interval cytoreductive surgery. No imbalance in subsequent therapy after disease recurrence was found that could explain the improved overall survival after HIPEC. Clinical trial information: NCT00426257 .

Real-world clinical outcomes in patients (pts) with HR+/HER2- metastatic breast cancer (mBC) treated with chemotherapy (CT) in the United States (US).

e18871 Background: HR+/HER2- mBC remains incurable, despite progress made with endocrine therapy (ET) + CDK4/6i in prolonging survival. After resistance to ET-based treatment, options are limited to CT and a decrease in survival is observed with every subsequent line of treatment received. This study describes real-world outcomes in pts with HR+/HER2- mBC initiating CT or previously treated with CT in the US. Methods: This retrospective, observational cohort study used the ConcertAI Patient360™ curated dataset of electronic medical record data from the US. Pts (≥18 years) diagnosed with HR+/HER2- mBC and initiating their first CT from January 2011 to June 2021 were included. Real-world outcomes were assessed for all pts who initiated treatment with a first CT, and those who were subsequently treated with a second, third, and fourth CT. Index date was defined as the CT start date of each systemic therapy line. Results: In total, 1545 pts met the eligibility criteria and were included for analysis. Pts were primarily female (99%) and White (76%); median age was 61 years (IQR, 52-69) and 68% had visceral metastases. Most pts (80%) were treated in a community setting and 41% received their first CT in 1L; 58% and 44% had prior exposure to ET and CDK4/6i in the mBC setting, respectively. The median time from mBC diagnosis to first CT was 12 months (IQR, 1.4-30.8). Among all pts included, 57%, 31% and 17% were subsequently treated with a second, third, and fourth CT, respectively, during the study period. Capecitabine and paclitaxel were the most used as the first (45% and 29%), second (35% and 30%), and third (25% and 22%) CT, while gemcitabine (22%) and eribulin (20%) were used most as fourth CT. Clinical outcomes assessed are summarized in the table. Median real-world overall survival (rwOS; 95% CI) from time of mBC diagnosis was 48.5 months (45.5-51.5). Median rwOS from first CT treatment start date was 23.3 months (21.3-25.4). In pretreated pts with 1, 2, or 3 prior lines of CT, median rwOS from each index date was 16.5 months (14.8-18.3), 11.8 months (10.4-13.1), and 9.1 months (7.3-11.2), respectively. Conclusions: Among pts with HR+/HER2- mBC in this analysis, CT choice and real-world clinical outcomes per systemic therapy line were comparable to existing literature. Outcomes decreased as pts advanced CT lines, indicating that in this setting the unmet need remains high. More efficacious treatment options are needed for ET-resistant, chemo-naïve pts and pts pretreated with CT with HR+/HER2- mBC. [Table: see text]

LIFETIME TREATMENT BURDEN OF PATIENTS WITH MANTLE CELL LYMPHOMA: SIMULATION‐BASED ANALYSIS OF REAL‐WORLD DATA FROM 20 YEARS

Background: Mantle cell lymphoma (MCL) is a rare subtype of B-cell lymphoma that is currently considered incurable, yet treatable condition with increasing amount of treatment options. Alas, the availability of novel therapies is often limited to later treatment lines due to their excessive cost. In this study, we aimed to conduct a baseline analysis on the lifetime treatment burden of MCL patients treated with conventional chemoimmunotherapy regimes. Specifically, we wanted to estimate the number of treatment lines received during 20-year follow-up to determine the number of MCL patients that could potentially receive novel, targeted therapies during the follow-up period. Methods: A real-world data set of 548 patients diagnosed and treated for MCL between the years 2000 and 2020 was collected from seven Finnish hospitals and one Spanish hospital. First, this data was analyzed using the traditional methods of survival analysis for overall survival, time to progression and follow-up time. From these initial results, we estimated the risk of progression from the first treatment line to subsequent treatment lines, to death from MCL, or death from other causes. These estimates were then applied in our competing risk analysis based on Weibull distribution and the data was completed by dynamic imputation of health event histories using discrete semi-Markov transitions in a limited time space to extrapolate the censored variables from our data set up to 20 years of follow-up for each patient. A state distribution plot from our analysis is shown below (Figure 1). Results: In our original data set, the median duration of follow-up was three years (range 0 to 18 years). At 10 years of simulated follow-up, 525 (95.8%) patients had received first-line therapy, 307 (56.0%) had received second-line therapy, 148 (27.0%) had received third-line therapy and 64 (11.7%) had received fourth-line therapy. A total of 262 (47.8%) patients had died from MCL and 113 (20.6%) from other causes. After 20 years of simulated follow-up, the respective figures were 525 (95.8%), 373 (68.1%), 192 (35.0%) and 85 (15.5 %). A total of 362 (66.1%) of patients had died from MCL and 166 (30.3%) from other causes. The median number of treatment lines received both at 10 and 20 years of follow-up was three. Figure 1. State distribution plot from 20-year follow-up The research was funded by: North Ostrobothnia Health Care District Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cancer Health Disparities No conflicts of interests pertinent to the abstract.

Comparison of Two Chemotherapy Regimens After First-Line Treatment for HER2-Negative Metastatic Gastric Cancer.

Metastatic stage gastric cancer is a disease with a poor prognosis and the likelihood of achieving a cure in these patients is low. Treatment response to subsequent-line treatments is poor. We aimed to investigate the effectiveness of the folinic acid, fluorouracil and irinotecan (FOLFIRI) and paclitaxel+carboplatin regimens, which are used in subsequent lines of therapy in advanced-stage gastric cancer. This study included 40 patients who have metastatic stage gastric cancer and received FOLFIRI or paclitaxel+carboplatin therapy in subsequent lines of therapy between 2017 and 2022. The data of the patients were analyzed retrospectively. At diagnosis median age was 51 (23-88) years. The tumor was localized in the gastroesophageal junction in eight (20%) patients and in other gastric locations in 32 (80%) patients. At diagnosis, 75% (n=30) of the patients presented with the disease in the metastatic stage, while 25% (n=10) presented with stage II-III disease. Regarding the treatments received in the second and further lines of therapy, 18 (45%) patients received paclitaxel+carboplatin and 22 (55%) patients received a FOLFIRI regimen. Of these treatments, 67.5% (n=27) were given as the second line and 32.5% (n=13) were given as third-line therapy. The objective response rate (ORR) was 45.5% in the FOLFIRI arm compared to 16.7% in the paclitaxel+carboplatin arm (p=0.05). Both treatment arms had a median progression-free survival (PFS) of three months (p=0.82). The median overall survival (OS) time was seven months in the FOLFIRI arm compared to eight months in the paclitaxel+carboplatin arm (p=0.71). Side effects were similar between both treatment arms. This study determined that FOLFIRI and paclitaxel+carboplatin treatments have similar OS, PFS, and side effect profiles in subsequentline treatment of gastric cancer. The FOLFIRI treatment regimen yielded a higher ORR.

Comparative efficacy and safety of multitarget angiogenesis inhibitor combined with immune checkpoint inhibitor and nivolumab monotherapy as second-line or beyond for advanced lung adenocarcinoma in driver-negative patients: a retrospective comparative cohort study.

The efficacy of immune monotherapy is not satisfactory in patients with advanced, treated non-small cell lung cancer (NSCLC). Combining antiangiogenic agents and immune checkpoint inhibitors (ICIs) can counteract the immunosuppression and confer synergistic therapeutic benefits. We explored the efficacy and safety of anlotinib and ICIs as a second- and subsequent-line treatment for advanced lung adenocarcinoma (LUAD) in patients without oncogenic driver alterations. We reviewed patients with driver-negative LUAD who had received anlotinib, a multityrosine kinase inhibitor affecting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and c-Kit, in combination with ICIs from October 2018 to July 2021 at Shanghai Chest Hospital as second- and subsequent-line treatment. Patients with advanced driver-negative LUAD who received nivolumab monotherapy as second-line treatment were included as a control group. In this study, 71 patients were included who had received anlotinib and programmed cell death-1 (PD-1) blockade combination therapy as second- and subsequent-line treatment, and 63 patients who had received nivolumab monotherapy as second-line therapy were included as controls, most of whom were male smokers at stage IV. The median progression-free survival (PFS) of the combination therapy and nivolumab monotherapy groups were 6.00 and 3.41 months, respectively (P<0.001). The median overall survival (OS) of the combination therapy and nivolumab monotherapy groups were 16.13 and 11.88 months, respectively (P=0.046). Twenty-nine patients (40.8%) in the combination group underwent previous immunotherapy (15 of whom were in first line), and they also achieved good survival (median OS: 25.67 months). The adverse reactions in the combination therapy group were mainly associated with either anlotinib or ICI administration, and there was a low incidence of grade 3 adverse events, all of which were resolved after intervention or discontinuation. The combination of the multitargeting tyrosine kinase inhibitor anlotinib and PD-1 blockade demonstrated significant benefits as the second- and subsequent-line treatment in driver-negative patients with advanced LUAD, even in those who underwent previous immunotherapy.

Outcome of Patients with Diffuse Large B-Cell Lymphoma Relapsing after Autologous Transplant before Availability of CAR-T Cell Treatment.

Autologous stem cell transplantation (ASCT) following high-dose chemotherapy is applied as salvage therapy in patients with relapsed disease or as first-line consolidation in high-risk DLBCL with chemo-sensitive disease. However, the prognosis of relapsing DLBCL post-ASCT remained poor until the availability of CAR-T cell treatment. To appreciate this development, understanding the outcome of these patients in the pre-CAR-T era is essential. We retrospectively analyzed 125 consecutive DLBCL patients who underwent HDCT/ASCT. After a median follow-up of 26 months, OS and PFS were 65% and 55%. Fifty-three patients (42%) had a relapse (32 patients, 60%) or refractory disease (21 patients, 40%) after a median of 3 months post-ASCT. 81% of relapses occurred within the first year post-ASCT with an OS of 19% versus 40% at the last follow-up in patients with later relapses (p=0.0022). Patients with r/r disease after ASCT had inferior OS compared to patients in ongoing remission (23% versus 96%; p<0.0001). Patients relapsing post-ASCT without salvage therapy (n=22) had worse OS than patients with 1-4 subsequent treatment lines (n=31) (OS 0% versus 39%; median OS 3 versus 25 months; p<0.0001). Forty-one (77%) of patients relapsing after ASCT died, 35 of which due to progression. Additional therapies can extend OS but mostly cannot prevent death in DLBCL relapsing/refractory post-ASCT. This study may serve as a reference to emerging results after CAR-T treatment in this population.

Outcome measures of phase III anticancer drug trials in China.

Outcome measures of phase III anticancer drug trials in China.

Immune Environment and Immunotherapy in Endometrial Carcinoma and Cervical Tumors

Endometrial cancer (EC) is the seventh most common tumor in women, and prognosis of recurrent and metastatic disease is poor. Cervical cancer (CC) represents the fifth most common gynecological cancer. While ECs are more common in developed countries, the incidence of CC has decreased due to the recent implementation of large screening and vaccination programs. Until very recently, patients with advanced or unresectable EC or CC had very limited treatment options and were receiving in first line setting platinum/taxane-based chemotherapy (CT). Significant progress in the treatment of gynecological cancers has occurred in the last few years, with the use of innovative targeted therapies and immunotherapy. However, targeting the immune system in patients with gynecological tumors remains challenging and is not always successful. In ovarian cancer, several immunotherapy treatment regimens have been investigated (as monotherapy and combination therapy in first and subsequent lines of treatment) and showed poor responses. Therefore, we specifically focused our review on EC and CC for their specific immune-related features and therapeutic results demonstrated with immunotherapy. We report recent and current immunotherapy-based clinical trials and provide a review of emerging data that are likely to impact immunotherapy development based on increased biomarkers' identification to monitor response and overcome resistance.

Abstract P2-03-15: Retrospective study using database for the effectiveness of medroxyprogesterone acetate in patients with ER-positive/HER2-negative postmenopausal advanced breast cancer: An additional analysis of the JBCRG-C06 Safari study

Abstract Background: Only old evidence exist to back up the use of medroxyprogesterone acetate (MPA) in endocrine therapy. Therefore, this study aimed to explore the factors that influence the time to treatment failure (TTF) of MPA in real world settings as late-line treatment following aromatase inhibitors and fulvestrant. Methods: This was a cohort study that used the database of the Safari study, on estrogen receptor-positive (ER+) post-menopausal advanced breast cancer previously treated with fulvestrant (UMIN000015168). We created Kaplan-Meier curves for TTF treated with MPA. Further, univariate and multivariate analyses were performed using a Cox hazard model of the clinicopathological factors involved in the TTF of MPA. Results: Fist, we made Kaplan-Meier curves by treatment line for MPA in TTF analysis population 1 (n = 244), excluding HER2+ and HER2 with unknown status. The median TTF for MPA was 8.2 months (95% CI 5.1–14.9) for first- and second-line treatments, 3.0 months (95% CI 2.5–3.9) for third-line treatment, and 4.1 months (95% CI 3.5–5.0) for fourth or later treatment lines. The first- and second-line treatments had significantly longer TTF than the third-line treatment (P &amp;lt; 0.001) and fourth-line or later treatments (P &amp;lt; 0.001). No difference in TTF was observed between the third and fourth or later treatment lines. Similar results were obtained in the analysis population 2 (n = 203) for TTF, excluding cases in which MPA was considered to have been used in palliative care. The median TTF for MPA was 7.9 months (95% CI, 5.1-16.0) for first- and second-line treatments, 3.0 months (95% CI 2.8–4.6) for third-line treatment, and 4.3 months (95% CI 3.7–5.6) for fourth or later treatment lines. The first- and second-line treatments had significantly longer TTF than the third-line treatment (P &amp;lt; 0.001) and the fourth-line or later treatments (P &amp;lt; 0.001). No difference in TTF was observed between the third and fourth or later treatment lines. Second, Table 1 shows the clinicopathological factors involved in the TTF of MPA. In univariate analysis, long DFI (≥ 6 years), small nuclear or histological grade, and the presence of visceral metastases correlated with significantly long TTF (P &amp;lt; 0.05). Whereas PgR, adjuvant chemotherapy, and adjuvant endocrine therapy did not affect the TTF of patients treated with MPA. However, in the multivariate regression analysis, only longer DFI (≥ 6 years) was correlated with a significantly longer TTF. Third, we compared the clinicopathologic factors in the groups that received MPA as the fourth or later treatment lines and achieved a TTF of more than 1 year with those that did not. There were no characteristic clinicopathological factors distinct between the two groups. Conclusion: In actual clinical practice, patients treated with MPA alone as the fourth or subsequent treatment lines showed a TTF of 4 months, suggesting that there is merit in using MPA even in late treatment lines, especially in patients with long DFI and those who are difficult to treat with other antineoplastic agents. Table 1. Univariate and Multivariate analyses to investigate association between clinicopathological factors and TTF of MPA (n=170) Citation Format: Kaho Utsunomiya, Hidetoshi Kawaguchi, Yutaka Yamamoto, Shigehira Saji, Norikazu Masuda, Takahiro Nakayama, Kenjiro Aogi, Keisei Anan, Shoichiro Ohtani, Nobuaki Sato, Toshimi Takano, Eriko Tokunaga, Seigo Nakamura, Yoshie Hasegawa, Masaya Hattori, Tomomi Fujisawa, Satoshi Morita, Miki Yamaguchi, Toshinari Yamashita, Daisuke Yotsumoto, Masakazu Toi, Shinji Ohno. Retrospective study using database for the effectiveness of medroxyprogesterone acetate in patients with ER-positive/HER2-negative postmenopausal advanced breast cancer: An additional analysis of the JBCRG-C06 Safari study [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 P2-03-15.

Cabozantinib in the elderly with metastatic renal cell carcinoma undergoing geriatric G8 screening test: A prospective multicenter observational study (ZEBRA/MEET-URO 9).

647 Background: Cabozantinib (CABO) is an oral tyrosine kinase inhibitor registered for the treatment of metastatic renal cell carcinoma (mRCC) for the first or subsequent lines. Tolerability in real world elderly patients is poorly documented. G8 is a short test for vulnerability gaining increased interest as a screening tool for trials in geriatric oncology. Methods: ZEBRA/MEET-URO 9 was a prospective multicenter study of safety and activity of CABO administered to pts ≥70 years with mRCC, either in the first or subsequent lines of treatment, until progression or unacceptable toxicity. All pts underwent G8 score at baseline, with a cut-off for vulnerability of 14 or below. Data on tolerability and activity were collected prospectively after signature of informed consent. Results: A total of 104 pts started CABO at 13 Italian Centers, 38,5% as first line. Median age was 75.8 yrs (range 70.2-87.4 yrs, 26 pts ≥80 yrs), 73.1% males. IMDC score was good 19.2%, intermediate 53.9%, poor 26.9%. Primary tumor had been removed in 82.7% of pts, histology was clear cell 78.8%, papillary 8.7%, chromophobe 5.8%, unclassified 6.7%. G8 score was ≤14 in 65.4% of pts. Up-front dose reduction of CABO was more frequent in pts with low G8 score (79.4 vs 41.7%, p=0.003), but eventually the majority of pts (91.4%) underwent dose reductions of CABO. After a median treatment of 6.4 months (0.5-26.1 months), 38.4% of pts developed G3-4 toxicities, 22.1% interrupted treatment due to adverse events, 2.8% (3 pts) died due to cardiovascular or thromboembolic events. Median PFS was 7.6 months (95% CI=5.8-12.6 months) in first line, 10.0 months (5.8-15.6) in second or further lines, median OS was 20.1 months (11.1-not reached) and 15.6 months (12.5-not reached), respectively. G8 score ≤14 did not correlate with rate of temporary interruptions &gt;7 days, hospitalization, incidence of G3-5 toxicities, as well as with PFS. Pts with G8 score ≤14 had a trend for reduced OS, but difference was not statistically significant both in the first and further lines of treatment. Conclusions: Screening G8 test was positive in more than a half of pts, underlying the need for detailed geriatric assessment and increased clinical monitoring of such patients. A G8 score ≤14 correlated with up-front dose reduction of CABO but not with G3-5 toxicities probably due to the high rates of dose reductions in the whole cohort. Correlation between low G8 score and OS could not be demonstrated in this population.