Later Lines Of Therapy Research Articles

Cost-effectiveness analysis of later-line therapies for metastatic colorectal cancer (mCRC) based on a novel methodology of network meta-analysis (NMA) of survival curves.

3605 Background: With advances in the management of mCRC, survival outcomes of patients have improved. While some patients still progress after first and second lines of treatment, there remain options for third or later-line treatment. This study aimed to determine the cost-effectiveness of later-line (>3) treatments for patients with mCRC in the US, based on a NMA of survival curves. Unlike conventional NMA using constant hazard ratios, this method is not constrained by the proportional hazard assumption and uses parametric fitting that incorporates the shape and scale parameters to provide time-varying treatment effects. Methods: The NMA compared the efficacy of 6 treatments, atezolizumab+/-cobimetinib (ATE+/-COB), fruquintinib (FRU), regorafenib (REG), TAS-102+/-bevacizumab (TAS+/-BEV), including biosimilar, to placebo (PBO). The study used a 3-state partitioned survival model over a 5-year time horizon incorporating drug acquisition, administration, adverse events, monitoring, and end of life costs, and utilities sourced from literature. Total costs, life-years (LY) and quality-adjusted LYs (QALY) for each treatment were determined. Incremental cost-effectiveness (ICER) and incremental cost-utility ratios (ICUR) were estimated using PBO as a common comparator. Results: Over the 5-year period and across the 6 therapies, survival ranged from 0.62 LYs for PBO to 1.15 LYs for TAS+BEV, translating to QALYs ranging from 0.44 for PBO to 0.85 for TAS+BEV. Total costs of treatment ranged from 278,877 for PBO to 417,495 for TAS+BEV (405,002 with biosimilar). TAS+BEV yielded the lowest ICER of an additional 261,421 (237,860 with biosimilar)/LY gained (g) and ICUR of an additional 343,458 (312,504 with biosimilar)/QALYg; while ATE presented the least favorable ICER and ICUR of an additional $522,602/LYg and $701,381/QALYg, respectively (Table). Conclusions: Among the 6 treatments evaluated, TAS+BEV emerged as the most cost-effective later-line treatment for mCRC while atezolizumab was the least cost-effective. Additionally, replacing BEV with a biosimilar reduces costs and enhances cost-effectiveness, improving access for patients. [Table: see text]

Genomic biomarker testing and treatment in advanced NSCLC: Practice patterns and barriers in a global survey of oncology point-of-care mobile app users.

e21004 Background: Appropriate molecular testing and oncogene-directed treatment planning are essential best practices for managing patients with advanced non-small cell lung cancer (aNSCLC) who are potential candidates for targeted therapy. Understanding real-world practices and challenges among oncology health care professionals (HCPs) is necessary to inform the development of digital tools and other initiatives that support optimal care. Methods: From 12/2022 to 01/2023, 142 HCPs who treat aNSCLC completed an online survey related to NSCLC genomic biomarker testing and treatment planning. Participants were recruited from a global cohort of HCPs who are active users of an oncology point-of-care mobile app following the launch of an NSCLC decision-support tool and educational intervention. Results: Participants included medical oncologists (87%), surgical oncologists (3%), pulmonologists (2%), and nurses (4%) from 62 countries. Most (72%) reported providing care for ≥5 pts/month with aNSCLC; 27.5% provide care for ≥20 pts/month. HCPs reported testing the following genomic biomarkers in 100%, 50-99%, 1-49%, and 0% of patients with aNSCLC, respectively: EGFR (44%, 23%, 27%, 4%), ALK (41%, 20%, 29%, 8%), ROS1 (32%, 19%, 23%, 22%), BRAF (23%, 20%, 23%, 31%), NTRK (12%, 14%, 22%, 47%), HER2 (11%, 17%, 27%, 42%), KRAS (23%, 15%, 25%, 33%), RET (13%, 13%, 25%, 44%), MET exon 14 (15%, 12%, 27%, 42%). Reported barriers varied in frequency (Table 1), with the most common involving biomarker test turnaround time. The majority of HCPs reported often or sometimes feeling that “results take too long,” and they (80%) and/or their patients (81%) are eager to start treatment. HCPs also commonly reported often or sometimes not being sure about which tests to order (45%), when to test (43%), which 1st-line therapy to select (45%), which 2nd- or later-line therapy to select (57%), and how to manage adverse events of oncogene-targeted therapy (50%). Conclusions: In current real-world practice, the majority of HCPs report suboptimal testing for targetable genomic alterations ( EGFR, ALK, ROS1, BRAF, NTRK, HER2, KRAS, RET, and MET exon 14) in patients with aNSCLC. Identified common barriers represent opportunities for future interventions to improve biomarker-directed NSCLC care. [Table: see text]

The preventive effect of celecoxib on regorafenib-associated hand-foot syndrome in patients with liver metastasis from colorectal cancer: A single-center, retrospective, real-world study.

e15576 Background: Regorafenib, an oral multi-kinase inhibitor, is the third- or later-line therapy for colorectal cancer with liver metastasis (CRLM), but the hand-foot syndrome (HFS) is its most common adverse reaction. Celecoxib, a selective COX-2 inhibitor, can treat inflammation. This study aimed to explore whether additing celecoxib to the cancer therapy regorafenib can prevent or alleviate the HFS, improve drug tolerance, and prolong the patient’s survival. Methods: In the retrospective cohort analysis, patients with colorectal cancer and liver metastasis, to whom regorafenib and celecoxib were administered in the Department of Hepatopancreatobiliary Surgery of Beijing Cancer Hospital between November 2021 and October 2022, were included. Upon the medical records from physical examination and other means of follow-ups, the Kaplan-Meier estimator analyzed the survival function and the severity of adverse events was described according to the CTCAE v.5.0 standards. Results: Twenty-six patients were included in the analysis and 14 colorectal cancer patients had extrahepatic metastases at the onset of the treatment. All patients received regorafenib and celecoxib. Further, 15 patients were treated with a combination of immune checkpoint inhibitors, 3 patients underwent combined local-regional therapy, 1 patient received combined chemotherapy, and 7 patients received regorafenib. Among all the patients, the incidence of grades 1 & 2 HFS was 46% and no grade 3 HFS was observed. The other main adverse events were hoarseness (35%), fatigue (27%), rash (27%), and neutropenia (15%). The most frequent adverse events from the CONCUR study and current analysis are shown in Table 1. Five patients (19%) had their treatment interrupted or their drug dose reduced due to adverse events. The median follow-up time of all patients was 5.3 (range, 1.6-13.1) months, the overall survival was not reached, and the median progression free survival was 2.9 (95% CI: 1.5-4.3) months. As the overall response in all patients after treatment, 3 cases (12%) achieved PR, 11 cases (42%) had SD and 12 cases (46%) showed PD. Conclusions: The addition of celecoxib to the cancer-line therapy regorafenib in CRLM patients did not reduce the incidence of HFS, but reduced the severity of HFS (grade 3). Also, it did not shorten the survival time of the patients. The addition of celecoxib to the main therapy might alleviate some adverse effects. [Table: see text]

Comparative efficacy of later-line therapies for metastatic colorectal cancer (mCRC) using novel methods for patient survival data reconstruction and network meta-analysis (NMA) of survival curves.

e15611 Background: NMAs of cancer treatments are usually based on the proportional hazard assumption (PHA) which implies a constant hazard ratio as well as treatment effect on only scale parameter and therefore not reflecting clinical dynamics of survival outcomes over time. Multivariate NMA which does not rely on the PHA is often constrained by lack of individual patient-level data (IPD). We applied a novel method of reconstructing pseudo-IPD from published survival curves that enabled application of a dynamic method of NMA of survival curves without PHA constraint to compare the efficacy of 6 later-line therapies for metastatic colorectal cancer (mCRC), compared to placebo. Methods: We identified 8 phase II/III trials reporting the efficacy of 6 later-line therapies for mCRC from PubMed, Embase, Scopus and Cochrane Library. Trial survival curves were reconstructed based on pseudo-IPD generated using the Guyot method, and the estimated survival proportions and hazard ratios (HRs) over 12 months (12m) of follow up were calculated using a random effects lognormal distribution model with placebo as the common comparator. Results: Compared to placebo, 12m PFS HRs varied from 0.29 (95%CrI = 0.19-0.44) for TAS+bevacizumab to 0.72 (95%CrI = 0.62-0.85) for atezolizumab. Similarly, OS HRs ranged from 0.55 (95%CrI = 0.26-0.92) for TAS+bevacizumab to 1.01 (95%CrI = 0.79-1.20) for atezolizumab (Table). Conclusions: In this NMA of survival curves, all therapies except atezolizumab were superior to placebo in PFS and OS over 12m follow up period. TAS+bevacizumab provided the highest survival advantage over placebo, with fruquintinib, regorafenib, and TAS-102 also showing survival benefits. TAS+bevacizumab may be the preferred choice for later-line mCRC treatment. [Table: see text]

Clinical Effect of the C-Reactive Protein to Serum Albumin Ratio in Patients with Metastatic Gastric or Gastroesophageal Junction Cancer Treated with Trifluridine/Tipiracil.

Trifluridine/tipiracil (FTD/TPI) is an oral anticancer agent used as a third- or later-line treatment for patients with metastatic gastric cancer/gastroesophageal junction cancer (mGC/GEJC). The C-reactive protein-to-serum albumin ratio (CAR) is an inflammation-based prognostic marker in gastric cancer. This retrospective study evaluated CAR's clinical significance as a prognostic factor in 64 patients with mGC/GEJC administered FTD/TPI as a third- or later-line therapy. Patients were categorized into high- and low-CAR groups based on pre-treatment blood data. This study evaluated associations between CAR and overall survival (OS), progression-free survival (PFS), clinicopathological features, treatment efficacy, and adverse events. The high-CAR group had significantly worse Eastern Cooperative Oncology Group performance status, a higher prevalence of patients administered with a single course of FTD/TPI, and a higher rate of patients not administered chemotherapy after FTD/TPI therapy than the low-CAR group. Median OS and PFS were significantly poorer in the high-CAR group than in the low-CAR group (113 vs. 399 days; p < 0.001 and 39 vs. 112 days; p < 0.001, respectively). In multivariate analysis, high CAR was an independent prognostic factor for OS and PFS. The overall response rate was not significantly different between the high- and low-CAR groups. Regarding adverse events, the high-CAR group had a significantly lower incidence of neutropenia and a higher incidence of fatigue than the low-CAR group. Therefore, CAR may be a potentially useful prognostic factor for patients with mGC/GEJC treated with FTD/TPI as third- or later-line chemotherapy.

Real-world effectiveness of nivolumab and subsequent therapy in Japanese patients with metastatic renal cell carcinoma (POST-NIVO study): 36-month follow-up results of a clinical chart review.

To examine the long-term effectiveness of nivolumab monotherapy and following subsequent therapies for metastatic renal cell carcinoma (mRCC) in Japanese real-world settings. This was a multicenter, retrospective, observational study, with a 36-month follow-up, and conducted in Japanese patients with mRCC who initiated nivolumab monotherapy between 1 Feb 2017 and 31 Oct 2017. Endpoints included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Of the 208 patients, 36.5% received nivolumab monotherapy as second-line, 30.8% as third-line, and 31.7% as fourth- or later-line therapy. By 36 months, 12.0% of patients continued nivolumab monotherapy; 88.0% discontinued, mainly because of disease progression (66.7%). The median (m) OS was not reached irrespective of treatment line, with a 36-month OS rate of 54.3% (second-line, 57.4%; third-line, 52.6%; fourth- or later-line, 52.9%). The ORR was 24.2% and five patients achieved complete response. The OS from first-line therapy was 8.9 years. In the 95 patients receiving therapy after nivolumab, 87.4% received vascular endothelial growth factor receptor-tyrosine kinase inhibitors, with mOS and mPFS of 27.4 and 8.1 months, respectively. Irrespective of treatment line, the mOS was not reached in patients with International Metastatic RCC Database Consortium (IMDC) favorable or intermediate risk at mRCC diagnosis. This 36-month real-world follow-up analysis showed a survival benefit of nivolumab monotherapy for patients with mRCC. The long-term effectiveness of sequential therapy from first-line therapy to therapy after nivolumab was also demonstrated. Additionally, nivolumab monotherapy was beneficial for patients with favorable IMDC risk at the time of mRCC diagnosis.

Impact of first-line systemic therapy with atezolizumab plus bevacizumab in patients with hepatocellular carcinoma.

The study goal was to compare the outcomes of patients with unresectable hepatocellular carcinoma (HCC) who received atezolizumab plus bevacizumab (Atezo/Bev) as either first- or later-line systemic therapy. A total of 430 patients with HCC treated with Atezo/Bev at 22 institutions in Japan were included. Patients treated with Atezo/Bev as first-line therapy for HCC were defined as the first-line group (n=268) while those treated with Atezo/Bev as second- or later-line therapy were defined as the later-line group (n=162). The median progression-free survival times in the first- and later-line groups were 7.7months (95% confidence interval [CI], 6.7-9.2) and 6.2months (95% CI, 5.0-7.7) (P=0.021). Regarding treatment-related adverse events, hypertension of any grade was more common in the first-line group than in the later-line group (P=0.025). Analysis adjusted by inverse probability weighting, including patient and HCC characteristics, showed that the later-line group (hazard ratio, 1.304; 95% CI, 1.006-1.690; P=0.045) was significantly associated with progression-free survival. In patients with Barcelona Clinic Liver Cancer stage B, the median progression-free survival times in the first- and later-line groups were 10.5months (95% CI, 6.8-13.8) and 6.8months (95% CI, 5.0-9.4) (P=0.021). Among patients with a history of lenvatinib therapy, the median progression-free survival times in the first- and later-line groups were 7.7months (95% CI, 6.3-9.2) and 6.2months (95% CI, 5.0-7.7) (P=0.022). The use of Atezo/Bev as first-line systemic therapy in patients with HCC is expected to prolong survival.

Efficacy and safety of combined immunotherapy and antiangiogenic therapy for advanced non-small cell lung cancer: a real-world observation study

PurposeThis study was performed to investigate the efficacy and safety of combined immunotherapy and antiangiogenic therapy for advanced non-small cell lung cancer (NSCLC) in the real world.MethodsData on clinicopathological features, efficacy and adverse events (AEs) were collected retrospectively in advanced NSCLC patients who received immunotherapy combined with antiangiogenic therapy.ResultsA total of 85 advanced NSCLC patients were enrolled. The patients had a median progression-free survival (PFS) of 7.9 months and a median overall survival (OS) of 18.60 months. The objective response rate and disease control rate were 32.9% and 83.5%, respectively. Subgroup analysis revealed that NSCLC patients with stage IV (p = 0.042), brain metastasis (p = 0.016) and bone metastasis (p = 0.016) had shorter PFS. NSCLC patients with brain metastasis (p = 0.025), liver metastasis (p = 0.012), bone metastasis (p = 0.014) and EGFR mutations (p = 0.033) had shorter OS. Multivariate analysis revealed that brain metastasis (HR = 1.798, 95% CI: 1.038, 3.112, p = 0.036) and bone metastasis (HR = 1.824, 95% CI: 1.077, 3.090, p = 0.025) were independent predictive factors of PFS, and bone metastasis (HR = 2.00, 95% CI: 1.124, 3.558, p = 0.018) was an independent predictive factor of OS. In addition, patients receiving immunotherapy combined with antiangiogenic therapy in second-line therapy had longer OS than those receiving immunotherapy in third- or later-line therapy (p = 0.039). Patients with EGFR mutations who received combination therapy had worse OS than those with KRAS mutations (p = 0.026). Furthermore, PD-L1 expression was associated with treatment responses in advanced NSCLC (χ2 = 22.123, p = 0.000). AEs of different grades occurred in 92.9% (79/85) of NSCLC patients, most of which were mild grade 1/2 AEs. No grade 5 fatal AEs occurred.ConclusionImmunotherapy combined with antiangiogenic therapy was an option for advanced NSCLC patients with good safety and tolerability. Brain metastases and bone metastases were potentially independent negative predictors of PFS. Bone metastases were a potential independent negative predictor of OS. PD-L1 expression was a potential predictor of response for immunotherapy combined with antiangiogenic therapy.

Pertuzumab as second‑ or later‑line therapy for human epidermal growth factor receptor 2‑positive metastatic breast cancer: A clinical experience.

Trastuzumab and pertuzumab with taxane-based chemotherapy are considered the first-line standard therapy for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC). Pertuzumab is also a later-line therapy for mBC in Switzerland, although limited safety and efficacy data are available. The present study assessed the therapeutic regimens, toxicities and clinical outcomes after second- or later-line pertuzumab therapy in patients with mBC who did not receive pertuzumab as a first-line therapy. Physicians from nine major Swiss oncology centers retrospectively completed a questionnaire for each pertuzumab-naive patient who was treated with pertuzumab as a second- or later-line therapy. Of 35 patients with HER2-positive mBC (median age, 49 years; range, 35-87 years), 14 received pertuzumab as a second-line therapy, 6 as a third-line therapy, and 15 as a fourth- or later-line therapy. A total of 20 patients (57%) died during the study period. The median overall survival was 74.2 months (95% confidence interval, 47.6-139.8 months). Grade (G) 3/4 adverse events (AEs) were reported in 14% of patients, with only 1 patient discontinuing therapy due to pertuzumab-related toxicities. The most common AE was fatigue (overall, 46%; G3, 11%). Overall, congestive heart disease occurred in 14% of patients (G3, 6%), nausea in 14% of patients (all G1), and myelosuppression in 12% of patients (G3, 6%). In conclusion, the median overall survival of patients who underwent second- or later-line pertuzumab treatment was similar to that reported for patients who underwent first-line pertuzumab treatment, and the safety profile was acceptable. These data support the use of pertuzumab for second- or later-line therapy when it was not administered as first-line therapy.

209P Trastuzumab plus lapatinib or chemotherapy in patients with HER2-positive advanced breast cancer refractory to anti-HER2 therapies: A randomized, multicenter, phase II trial (GIM12-TYPHER)

Trastuzumab (T) and chemotherapy (CT) is a standard treatment in patients (pts) with HER2-positive (+) advanced breast cancer (ABC) at later lines of therapy. Lapatinib (L) and T have proven to be active in the same setting. The present study evaluated the efficacy, toxicity and quality of life (QoL) of T+L versus T + physician’s choice CT in pts with HER2+ ABC pretreated with at least two lines of anti-HER2 treatment. In this open-label, multicenter, phase II trial, pts were randomly assigned 1:1 to receive either T+L with endocrine therapy at the physician’s discretion in case of hormone receptor positive ABC (arm A) or T+CT (arm B). The primary endpoint was the clinical benefit rate (CBR) and the secondary endpoints included overall survival (OS), progression-free survival (PFS), quality of life (QoL), and safety. Between 2015 and 2020, 59 pts were randomized and evaluated for the present analyses. After a median (m) follow-up of 57.5 months (mo), the CBR was 20.7% (95% CI 9.4-39.3) vs 26.7% (95% CI 13.1-44.9; P= 0.76), the mOS was 29.9 mo (95% CI 19.6-NE) vs 31.1 mo (95% CI 26.1-NE; hazard ratio [HR] 1.07, 95% CI 0.57-2.0; P=0.82) and mPFS was 3.6 mo (95% CI 3.0-5.3) vs 6.1 mo (95% CI 4.0-14.3; HR 0.63, 95% CI 0.37-1.37; P=0.08) in arm A vs arm B, respectively. Any grade (G) adverse events (AEs) occurred in 86.2% and 66.7% of pts in arm A and B, respectively. The incidence of G3-4 AEs was 24.1% and 13.3% in arm A and B, respectively. The impact on QoL significantly favored arm A (P=0.03).Table: 209PAEsOverall (N=59)Arm A (N=29)Arm B (N=30)Patients with at least one AE45 (76.3)25 (86.2)20 (66.7)Diarrhea14 (23.7)11 (37.9)3 (10)Fatigue13 (22)7 (24.1)6 (20)Abdominal pain7 (11.9)3 (10.3)4 (13.3)Anemia7 (11.9)4 (13.8)3 (10)Neutropenia5 (8.5)0 (0)5 (16.7)Nausea5 (8.5)3 (10.3)2 (6.7)Thrombocytopenia5 (8.5)4 (13.8)1 (3.3)Paresthesia4 (6.8)0 (0)4 (13.3)Fever3 (5.1)3 (10.3)0 (0)Skin disorders3 (5.1)3 (10.3)0 (0) Open table in a new tab No difference in efficacy was observed between T+L and T+CT. QoL deterioration was less frequent in pts in T+L arm though a higher number of any AEs was observed in these patients compared with those who received T+CT. Overall, the chemotherapy-free combination of T+L may be a valid therapeutic option for pretreated pts with HER2+ ABC.

Multi-target angiogenesis inhibitor combined with PD-1 inhibitors may benefit advanced non-small cell lung cancer patients in late line after failure of EGFR-TKI therapy.

Treatments for NSCLC patients with EGFR-TKI resistance are limited. Given that immunotherapy and antiangiogenic agents may have synergistic antitumor effects, we aimed to analyze the effect of multi-target angiogenesis inhibitor anlotinib and immune checkpoint inhibitors (ICIs) combination therapy in NSCLC patients who failed EGFR-TKI. The medical records of lung adenocarcinoma (LUAD) patients with EGFR-TKI resistance were reviewed. After EGFR-TKI resistance, patients who simultaneously received anlotinib and ICIs were enrolled in the observation group, and those who received platinum-pemetrexed chemotherapy were included in the control group. A total of 80 LUAD patients were reviewed and allocated to the anlotinib and ICIs combination therapy (n = 38) and chemotherapy (n = 42) groups. A re-biopsy was performed in all patients in the observation group before the administration of anlotinib and ICIs. The median follow-up was 15.63 months (95% CI: 12.19-19.08). Combination therapy exhibited better PFS (median PFS: 4.33 months [95% CI: 2.62-6.05] vs 3.60 months [95% CI: 2.48-4.73], P = .005), and better OS (median OS: 14.17 months [95% CI: 10.17-18.17] vs 9.00 months [95% CI: 6.92-11.08], P = .029) than chemotherapy. Most patients (73.7%) received combination therapy as fourth and later lines of therapy, with a median PFS of 4.03 months (95% CI: 2.05-6.02) and a median OS of 13.80 months (95% CI: 8.25-19.36). The disease control rate was 92.1%. Four patients discontinued the combination therapy due to adverse events, but the other adverse reactions were manageable and reversible. The combination of anlotinib and PD-1 inhibitors is a promising regimen for the late-line treatment of LUAD patients with EGFR-TKI resistance.

Real-world clinical outcomes of nivolumab and taxane as a second- or later-line therapy for recurrent or unresectable advanced esophageal squamous cell carcinoma.

Nivolumab is approved in Japan as a second-line treatment for patients with advanced esophageal squamous cell carcinoma (ESCC) resistant to fluoropyrimidine and platinum-based drugs. It is also used in adjuvant and primary postoperative therapies. This study aimed to report real-world data on nivolumab use for esophageal cancer treatment. In total, 171 patients with recurrent or unresectable advanced ESCC who received nivolumab (n = 61) or taxane (n = 110) were included. We collected real-world data of patients treated with nivolumab as a second- or later-line therapy and evaluated treatment outcomes and safety. Median overall survival was longer and progression-free survival (PFS) was significantly longer (p = 0.0172) in patients who received nivolumab than in patients who received taxane as a second- or later-line therapy. Furthermore, subgroup analysis for second-line treatment only showed the superiority of nivolumab in increasing the PFS rate (p = 0.0056). No serious adverse events were observed. In real-world practice, nivolumab was safer and more effective than taxane in patients with ESCC with diverse clinical profiles who did not meet trial eligibility criteria, including those with poor Eastern Cooperative Oncology Group performance status, comorbidities, and receiving multiple treatments.

Efficacy of immunotherapy as second-line or later-line therapy and prognostic significance of KRAS or TP53 mutations in advanced non-small cell lung cancer patients.

In this retrospective study, we aimed to assess the relationship between mutations in the Kirsten rats sarcoma viral oncogene (KRAS )/ tumor protein p53 (TP53 ) genes and the efficacy of immune checkpoint inhibitors (ICIs) therapy as a second-line or later-line treatment for patients with stage IIIB/IV non-small cell lung cancer (NSCLC). We retrospectively analyzed the clinical data of 143 patients with stage IIIB/IV NSCLC who were admitted to the Cancer Hospital of Harbin Medical University between January 2019 and September 2022. Kaplan-Meier survival curve analysis was performed to analyze the survival outcomes. Univariate and multivariate Cox proportional risk models were used to analyze the factors associated with the progression-free survival (PFS) and overall survival (OS) of advanced-stage NSCLC patients who received ICIs as second-line or later-line therapy. NSCLC patients with KRAS or TP53 mutations treated with ICIs showed significantly higher objective response rate, disease control rate, PFS, and OS compared to NSCLC patients with wild-type KRAS / TP53 (P < 0.05). Multivariate Cox regression analysis showed that a combined treatment regimen of ICIs plus chemotherapy was significantly associated with prolonged PFS [hazard ratio = 0.192; 95% confidence interval (CI), 0.094-0.392; P < 0.001] and OS (hazard ratio = 0.414; 95% CI, 0.281-0.612; P < 0.001). KRAS or TP53 mutations were associated with improved PFS of advanced NSCLC patients treated with ICIs as second-line or later-line therapy. KRAS or TP53 mutations show great potential as clinical biomarkers to predict the efficacy of ICIs therapy.

Abstract 930: Treatment patterns and overall survival among men with metastatic castration-resistant prostate cancer harboring DDR mutations

Abstract Background: Limited information is available about treatments and clinical outcomes among men with metastatic castration-resistant prostate cancer (mCRPC) whose tumors harbor DNA damage repair (DDR) mutations. Methods: This retrospective chart review study included men diagnosed with mCRPC with ≥1 DDR mutation detected by tumor comprehensive genomic profiling who began a line of therapy on or after July 1, 2014, at oncology centers in the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) consortium. The index date was the initiation of a new therapy in this period, in patients who developed castration-resistant disease and progressed while receiving androgen deprivation therapy. Data on all available lines of therapy post-index were collected. Outcomes reported include time to treatment discontinuation for any reason (TTTD) and overall survival (OS), which were assessed using Kaplan-Meier analyses. Results for tumor response-related endpoints are forthcoming. Results: A total of 138 patients with mCRPC met the inclusion criteria. The mean age at index was 68 years, and 76% of patients were White. The median follow-up time was 27.1, 15.9, 11.3, and 9.4 months for 1L, 2L, 3L, and 4L+ therapy, respectively. Common sites of metastases included bone (74%), lymph nodes (69%), and lungs (10%). Common tumor DDR mutations included CDK12 (48%), BRCA2 (23%), ATM (21%), and BRCA1 (8%). Assessment of germline mutations was conducted in 114 (83%) patients; the most common was BRCA2 (8%). First-line (1L) treatment information was available for 119 (86%) patients, 2L for 101 (73%), and 3L for 75 (54%) patients. Novel hormonal therapy (NHT; 55%) and taxane chemotherapy (20%) were most common in 1L. Enzalutamide (35%) and abiraterone acetate (14%) were the most frequently used NHTs. Compared to 1L, the proportion of patients receiving NHTs was lower in 2L (33%) and 3L (17%), while the proportion of patients receiving taxanes was higher (36% in 2L and 31% in 3L). In 3L, poly ADP-ribose polymerase (PARP) inhibitors were used in 21% of patients. Median TTTD was 5.6 months (95% CI: 4.2, 7.2) in 1L, 3.9 months (95% CI: 3.0, 4.6) in 2L, and 4.0 months (95% CI: 3.3, 4.7) in 3L. Median OS was 36.3 months (95% CI: 30.7, 47.8) from the start of 1L, 21.1 months (95% CI: 15.6, 29.3) from the start of 2L, and 14.1 months (95% CI: 9.5, 20.5) from the start of 3L. Conclusions: These findings provide real-world insights about treatment patterns and clinical outcomes among patients with mCRPC harboring DDR mutations. Such insight may provide a helpful benchmark for research aimed at improving clinical outcomes, particularly in later lines of therapy. Citation Format: David B. Solit, Niharika B. Mettu, Shannon J. McCall, Mallika Dhawan, Priyanka J. Bobbili, Maral DerSarkissian, Jasmina Ivanova, Bhakti Arondekar, Jane Chang, Alexander Niyazov, Jocelyn Lee, Risha Huq, Michelle Green, Michelle Turski, Aruna Muthukumar, Tracy Guo, Mei Sheng Duh, William K. Oh. Treatment patterns and overall survival among men with metastatic castration-resistant prostate cancer harboring DDR mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 930.

Outcomes With Combination Pembrolizumab and Axitinib in Second and Further Line Treatment of Metastatic Renal Cell Carcinoma.

Combination immune checkpoint inhibitors (ICI) and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGF-R-TKI), including pembrolizumab/axitinib, are approved for first-line treatment of metastatic renal cell carcinoma (mRCC). Pembrolizumab/axitinib is associated with superior progression free survival (PFS), objective response rate (ORR), and overall survival over sunitinib. However, to date, the activity and safety of pembrolizumab/axitinib in later lines of therapy has not been reported. Clinical data of consecutive patients receiving pembrolizumab/axitinib in the second-line or beyond for mRCC at Yale-New Haven Hospital were retrospectively collected. Best objective response was assessed using RECIST 1.1 criteria. Kaplan-Meier function was used to analyze survival. Thirty-eight patients were included. Median age was 64, 92.1% had clear cell mRCC, 18.4% had sarcomatoid dedifferentiation; 94.7% had prior ICI and 39.5% had prior VEGF-R-TKI. Pembrolizumab/axitinib was administered as second-line therapy in 21 (55.5%) patients, third-line in 5 (13.2%) and beyond in 12 (30.2%). Adverse events (AEs) occurred in 86.8% of patients. Grade 3-4 AEs attributed to pembrolizumab and axitinib were seen in 18.4% and 6.4% of patients, respectively. No grade 5 AEs occurred. At a median follow up of 17.1 months, median PFS was 9.7 months (95% CI, 4.1-15.3). Amongst 36 response evaluable patients, the ORR was 25.0% (all partial) and disease control rate (including stable disease for at least 6 months) was 66.6%. The most frequent treatment sequence was first-line nivolumab/ipilimumab followed by second-line pembrolizumab/axitinib (n=17, 44.7%); among this cohort, median PFS with pembrolizumab/axitinib was 11.1 (95% CI, 8.4-13.7) months, with an ORR of 31.4%. Combination pembrolizumab/axitinib among previously treated mRCC patients has activity, with AE rates comparable to those reported in the first line. Prospective studies evaluating ICI-VEGF-R-TKI combinations beyond first-line are warranted to identify the most beneficial treatment sequencing in mRCC.

Impact of sex on prognosis in patients with advanced renal cell carcinoma treated with immune checkpoint inhibitors.

Prognostic impact of sex in patients with malignancies treated with immune checkpoint inhibitors has been intensively discussed but remains unclear, especially in advanced renal cell carcinoma. We retrospectively evaluated a total of 184 patients with advanced renal cell carcinoma treated with either nivolumab plus ipilimumab combined treatment as first-line therapy (n=73) or nivolumab as later-line therapy (n=111) at our affiliated institutions. Progression-free survival, overall survival and objective response rate as well as adverse event profile were compared between sexes. Of the total 184 patients, 48 (26%) were female. Female patients had a significantly shorter progression-free survival than male patients (median: 3.8 vs. 8.3months, P=0.0005), but overall survival (median: 39.2 vs. 45.1months, P=0.283) and objective response rate (29% vs. 42%, P=0.119) were not different between them. Similar findings were observed when analyzing within each treatment; in both patient groups treated with nivolumab plus ipilimumab combined therapy and nivolumab monotherapy, progression-free survival was significantly shorter in female than in male patients (P=0.007, P=0.017), but overall survival (P=0.914, P=0.117) and objective response rate (P=0.109, P=0.465) were comparable between them. Moreover, in a more restricted cohort consisting of patients with clear-cell renal cell carcinoma, a shorter progression-free survival in female patients was also observed (3.8 vs. 11.0months, P<0.0001). This retrospective study showed that immune checkpoint inhibitors-based treatment for renal cell carcinoma exhibited less marked effects in female than in male patients. Thus, sex may be an important factor for decision-making on systemic therapy as renal cell carcinoma treatment, although further studies are required to validate the present findings.

Therapeutic advances in leiomyosarcoma.

Leiomyosarcoma is an aggressive mesenchymal malignancy and represents one of the most common subtypes of soft tissue sarcomas. It is characterized by significant disease heterogeneity with variable sites of origin and diverse genomic profiles. As a result, the treatment of advanced leiomyosarcoma is challenging. First-line therapy for metastatic and/or unresectable leiomyosarcoma includes anthracycline or gemcitabine based regimens, which provide a median progression-free survival time of about 5 months and overall survival time between 14-16 months. Effective later-line therapies are limited. Molecular profiling has enhanced our knowledge of the pathophysiology driving leiomyosarcoma, providing potential targets for treatment. In this review, we explore recent advances in our understanding of leiomyosarcoma tumor biology and implications for novel therapeutics. We describe the development of clinical trials based on such findings and discuss available published results. To date, the most promising approaches for advanced leiomyosarcoma include targeting DNA damage repair pathways and aberrant metabolism associated with oncogenesis, as well as novel chemotherapy combinations. This review highlights the recent progress made in the treatment of advanced leiomyosarcoma. Ongoing progress is contingent upon further development of clinical trials based on molecular findings, with careful consideration for clinical trial design, strong academic collaborations, and prospective correlative analyses.

Abstract P3-02-04: Phase II study of Pembrolizumab Maintenance treatment in patients with HER2-negative inflammatory breast cancer (IBC) and triple-negative breast cancer (TNBC) after response to chemotherapy

Abstract Accumulating physical and hematologic toxicities make the indefinite use of chemotherapy unfeasible for many patients with metastatic/recurrent HER2– IBC or TNBC. Whether maintenance immunotherapy has a role in the treatment of these patients is unclear. We conducted a single-arm phase II trial of pembrolizumab monotherapy in patients with metastatic/recurrent HER2– IBC or TNBC (regardless of their PD-L1 expression status) and report here the clinical data from this trial. Methods: Eligible patients were enrolled between 2015 and 2022 and had had a CR, a PR, or SD after a minimum of 3 cycles of chemotherapy for metastatic/recurrent disease. PD-L1 expression status was not used to determine eligibility. Patients received 200 mg of pembrolizumab every 3 weeks (q3w) until disease progression, intolerable toxicity, or 2 years. In late 2021, the study was amended to allow patients who had received ≥8 cycles of q3w therapy to transition to q6w dosing (400 mg), based on the FDA’s approval of both dosing regimens across all indications. The primary endpoint was the 4-month disease control rate (DCR); exploratory endpoints included safety and correlative biomarkers from tissue and blood to ascertain associations between clinical response and PD-L1 expression, T-cell clonality, and immune profiling. Results: Of 43 patients (median age, 54 years; range, 34-77 years), 11 had IBC (10 with triple-negative IBC and 1 with ER+ HER2– IBC), and 32 had TNBC. The 4-month DCR was 58.1% (95% CI: 43.4%-72.9%). During a median follow-up of 11.4 months, 25 patients died. The entire cohort’s median OS and PFS times were 26.0 months (95% CI: 11.0-33.5 months) and 4.8 months (95% CI: 3.0-7.1 months), respectively. The median OS times of the IBC and TNBC groups did not differ significantly, nor did those of the CR, PR, and SD groups. The median PFS times of the IBC group (2.2 months) and TNBC group (4.8 months) did not differ significantly (p = .12), but those of the CR, PR, and SD groups did (not reached, 10.3 months, and 3.4 months, respectively; p = .01). Among the 37 patients who are off study treatment, most patients (84%; n=31/37) discontinued treatment owing to disease progression rather than toxicities (n=2), and the toxicities overall were consistent with the known profile of single-agent anti-PD1. Five patients had grade 3 events; there were no grade 4 or 5 events. Three patients had irreversible endocrinopathies (thyroiditis and adrenal insufficiency) requiring hormone replacement, but only 1 patient discontinued pembrolizumab because of these events. One patient discontinued treatment because of optic neuritis requiring steroids. Four patients completed 2 years of treatment without disease progression. Conclusions: Pembrolizumab maintenance therapy achieves acceptable disease control after induction chemotherapy. The PFS in this trial compares favorably to the expected durations of response to later lines of therapy. The toxicity profile of pembrolizumab compares favorably with those of chemotherapy and ADCs, which may provide a rationale for the use of ICIs in this setting. However, whether pembrolizumab maintenance therapy is helpful in TNBC patients who have received concurrent pembrolizumab with neoadjuvant chemotherapy is unknown, as these patients were excluded from the trial. Acknowledgements: This trial was supported by Merck. Citation Format: Toshiaki Iwase, Angela Alexander, Vivian Chiv, Megumi Kai, Kumiko Kida, Charla Parker, Angela N. Marx, Evan Cohen, Hui Gao, James Reuben, Xiaoping Wang, Savitri Krishnamurthy, Diane Liu, Yu Shen, David Ramirez, Debu Tripathy, Daniel Booser, Clinton Yam, Vicente Valero, Bora Lim, Naoto T. Ueno, Jie S. Willey. Phase II study of Pembrolizumab Maintenance treatment in patients with HER2-negative inflammatory breast cancer (IBC) and triple-negative breast cancer (TNBC) after response to chemotherapy [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 P3-02-04.

Effectiveness and safety of radiotherapy plus programmed death-1 inhibitors and lenvatinib in patients with advanced biliary tract carcinoma: a real-world study.

Radiotherapy (RT) may function synergistically with immunotherapy and targeted agents (TA). This study aimed to assess the effectiveness and safety of RT combined with programmed death-1 (PD-1) inhibitors and lenvatinib in patients with relapsed or refractory advanced biliary tract carcinoma (BTC). This retrospective study included patients with relapsed or refractory advanced BTC who received RT combined with PD-1 inhibitors and lenvatinib at the Peking Union Medical College Hospital (PUMCH). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety were evaluated. Thirty-one patients who received RT combined with PD-1 inhibitors and lenvatinib as a second- or later-line therapy were analyzed. RT sites were mainly distributed in the liver lesions (64.5%) and lymph nodes (58.1%). The ORR and DCR were 32.3% (10/31; 95% CI: 14.8-49.7) and 87.1% (27/31; 95% CI: 74.6-99.6), respectively. The median PFS (mPFS) and median OS (mOS) were 7.9 (95% CI: 7.1-8.7) and 11.7 (95% CI: 8.3-15.0) months, respectively. Subgroup analyses of this cohort included 12 and 19 patients who received concurrent and salvage (> 6weeks after commencing PD-1 inhibitor therapy) RT, respectively. The salvage RT group had higher mOS (11.7 vs. 10.5; p = 0.75) and mPFS (7.9 vs. 6.9; p = 0.85) than the concurrent RT group; however, statistical significance was not reached. All patients experienced any-grade adverse events (AEs), and excessive PD-1 inhibitors or RT toxicity were not observed. RT, PD-1 inhibitors, and lenvatinib may be safely combined and have antitumor effectiveness in patients with advanced BTC.

Phase 2 clinical study evaluating the efficacy and safety of disitamab vedotin with or without pembrolizumab in patients with HER2-expressing urothelial carcinoma (RC48G001).

TPS594 Background: Urothelial carcinoma (UC) is the 10th most diagnosed cancer worldwide, and nearly 50% of patients cannot tolerate the current first-line (1L) standard of care. There is a need to improve outcomes in 1L and later lines of therapy. HER2 is overexpressed in UC and may be associated with poor outcomes. Despite this, no HER2-directed therapies are currently approved for UC. Disitamab vedotin (DV; RC48-ADC) is an investigational antibody-drug conjugate comprising a novel HER2-directed monoclonal antibody, disitamab, conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable mc-vc linker. DV elicits antitumor activity through multimodal mechanisms of action including MMAE-mediated direct cytotoxicity, bystander effect, and immunogenic cell death. Methods: RC48G001 (NCT04879329) is a phase 2, multi-cohort, open-label, multicenter trial to evaluate DV in patients with HER2-expressing locally advanced/metastatic UC (LA/mUC). Patients are enrolled in 3 cohorts based on prior treatment and tumor HER2 expression by immunohistochemistry (IHC) and gene amplification (via in situ hybridization [ISH]), assessed centrally. Cohorts A and B are enrolling patients who have received prior systemic therapy (1 or 2 lines, including platinum-containing chemotherapy) and whose tumors are HER2-positive (IHC 3+, or 2+ and ISH-positive) or HER2-low (IHC 2+ and ISH-negative, or IHC 1+), respectively. Cohort C is enrolling 1L treatment-naive patients in the LA/mUC setting, whose tumors have HER2-positive or HER2-low expression. Cohorts A and B will evaluate DV as monotherapy (intravenous [IV] administration, once every 2 weeks [Q2W]). Cohort C will evaluate DV (IV, Q2W) +/– pembrolizumab (IV, Day 1 of each 6-week cycle). Patients in all cohorts must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and an Eastern Cooperative Oncology Group Performance Status of 0–1 in Cohorts A and B, and 0–2 in Cohort C. The primary endpoint is confirmed objective response rate (cORR) per blinded independent central review (BICR). Secondary endpoints include cORR by investigator assessment, overall survival, duration of response, progression-free survival, disease control rate per RECIST v1.1 by BICR and investigator, safety, and pharmacokinetic parameters. Enrollment for all cohorts is ongoing in North America and Europe, and planned in Latin America, Asia-Pacific, and Israel. Clinical trial information: NCT04879329 .