Second-line Setting Research Articles

Real-World Health Care Resource Use and Costs Among Patients With Chronic Lymphocytic Leukemia Treated With Venetoclax-Based and Bruton Tyrosine Kinase Inhibitor-Based Regimens in the Second-Line Setting.

Real-world evidence comparing health care resource use (HRU) and costs between novel targeted therapies among patients with chronic lymphocytic leukemia (CLL) is lacking. We compared all-cause and CLL-specific HRU and costs between patients initiated on B-cell lymphoma 2 inhibitor (venetoclax)- or Bruton tyrosine kinase inhibitor (BTKi)-based regimens in the second-line (2L) setting. This is a retrospective observational study using Optum Clinformatics Data Mart of adult patients with CLL/small lymphocytic lymphoma who received 2L venetoclax- or BTKi-based regimens (January 2018-December 2021) for the first time and had ≥one CLL diagnostic claim after 2L initiation and ≥two claims for venetoclax or BTKi. Baseline characteristics were balanced using stabilized inverse probability of treatment weights. Mean monthly cost difference (MMCD) between cohorts for all-cause and CLL-specific per patient per month (PPPM) costs was estimated. Rates of PPPM-HRU were compared between cohorts using rate ratios (RRs). Of 280 patients, median age 75.5 years, 64.6% and 35.4% received BTKi- versus venetoclax-based regimens, respectively. Most BTKi-treated patients received monotherapy (88.4%), whereas 62.3% of venetoclax-treated patients received combination therapy with anti-CD20 agents. The median duration of 2L therapy was 11.6 and 11.0 months for BTKi versus venetoclax cohorts, respectively. All-cause total costs were lower for venetoclax versus BTKi (MMCD [SE], $-2,497.64 [$1,006.77] in US dollars (USD); P = .01), driven by lower medication costs offsetting medical costs; trends were similar for CLL-specific estimates. Outpatient HRU was higher for venetoclax versus BTKi (RR all-cause: 1.22 versus CLL-specific: 1.64). Venetoclax was associated with total monthly cost savings versus BTKis, illustrating the economic value of time-limited venetoclax-based regimens in the 2L setting.

Real-world treatment outcomes from nationwide Onco-colon Turkey registry in RAS wild-type patients treated with biologics second-line mCRC.

Colorectal cancer is one of the leading causes of mortality both globally and in our country. In Turkey, we conducted a multicenter investigation into the effectiveness of second-line treatments and real-life data for patients with RAS wild-type metastatic colorectal cancer (NCT04757311). In this retrospective analysis, records from 28 centers were collected, and histopathological, molecular, and clinical characteristics were documented. Patients were categorized into groups based on their second-line biological treatments: anti-EGFR (Group A and Group B, panitumumab and cetuximab) and anti-VEGF (Group C, bevacizumab and aflibercept). They were then compared within these groups. A total of 588 patients with documented RAS wild-type status were evaluated. The median OS was 15.7, 14.3 and 14.7 months in Group A, Group B and Group C, respectively (p = 0.764). The median PFS of the patients in second-line setting that received panitumumab, cetuximab and bevacizumab/aflibercept were 7.8, 6.6 and 7.4 months, respectively (p = 0.848). According to the results of our real-life data study, there is no significant difference in efficiency between the combination of biological agent and chemotherapy used in the second-line treatments.

Real-life clinical management patterns in extensive-stage small cell lung cancer across France: a multi-method study

BackgroundWe designed this study based on both a physician practice survey and real-world patient data to: (1) evaluate clinical management practices in extensive-stage small cell lung cancer (ES-SCLC) among medical centers located across France; and (2) describe first-line treatment patterns among patients with ES-SCLC following the introduction of immunotherapy into clinical practice.MethodsA 50-item questionnaire was completed by physicians from 45 medical centers specialized in SCLC management. Responses were collected from June 2022 to January 2023. The survey questions addressed diagnostic workup of ES-SCLC, chemoimmunotherapy in first-line and second-line settings, and use of prophylactic cranial irradiation (PCI) and radiotherapy. In parallel, using a chart review approach, we retrospectively analyzed aggregated information from 548 adults with confirmed ES-SCLC receiving first-line treatment in the same centers.ResultsIn ES-SCLC, treatment planning is based on chest computed tomography (CT) (as declared by 100% of surveyed centers). Mean time between diagnosis and treatment initiation was 2–7 days, as declared by 82% of centers. For detection of brain metastases, the most common imaging test was brain CT (84%). The main exclusion criteria for first-line immunotherapy in the centers were autoimmune disease (87%), corticosteroid therapy (69%), interstitial lung disease (69%), and performance status ≥ 2 (69%). Overall, 53% and 36% of centers considered that patients are chemotherapy-sensitive if they relapse within ≥ 3 months or ≥ 6 months after first-line chemoimmunotherapy, respectively. Among the 548 analyzed patients, 409 (75%) received chemoimmunotherapy as a first-line treatment, 374 (91%) of whom received carboplatin plus etoposide and 35 (9%) cisplatin plus etoposide. Overall, 340/548 patients (62%) received maintenance immunotherapy. Most patients (68%) did not receive radiotherapy or PCI.ConclusionsThere is an overall alignment of practices reflecting recent clinical guidelines among medical centers managing ES-SCLC across France, and a high prescription rate of immunotherapy in the first-line setting.

Entrectinib as first-line vs. second-line therapy in ROS1 fusion-positive non-small cell lung cancer: a cost-effectiveness analysis.

The concept of cost-effectiveness is crucial for the optimal allocation of scarce healthcare resources. However, the cost-effectiveness of entrectinib in ROS1 fusion-positive non-small cell lung cancer (NSCLC) has not been evaluated. We aim to evaluate the cost-effectiveness of entrectinib as a first-line treatment compared to its reservation for second-line therapy or the exclusive use of chemotherapy in ROS1 fusion-positive advanced NSCLC. A Markov model was created to assess the clinical outcomes and healthcare costs associated with these three treatment approaches. Cost and utility values were obtained from established literature and cost databases. To test model robustness, probabilistic and univariate sensitivity analyses were conducted. In the first-line setting, where entrectinib was administered as the initial therapy, it yielded an extra 0.07 quality-adjusted life years (QALYs) at an incremental cost of $73,453, leading to an incremental cost-effectiveness ratio (ICER) of $1,090,594.30 per QALY compared to chemotherapy. Conversely, in the second-line setting, when entrectinib was used as a second-line therapy following chemotherapy, it provided an extra 0.11 QALYs at an incremental cost of $53,480, resulting in an ICER of $494,290.39 per QALY compared to chemotherapy. Furthermore, the analysis revealed that the cost of entrectinib and utility values of progressed disease were the most influential factors for the ICER. Considering the current pricing of entrectinib, it is not deemed cost-effective as a first-line or second-line therapy for patients with ROS1 fusion-positive advanced NSCLC when compared to chemotherapy. Alternatively, reserving entrectinib exclusively for second-line therapy might strike a balance between healthcare expenditures and patient outcomes.

HER2-Positive Gastric Cancer and Antibody Treatment: State of the Art and Future Developments.

Despite a decreasing incidence in Western countries, gastric cancer is among the most common cancer subtypes globally and is associated with one of the highest tumor-related mortality rates. Biomarkers play an increasing role in the treatment against gastric cancer. HER2 was one of the first biomarkers that found its way into clinical practice. Since the ToGA trial, trastuzumab has been part of first-line palliative chemotherapy in metastatic or unresectable gastric cancer. HER2-targeting agents, such as the tyrosine kinase inhibitor lapatinib, the antibody drug conjugate (ADC) trastuzumab-emtansine or dual HER2 inhibition (pertuzumab and trastuzumab), have been investigated in the second-line setting but led to negative study results. More recently, the ADC trastuzumab-deruxtecan was authorized after the failure of trastuzumab-based treatment. However, further improvements in HER2-directed therapy are required as resistance mechanisms and HER2 heterogeneity limit the existing treatment options. This review aims to give an overview of the current standard-of-care HER2-directed therapy in gastric cancer, as well as its challenges and future developments.

A phase II study of belumosudil for chronic graft-versus-host disease in patients who failed at least one line of systemic therapy in China

BackgroundChronic graft-versus-host disease (cGVHD) is an immune-related disorder that is the most common complication post-allogenic hematopoietic stem cell transplant. Corticosteroids with or without calcineurin inhibitors (CNIs) remain the mainstay of cGVHD treatment for first-line therapy. However, for many patients, cGVHD symptoms cannot be effectively managed and thus require second-line therapy. Currently, there is no approved treatment for second-line cGVHD treatment in China. In this study, belumosudil, a highly selective and potent rho-associated coiled-coil-containing protein kinase-2 inhibitor demonstrated to be effective for cGVHD in the United States and other Western countries, is investigated in patients with cGVHD in China for its overall benefit–risk balance.MethodsThis multicenter, open-label phase II study evaluated the safety, efficacy, and pharmacokinetics of oral belumosudil 200 mg once daily in cGVHD patients who had been treated with at least one line of systemic therapy in China. The primary endpoint was overall response rate (ORR); each individual patient’s response was assessed by the investigator using the 2014 National Institutes of Health consensus criteria. Secondary endpoints were duration of response (DOR), time to response (TTR), changes in Lee Symptom Scale (LSS) score, organ response rate, corticosteroid dose change, CNI dose change, failure-free survival, time-to-next-treatment, overall survival, and safety.ResultsThirty patients were enrolled in the study with a median follow-up time of 12.9 months. ORR was 73.3% (95% confidence interval: 54.1–87.7%) and all responders achieved partial response. Median DOR among responders was not reached and median TTR was 4.3 weeks (range: 3.9–48.1). Fifteen patients (50.0%) achieved clinically meaningful response in terms of reduction in LSS score by ≥ 7 points from baseline. Corticosteroid and CNI dose reductions were reported in 56.7% (17/30) and 35.0% (7/20) of patients, respectively. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity, with 11 patients (36.7%) experiencing grade ≥ 3 TEAEs. The most common grade ≥ 3 TEAE was pneumonia (n = 5, 16.7%).ConclusionsBelumosudil treatment demonstrated a favorable benefit–risk balance in treating cGVHD patients who previously have had standard corticosteroid therapy in China where approved second-line setting is absent.Trial registrationClinicalTrials.gov identifier NCT04930562.

Gedatolisib in combination with palbociclib and endocrine therapy in women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the dose expansion groups of an open-label, phase 1b study

The PI3K-mTOR pathway is frequently dysregulated in breast cancer. Combining an inhibitor targeting all class I PI3K isoforms and mTOR complex 1 (mTORC1)-mTOR complex 2 (mTORC2) with endocrine therapy and a CDK4/6 inhibitor might provide more effective tumour control than standard-of-care therapy. To evaluate this hypothesis, gedatolisib, a pan-PI3K-mTOR inhibitor, was assessed in a phase 1b trial combined with palbociclib and endocrine therapy in patients with hormone receptor-positive, HER2-negative, advanced breast cancer. Results from the dose expansion portion of this trial are reported herein. This multicentre, open-label, phase 1b study recruited female patients aged at least 18 years from 17 sites across the USA with hormone-receptor-positive, HER2-negative, advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-1. Four patient groups were studied in the dose expansion portion of the study: treatment-naive in the advanced setting (first line; group A), progression on 1-2 lines of endocrine therapy but CDK4/6 inhibitor-naive (group B); and one or more previous lines (second-line and higher) of therapy, including a CDK4/6 inhibitor (groups C and D). Gedatolisib 180 mg was administered intravenously weekly in 28-day treatment cycles for groups A-C, and on days 1, 8, and 15 for group D. Letrozole (group A), fulvestrant (groups B-D), and palbociclib (all groups) were administered at standard doses and schedules. The primary endpoint was investigator-assessed objective response rate per RECIST version 1.1 in the evaluable analysis set. This trial is completed and registered with ClinicalTrials.gov, NCT02684032. Between Dec 19, 2017, and June 19, 2019, 103 female participants were enrolled in the dose expansion groups A (n=31), B (n=13), C (n=32), and D (n=27). Median follow-up was 16·6 months (IQR 5·7-48·4) for group A, 11·0 months (7·6-16·9) for group B, 3·6 months (1·8-7·5) for group C, and 9·4 months (5·3-16·7) for group D for the primary endpoint. Gedatolisib, palbociclib, and endocrine therapy induced an objective response in 23 (85·2%; 90% CI 69·2-94·8) of 27 evaluable first-line participants (group A). In the second-line and higher setting, an objective response was observed in eight (61·5%; 90% CI 35·5-83·4) of 13 evaluable group B participants, seven (25·0%; 12·4-41·9) of 28 evaluable group C participants, and 15 (55·6%; 38·2-72·0) of 27 evaluable group D participants; this included participants with both wild-type and mutated PIK3CA tumours. The most common grade 3-4 treatment-related adverse events were neutropenia (65 [63%] of 103), stomatitis (28 [27%]), and rash (21 [20%]). Grade 3-4 hyperglycaemia was reported in six (6%) participants. 23 (22%) of 103 participants had a treatment-related serious adverse event, and there were no treatment-related deaths. Nine (9%) participants discontinued treatment because of a treatment-emergent adverse event. Gedatolisib plus palbociclib and endocrine therapy showed a promising objective response rate compared with the published results for standard-of-care therapies and had an acceptable safety profile. Pfizer and Celcuity.

Abstract 5098: Second-line treatment outcomes in Extensive Stage Small Cell Lung Cancer (ES-SCLC) patients after first-line immuno-chemotherapy

Abstract Background: First-line immune checkpoint inhibitors (ICIs) has significantly improved overall survival (OS) of ES-SCLC. However, second-line treatment options are still controversial with limited overall survival. This study aims to evaluate the efficacy of different second-line regimens for relapsed ES-SCLC after first-line immuno-chemotherapy. Patients and Methods: We retrospectively reviewed 96 ES-SCLC patients receiving first-line immuno-chemotherapy in Cancer Hospital Chinese Academy of Medical Sciences, from Jan 2019 to Dec 2022. Clinical data were collected from electronic medical records. The clinical outcomes, including objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier method and standard log-rank test. Results: From January 4, 2019 to December 18, 2022, a total of 96 ES-SCLC patients received first-line immuno-chemotherapy and 49 of them went through second-line treatment in our center. Patient characteristics were listed as follows : median age 63 (31-79), male 76 (79.2%) , heavy smoker 59 (61.5%), liver metastasis 40 (41.7%), brain metastasis 33 (34.4%) and refractory recurrence 58 (60.4%). Second-line treatments included immunotherapy crossover and combination with chemotherapy (n=40), anlotinib with or without chemotherapy (n=5), chemotherapy alone (n=4). ORR of the whole group in the second-line setting was 22.4%. Median PFS was 3.23 months (95% CI 1.96-4.50). Cross-line immunotherapy failed to improved survival for relapsed ES-SCLC compared with those without ICIs ( mPFS 3.23 vs 3.13m, p=0.829). Anlotinib based treatment showed numerically superior PFS for relapsed SCLC compared with those without anlotinib therapy (mPFS 6.00 vs 3.13m, p=0.089). Conclusion: This retrospective study indicated cross-line ICIs failure to improve clinical outcome for relapsed ES-SCLC, and implied the potential benefits of anlotinib in second-line setting. Citation Format: Rui Wan, Linjie Fan, Jia Zhong, Jianchun Duan, Zhijie Wang, Xuezhi Hao, Jie Wang. Second-line treatment outcomes in Extensive Stage Small Cell Lung Cancer (ES-SCLC) patients after first-line immuno-chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5098.

A real-world analysis of second-line treatment option, gemcitabine plus anlotinib and anti-PD1, in advanced pancreatic cancer

BackgroundIn the second-line treatment of advanced pancreatic cancer (APC), there is only one approved regimen based on the phase III NAPOLI-1 trial. However, for patients progressing after Nab-paclitaxel and Gemcitabine (Nab-P/Gem) or Nab-P combinations, second-line treatment were very limited. MethodsThis is a retrospective single-center analysis of patients. Our aim was to determine the effectiveness and tolerability of a novel regimen, gemcitabine plus Anlotinib and anti-PD1, in APC patients and to compare it with oxaliplatin, irinotecan, leucovorin, and fluorouracil (FOLFIRINOX) in the second-line setting who have failed on the first-line Nab-P combinations. ResultsIn total, twenty-three patients received Gemcitabine plus Anlotinib and anti-PD1 in the second-line, 28 patients were treated with FOLFORINOX. There was no significant difference in overall survival (OS) or progression free survival (PFS) for either of the two sequences (p > 0.05). Patients who received Gemcitabine plus Anlotinib and anti-PD1 had a median PFS of 4.0 months (95% CI: 1.1–6.9) versus 3.5 months (95% CI 1.8–5.2) in FOLFORINOX group (p = 0.953). The median OS of Gemcitabine plus Anlotinib and anti-PD1 was 9.0 months (95% CI: 4.0–13.7) and 8.0 months (95% CI: 5.5–10.5) in FOLFORINOX group (p = 0.373). Grade ≥3 treatment-emergent adverse events (AEs) occurred for 13% of patients with Gemcitabine plus Anlotinib and anti-PD1 and 40% for FOLFORINOX. ConclusionOur data confirms the effectiveness of Gemcitabine plus Anlotinib and anti-PD1 as a well-tolerated regimen in the second-line treatment of APC and extends available data on its use as a second-line treatment option when compared with FOLFIRINOX.

Effectiveness and Safety of Immune Checkpoint Inhibitors in Older Cancer Patients.

The development of immunotherapy checkpoint inhibitors (ICIs) has revolutionized cancer care. However, old patients are underrepresented in most clinical trials, although they represent a significant proportion of real-world patients. We aimed to evaluate the effectiveness and safety of ICIs in patients older than the age of 70. We performed a retrospective chart review of 145 patients aged 70 or older treated with ICIs for metastatic or unresectable cancer. Median progression-free survival (PFS) was 10.4 months (95% CI 8.6-13.7), with no differences between octogenarians and septuagenarians (p = 0.41). Female gender (p = 0.04) and first-line treatment setting (p < 0.0001) were associated with a longer median PFS. Median overall survival (OS) was 20.7 months (95% CI 13.5-35.0 months), with no difference based on performance status, cancer site, gender, or between septuagenarians and octogenarians (all p > 0.005). Patients treated with ICIs in the first-line setting reported longer OS compared to treatment in the second-line setting (p < 0.001). Discontinuation of ICIs due to adverse effects was associated with both shorter PFS (p = 0.0005) and OS (p < 0.0001). The effectiveness of ICIs in older cancer patients primarily depends on the line of treatment and treatment discontinuation. Octogenarians experienced similar treatment responses, PFS, OS, and adverse effects compared to septuagenarians.

Abstract A081: Real-world treatment patterns and clinical outcomes in patients with HER2+ metastatic breast cancer receiving systemic therapy in Ontario, Canada

Abstract Background: Real-world data on treatment patterns and prevalence of brain metastases in patients with HER2+ metastatic breast cancer (mBC) are limited. This study described treatment patterns and clinical outcomes among patients with HER2+ mBC in Canada. Methods: This was a retrospective chart review of adult patients diagnosed with de-novo or recurrent HER2+ mBC between Jan 1, 2014 and Mar 1, 2021 (prior to wide availability of new treatments) at Sunnybrook Research Institute and Sinai Health, two large BC treatment centres in Canada. Data on patient characteristics and treatment regimens were extracted. Treatment patterns, time to next treatment (TTNT; as a proxy for progression-free survival), and presence of brain metastases were assessed in the first-line (1L), second-line (2L), and third-line (3L) settings. TTNT analyses used Kaplan-Meier methodology to account for censoring. Results: Of 121 patients with HER2+ mBC, the median (IQR) age was 54.0 (17.0) years. 38.0% of patients had de-novo disease and 62.0% had recurrent mBC; 12 (9.9%) had brain metastases at the time of mBC diagnosis. Systemic therapies generally aligned with Canadian funded regimens for 1L (101 of 121 patients [83.5%] received trastuzumab + pertuzumab ± chemotherapy ± subsequent endocrine therapy; 8/121 [6.6%] received endocrine therapy only) and 2L (50/68 [73.5%] received T-DM1 ± endocrine therapy; 9/68 [13.2%] received endocrine therapy only). However, treatment patterns were heterogeneous in the 3L setting (14/46 [30.4%] received anti-HER2 TKI + chemotherapy ± trastuzumab; 10/46 [21.7%] received endocrine therapy only; 10/46 [21.7%] received chemotherapy). Median (95% CI) TTNT in months was 21.4 (16.1, 27.2) in 1L, 11.0 (8.5, 16.5) in 2L, and 8.7 (5.4, 15.6) in 3L. Median (IQR) follow-up was 29.9 (25.2) months. In total, 57 patients (47.1%) were diagnosed with brain metastases during the study period (17 pre-1L, 24 post-1L/pre-2L, 6 post-2L/pre-3L) and of these, 73.7% received radiation therapy. Conclusions: In patients with HER2+ mBC in Canada, 3L treatment patterns are heterogeneous, median TTNT is &amp;lt;1 year, and almost half develop brain metastases. These data from two large treating centres in Ontario suggest a high unmet need for more effective treatment regimens in later lines of therapy, particularly 3L, for patients with HER2+ mBC. Citation Format: Katarzyna J Jerzak, Ruth Moulson, Ling-I Hsu, Chris Lenhu, Dhivo Krishnathasan, Jessica Weiss, Christine Brezden-Masley. Real-world treatment patterns and clinical outcomes in patients with HER2+ metastatic breast cancer receiving systemic therapy in Ontario, Canada [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A081.

Regorafenib combined with a PD-1 inhibitor in the second-line setting for unresectable hepatocellular carcinoma in real-world practice.

Most advanced hepatocellular carcinoma (HCC) cases administered molecular targeted agents and/or anti-programmed cell death-1 (PD-1) inhibitors have no response or develop resistance. Moreover, second-line therapies still cannot provide beneficial clinical outcomes. A pilot study assessing combined regorafenib and PD-1 inhibitor as second-line treatment of advanced HCC reported promising effectiveness. The current single-center, retrospective, real-world study was carried out between January 2019 and July 2021. Advanced HCC cases were administered second-line regorafenib combined with a PD-1 inhibitor or regorafenib alone were assessed. Progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were determined. Totally 46 HCC cases were analyzed, most of whom underwent previous systemic treatment comprising targeted therapy and immunotherapy. Tumor response was evaluated in 25 and 21 individuals in the regorafenib + PD-1 inhibitor and regorafenib monotherapy groups, respectively: ORRs were 21.7% and 8.7%, and DCRs were 47.8% and 32.6%, respectively. Median PFS was markedly longer in the regorafenib plus PD-1 inhibitor group (11.5 months) compared with the regorafenib monotherapy group (5.1 months, P=0.049). This study suggested regorafenib and a PD-1 inhibitor in combination may provide significant clinical benefits in HCC cases showing progression following first-line treatment. Further analysis in real-world studies with large cohorts is warranted to confirm these findings.

Impact of the response to platinum-based chemotherapy on the second-line immune checkpoint inhibitor monotherapy in non-small cell lung cancer with PD-L1 expression ≤49%: a multicenter retrospective study.

The efficacy of second-line immune checkpoint inhibitor (ICI) therapy is limited in non-small cell lung cancer (NSCLC) patients with ≤ 49% PD-L1 expression. Although chemoimmunotherapy is a promising strategy, platinum-based chemotherapy followed by ICI monotherapy is often used to avoid synergistic adverse events. However, predictors of the efficacy of ICI monotherapy after platinum-based chemotherapy in NSCLC with ≤ 49% PD-L1 expression remain scarce. This multicenter retrospective study evaluated 54 advanced or recurrent NSCLC patients with ≤ 49% PD-L1 expression who were treated with second-line ICI monotherapy following disease progression on first-line platinum-based chemotherapy at nine hospitals in Japan. The impact of response to platinum-based chemotherapy on the efficacy of subsequent ICI monotherapy was investigated. The response to first-line platinum-based chemotherapy was divided into two groups: the non-progressive disease (PD) group, which included patients who did not experience disease progression after four cycles of chemotherapy, and the PD group, which included patients who showed initial PD or could not maintain disease control during the four cycles of chemotherapy and switched to second-line ICI monotherapy. Among the 54 patients, 32 and 22 were classified into the non-PD and PD groups, respectively. The non-PD group showed better response rates (p = 0.038) and longer overall survival (OS) with ICI monotherapy (p = 0.023) than the PD group. Multivariate analysis identified that maintaining a non-PD status after four cycles of chemotherapy was an independent prognostic factor for ICI monotherapy (p = 0.046). Moreover, patients with a modified Glasgow Prognostic Score (mGPS) of 0 showed a tendency for longer OS with ICI monotherapy (p = 0.079), and there was a significant correlation between maintaining non-PD after four cycles of chemotherapy and an mGPS of 0 (p = 0.045). Maintaining a non-PD status after four cycles of platinum-based chemotherapy was a predictor of OS after second-line ICI monotherapy. These findings will help physicians select the most suitable treatment option for NSCLC patients who were treated with platinum-based chemotherapy and switched to second-line treatment. Those who experienced early PD during platinum-based chemotherapy should not be treated with ICI monotherapy in the second-line setting.

REAL-WORLD RATE AND MAGNITUDE OF DOSE ESCALATION WITH BIOLOGICS IN PATIENTS WITH CROHN’S DISEASE

Abstract INTRODUCTION Advanced therapies (ATs), such as adalimumab (ADA), infliximab (INF), vedolizumab (VED), and ustekinumab (UST), referred to as biologics, are regularly used to treat moderate-to-severe Crohn’s disease (CD). Loss of response is a common problem with biologics in CD and one solution is to increase dose of biologics, affecting the cost of CD management. Assessing real-world dosing with biologics is important to inform the estimated treatment cost. The objective of this study was to assess the rate and magnitude of dose escalation with biologics in treatment of CD. METHODS This retrospective cohort study identified adult American patients in the IQVIA PharMetrics® Plus database who were diagnosed with CD and started an AT for CD between 01 Jan 2015 and 31 May 2021. Index date was the start date of a qualifying AT. Patients had ≥12 months of continuous pre- and post-index enrollment in a health plan, no claims for AT during the pre-index period, and no autoimmune diseases or indeterminate colitis. Rate and magnitude of dose escalation were assessed from the start of maintenance phase with AT until the end of follow-up period. Dose escalation was measured in first-line (1L) and second-line (2L) settings and defined as an increase in average dose ≥20% than expected dosing per FDA label during follow-up period after maintenance dose was reached. Dose escalations of ≥50% and ≥100% were also measured. RESULTS The study identified 7,353 CD patients starting an AT (1L setting) (median age, 38 years; 51.4% female; median follow-up, 28.5 [18.6-43.0] months), and 1,608 (21.9%) patients who received treatment with AT in a 2L setting. More patients reached maintenance dose in a 1L setting (89.4% [INF] to 93.8% [ADA]) than in a 2L setting (77.4% [INF] to 90.3% [UST]). The rate of dose escalation in patients who reached maintenance dose was 21.1% [ADA], 19.2% [IFX], 29.3% [VED], 49.5% [UST] in a 1L setting, vs 23.8% [ADA], 21.9% [IFX], 25.1% [VED], 52.0% [UST], respectively, in a 2L setting (Figure 1). The frequency of dose escalation ≥50% varied for different therapies, 13.8% [ADA], 6.1% [IFX], 19.1% [VED], and 40.0% [UST] in a 1L setting vs 15.3% [ADA], 9.0% [IFX], 17.6% [VED], and 42.3% [UST] in a 2L setting (Figure 2). Dose escalation ≥100% was uncommon with both 1L therapies (0.6% [ADA] to 10.1% [VED]) and 2L therapies (0% [ADA] to 7.7% [VED]). CONCLUSIONS A meaningful percentage of Crohn’s disease patients treated with adalimumab, infliximab, vedolizumab, or ustekinumab had dose escalation regardless of line of treatment. Understanding the impact of these utilization patterns may inform real-world cost management. Figure 1 Rate of dose escalation with advanced therapies in Crohn’s disease Figure 2 Magnitude of dose escalation with advanced therapies in Crohn’s disease

REAL-WORLD RATE AND MAGNITUDE OF DOSE ESCALATION WITH BIOLOGICS IN PATIENTS WITH ULCERATIVE COLITIS

Abstract INTRODUCTION Advanced therapies (ATs), such as adalimumab (ADA), infliximab (INF), golimumab (GOL), vedolizumab (VED), and ustekinumab (UST), referred to as biologics, are regularly used to treat moderate-to-severe ulcerative colitis (UC). Loss of response is a common problem with biologics in UC and one solution is to increase dose of biologics, affecting the cost of UC management. Assessing real-world dosing with biologics is important to inform the estimated treatment cost. The objective of this study was to assess the rate and magnitude of dose escalation with biologics in treatment of UC. METHODS This retrospective cohort study identified adult American patients in the IQVIA PharMetrics® Plus database who were diagnosed with UC and started an AT for UC between 01 Jan 2015 and 31 May 2021. Index date was the start date of a qualifying AT. Patients had ≥12 months of continuous pre- and post-index enrollment in a health plan, no claims for AT during the pre-index period, and no autoimmune diseases or indeterminate colitis. Rate and magnitude of dose escalation were assessed from the start of maintenance phase with AT until the end of follow-up period. Dose escalation was measured in first-line (1L) and second-line (2L) settings and defined as an increase in average dose ≥20% than expected dosing per FDA label during follow-up period after maintenance dose was reached. Dose escalations of ≥50% and ≥100% were also measured. RESULTS The study identified 5,997 UC patients starting an AT (1L setting) (median age, 40 years; 55.5% male; median follow-up, 27.5 [18.5-41.8] months), and 1,896 (31.6%) patients who received treatment with AT in a 2L setting. More patients reached maintenance dose in a 1L setting (86.6% [INF] to 92.7% [ADA]) than in a 2L setting (82.0% [INF] to 87.4% [ADA]). The rate of dose escalation in patients who reached maintenance dose for ADA, IFX, GOL, VED, UST was 22.0%, 17.9%, 7.0%, 28.8%, 50.6%, respectively, in a 1L setting, vs 21.9%, 19.2%, 7.7%, 25.9%, 55.1%, respectively, in a 2L setting (Figure 1). The frequency of dose escalation ≥50% varied for different therapies, 15.0% [ADA], 5.7% [IFX], 4.3% [GOL], 21.0% [VED], and 44.6% [UST] in a 1L setting vs 16.4% [ADA], 8.4% [IFX], 1.9% [GOL], 19.2% [VED], and 46.5% [UST] in a 2L setting (Figure 2). Dose escalation ≥100% was uncommon with both 1L therapies (0.4% [ADA] to 10.0% [VED]) and 2L therapies (0% [GOL] to 7.0% [VED]). CONCLUSIONS A meaningful percentage of ulcerative colitis patients treated with adalimumab, infliximab, vedolizumab, or ustekinumab had dose escalation regardless of line of treatment. Understanding the impact of these utilization patterns may inform real-world cost management. Figure 1 Rate of dose escalation with advanced therapies in ulcerative colitis Figure 2 Magnitude of dose escalation with advanced therapies in ulcerative colitis

Benefit of immune checkpoint inhibitors (ICI) for patients with advanced esophageal squamous cell carcinoma and low PD-L1 expression: A systematic review and meta-analysis.

346 Background: Immunotherapy has improved survival for patients with advanced esophageal squamous cell carcinoma (aESCC) and currently is the standard of care for patients with a positive PD-L1 status (CPS ≥10; TPS ≥1%) in the first-line setting. For PD-L1 negative/low, treatment options are limited, and chemotherapy is usually the first choice and associated with adverse events that may impair quality of life. Immunotherapy trials harbor conflicting results in this subgroup of patients, therefore, we performed a systematic review and meta-analysis to evaluate the potential benefit of ICI as single treatment for patients with aESCC and a PD-L1 expression negative/low. Methods: Studies that enrolled patients with aESCC treated with ICI versus chemotherapy in first and second-line settings and provided separate outcomes for patients with PD-L1 negative/low were identified by searching the EMBASE, PubMed and Cochrane databases. The outcomes evaluated were Overall Survival (OS), Progression Free-Survival (PFS) and Treatment-Emergent Adverse Events (TEAE). We pooled hazard ratio (HR) for PFS and OS endpoints and odds ratio (OR) with 95% confidence intervals (CI) for TEAE. Statistical analyses were performed using Revman 5.4 and a random-effects model. I² analysis was used to assess heterogeneity. This meta-analysis was recorded on Prospero ID CRD42023411251. Results: We included 6 randomized clinical trials with a total of 674 individuals in the final analysis. Most studies (5/6) included previously treated patients. ICI monotherapy in aESCC patients and PD-L1 expression negative/low was associated with a better OS (HR 0.86; 95% CI 0.76-0.97; p = 0.02; I² = 0%) and worse PFS (HR 1.37; 95% CI 1.10-1.71; p = 0.005; I² = 0%). Regarding the safety profile, it showed higher grade 3-5 toxicity rates (OR 1.8; 95% CI 1.17-2.78; p = 0.007; I² = 85%) for chemotherapy. Conclusions: ICI is effective for patients with aESCC and low/negative PD-L1 expression with an improvement in OS and a favorable safety profile.

Cost-utility analysis of sequential therapy with sorafenib followed by regorafenib versus single-line therapies in advanced hepatocellular carcinoma.

529 Background: Regorafenib is the only licensed second-line therapy available for patients with advanced hepatocellular carcinoma (HCC) that progress on first-line sorafenib in the UK. We evaluated the lifetime cost-effectiveness of a sequence of treatment with sorafenib followed by regorafenib (SOR-REG) compared with licensed single-line therapies for which there is no clear sequencing options available, including atezolizumab plus bevacizumab (ATEZO+BEV), which has become the standard of care in first-line treatment, as well as lenvatinib (LEN), followed by best supportive care (BSC). Methods: Assuming a UK National Health Service and Social Services perspective, we developed a probabilistic individual-level semi-Markov model with states reflecting progression-free survival, progression following first-line treatment, further progression following second-line treatment, and death. First-line overall survival (OS) and progression free survival (PFS) were informed by fractional polynomials network meta-analysis of published trials. Individual patient data from a phase 3 trial (RESORCE) on regorafenib and BSC informed OS and PFS in the second-line setting. Costs and utilities were sourced from published studies. Cost-effectiveness was summarized using incremental net monetary benefit (INMB), which could be positive or negative depending on direction of expected benefit associated with SOR-REG, and cost-effectiveness acceptability curves at willingness-to-pay (WTP) thresholds. Results: We found 1000 probabilistic samples and 1000 patients were sufficient for convergence. Lifetime costs were highest with ATEZO-BEV ([£80,963 [95% CI: £11,022, £97,369]), followed by SOR-REG (£38,373 [£31,064, £43,420]) and LEN (£37,351 [£5,020, £55,800]). Quality-adjusted life years (QALYs) were highest with ATEZO+BEV (1.021 [0.152, 1.239), followed by SOR-REG (0.942 [0.802, 1.057]) and LEN (0.755, [0.094, 1.092]). At a WTP threshold of £30,000 / QALY gained, SOR-REG had an INMB of £40,211 (95% CI -£2,099, £52,731) and £4,589 (-£8,044, £14,481) versus ATEZO+BEV and LEN, respectively. Conclusions: A sequence of SOR-REG for patients with advanced HCC is cost-effective at WTP thresholds of £30,000 / QALY gained due to lower lifetime costs and broadly comparable QALY gains with single-line ATEZO-BEV and LEN in the UK. Broader second-line treatment options are needed for patients receiving ATEZO+BEV and LEN as first-line therapies.

Clinical/molecular features and prognostic significance of RAS mutant-low versus RAS mutant-high in patients with metastatic colorectal cancer.

187 Background: Addressing tumor heterogeneity is one of the main advantage of liquid biopsy over tissue biopsy, as liquid biopsy is likely to better reflect the global molecular profile (primary tumor site and metastatic disease). Variant Allele Frequency (VAF) represents the fraction of sequencing reads in which a variant is observed. The aim was to evaluate the prognostic value of circulating tumor (ct) VAF for KRAS and NRAS genes in patients with ctRAS mutant metastatic colorectal cancer (MCRC). Methods: Circulating comprehensive genomic profiling using FoundationOne Liquid CDx (FO-Liq) was proposed to patients with histologically proven or highly suspected solid tumor whatever treatment line. FO-Liq is a next generation sequencing panel of 310 cancer related genes and 3 genomic signatures (blood tumor mutational burden (bTMB), microsatellite instability (MSI) and tumor fraction (TF)). The optimal threshold for ctVAF was determined by calculating Harrell’s C discrimination index extended for survival data. The primary endpoint was overall survival (OS). Results: From October 2020 to June 2023, 740 patients were screened for circulating molecular profiling. In the colorectal cohort (N=201), 198 (98.5%) patients had metastatic disease (ctRAS/BRAF wild-type, N=76 (38.4%) ; ctRAS mutant, N=106 (53.5%) and ctBRAF V600E mutant, N=16 (8.1%)). The optimal threshold for ctVAFRAS was 5% (C-index 0.67, 95% CI 0.62-0.73 ; P&lt;0.0001). Among patients with ctRAS mutant MCRC, 43 (40.6%) were ctRAS mutant-Low (VAFRAS&lt;5%) and 63 (59.4%) were ctRAS mutant-High (VAFRAS≥5%). Median follow-up was 18.5 months (95% CI 15.3-34.5). There was a significant increase in the the risk of death for RAS mutant-High compared to RAS mutant-Low (HR 2.81, 95% CI 1.70-4.63; P&lt;0.001). Patients with RAS mutant-low variants had the same prognosis that RAS/BRAF wild-type profile (HR 1.22 ; P=0.573), and patients with RAS mutant-high variants had the same prognosis that BRAF mutant profile (HR 0.82, P=0.563). The factors associated with RAS mutant-High profile were : bTMB-High, TF-High, RAS G12A and G13D variants. MAP kinase, TGFb and Wnt signaling pathways and BRCA1-2 genes were more frequently altered in patients with ctRAS mutant-High tumors. We observed a transient decrease of VAFRAS in second-line setting. Conclusions: The circulating VAF of RAS genes enables to split RAS mutant-Low (favorable prognosis similar to RAS/BRAF wild-type) from RAS mutant-High (poorer prognosis similar to BRAF mutant) metastatic colorectal cancer. These results provide further insights into prognostication and therapeutic strategies in patients with RAS mutant metastatic colorectal cancer.

A phase 1b study of sotorasib combined with panitumumab as second-line treatment of KRAS G12C-mutated colorectal cancer.

128 Background: In the CodeBreaK 101 phase 1b study, sotorasib, a KRASG12C inhibitor, plus panitumumab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, showed acceptable safety and promising efficacy for patients with chemorefractory KRAS G12C–mutated metastatic colorectal cancer: an objective response rate (ORR) of 30% and median progression-free survival (PFS) of 5.7 months were observed. Here, we evaluated sotorasib plus panitumumab in the second-line (2L) setting. Methods: CodeBreaK 101 (NCT04185883) subprotocol H includes dose exploration and expansion in multiple cohorts. Patients eligible for the 2L sotorasib plus panitumumab dose-expansion cohort were KRASG12C inhibitor–naïve and had received no more than one prior regimen for metastatic disease. Patients received oral sotorasib at 960 mg daily and IV panitumumab 6 mg/kg every 2 weeks. The primary endpoint was safety. Secondary endpoints included efficacy endpoints. Results: As of May 23, 2023, this cohort was fully enrolled; all 20 patients (50% female, median age 60.0 years) were included in this analysis. All patients received fluoropyrimidine-based treatment and 17 (85%) patients received oxaliplatin-based treatment as first-line therapy. Any-grade treatment-related adverse events (TRAEs) occurred in 19 (95%) patients. The most common any-grade TRAEs were dermatitis acneiform (60%), dry skin (55%), pruritus (45%), and hypomagnesemia (30%). Grade ≥3 TRAEs occurred in 4 (20%) patients and included fatigue, hypomagnesemia, decreased appetite, and rash (5% each). No TRAEs were grade ≥4 or resulted in treatment discontinuation or deaths. Confirmed ORR was 30% (95% CI: 11.9, 54.3). The disease control rate was 90% (95% CI: 68.3, 98.8). At a median follow-up of 11.3 months (95% CI: 5.6, not estimable), median PFS was 8.3 months (95% CI: 4.3, 14.1). Conclusions: This is the first report of safety and efficacy from a 2L cohort evaluating a KRASG12C inhibitor plus an anti-EGFR antibody in KRAS G12C-mutated metastatic colorectal cancer. The toxicities of sotorasib plus panitumumab were consistent with the expected safety profile of the individual agents and with that reported previously for this combination; the ORR was similar to that previously observed for this combination in a more chemorefractory population. The ORR and PFS of sotorasib plus panitumumab compare favorably to current standard approaches in the 2L treatment of metastatic colorectal cancer. Clinical trial information: NCT04185883 .

Phase 1b/2, open-label dose-escalation and -expansion study evaluating trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients (pts) with HER2+ and HER2-low gastric cancer (GC): DESTINY-Gastric03 (DG-03).

TPS424 Background: T-DXd is approved for treatment of advanced/metastatic HER2+ GC after a trastuzumab-based regimen. The efficacy of T-DXd in advanced HER2+ (IHC 3+ or IHC 2+/ISH+) GC has been shown (confirmed objective response rate [ORR], 43% vs 12% with standard chemotherapy) in previously treated Japanese or South Korean pts (DG-01) and in Western pts with progression on a trastuzumab-containing regimen (confirmed ORR, 42%; DG-02). Also, antitumor activity was shown in pts with HER2-low GC (confirmed ORR, 26.3% [IHC 2+/ISH−], 9.5% [IHC 1+]) in DG-01. Other studies have shown benefits of immunotherapies combined with trastuzumab and other chemotherapies for treatment of HER2+ GC. The DG-03 trial is evaluating the safety and efficacy of T-DXd in combination with chemotherapy and/or immunotherapy in HER2-expressing GC. Previously, confirmed ORRs of 50% and 43% were reported with T-DXd + 5-fluorouracil (5-FU) and T-DXd + capecitabine (Cap), respectively, in the second-line or later setting in part 1 of DG-03. The protocol was amended to add an additional arm in part 2 and a new part 3, which will investigate T-DXd in combination with a fluoropyrimidine and volrustomig (MEDI5752), a PD-1/CTLA-4 bispecific antibody, in pts with HER2+ and HER2-low (IHC 2+/ISH− or IHC 1+) GC. Methods: DG-03 (NCT04379596)is a multicenter, dose-escalation (part 1) and -expansion (parts 2 and 3) study in HER2-expressing, locally advanced or metastatic, unresectable gastric, gastroesophageal junction, or esophageal adenocarcinoma. In arm F of part 2, pts with previously untreated HER2+ GC will be treated with T-DXd + investigator’s choice of 5-FU or Cap + pembrolizumab. In part 3, pts with previously untreated HER2+ (arm 3A) or HER2-low (arm 3B) GC will receive T-DXd + investigator’s choice of 5-FU or Cap + volrustomig. The primary endpoint in parts 2 and 3 is investigator-assessed confirmed ORR per RECIST v 1.1. Secondary endpoints include safety, duration of response, disease control rate, progression-free survival, overall survival, pharmacokinetics, and immunogenicity. Clinical trial information: NCT04379596 .