Third-line Treatment For Patients Research Articles

Abstract PO3-05-05: The effect of histological breast cancer subtype on progression free survival in patients with CDK4/6 inhibitors

Abstract Background: Multiple trials have proven that adding CDK4/6 inhibitors to endocrine treatment increases progression free (PFS) and overall survival (OS) of patients with metastatic estrogen receptor (ER)-positive HER2 negative breast cancer. However, only limited evidence is available of treatment efficacy of CDK4/6 inhibitors for invasive lobular carcinoma (ILC). This retrospective study aims to compare treatment duration of the three FDA/EMA approved CDK4/6 inhibitors in patients with no special type (NST) breast cancer versus patients with ILC. Methods: All patients with metastatic ER-positive HER2-negative breast cancer who were treated with a CDK4/6 inhibitor (1st, 2nd; 3rd line) in University Hospitals Leuven between December 2014 and February 2023, were included. A comparison of PFS and OS was made between patients with NST and ILC by use of the Kaplan Meier method. Other histological subtypes as well as mixed subtypes were excluded. Uni- and multivariable cox regression models were performed to quantify the association of histological subtype with PFS and OS. Results: A total of 418 patients were included of which 119 (28.5%) patients with ILC (median age at primary diagnosis 59 years, range 36 – 89 years) and 299 (71.5%) patients with NST (median age at primary diagnosis 55 years, range 23 – 90 years). Median follow-up was 26.8 months (range 1.1 – 88.1 months). Median PFS was 15.2 months (range 1.0 – 74.6 months) and 14.7 months (range 1.0 – 89.3 months) for patients with ILC and NST respectively. The OS rate after 60 months follow up was 39.2 % (CI 26.8 – 51.4) for ILC and 40.1% (CI 32.2 – 47.8) for NST. As shown in table 1, clear differences were observed in PFS rates after 12, 24 and 60 months between patients with NST that received CDK4/6 inhibitors in first line versus second or third line. These differences were less apparent for patients with ILC. For both NST and ILC, endocrine resistance at start of CDK4/6 inhibition impacted PFS rates negatively (table 2). In multivariable analyses, histological subtype was not predictive for CDK4/6 inhibition outcome (PFS: hazard ratio (HR) 0.996, CI 0.728 – 1.364, p-value 0.981; OS: HR 0.872, CI 0.602 – 1.263, p-value 0.468). Endocrine sensitivity vs. resistance at the time CDK4/6 inhibitor was started, was proven to be predictive for both PFS (HR 0.478, CI 0.337 – 0.678, p-value < 0.001) and OS (HR 0.528, CI 0.347 – 0.804, p-value 0.003). Conclusion: In our center, the histological subtype of breast cancer did not seem to impact PFS and OS significantly after treatment with CDK4/6 inhibition. Patients with NST seemed to have an increased benefit in PFS from treatment with CDK4/6 inhibition in first line as compared to later lines. While for patients with ILC, no difference between treatment lines were observed. Therefore, clinicians might be able to safely postpone CDK4/6 inhibitors to second- or third-line treatment in patients with metastatic ILC. Table 1: PFS rates by histological subtype and line of CDK4/6 treatment Table 2: PFS rates by histological subtype and endocrine sensitivity at start of CDK4/6 inhibition Citation Format: Cedric Bauters, Karen Van Baelen, Hans Wildiers, Giuseppe Floris, Sileny Han, Patrick Berteloot, Thaïs Baert, Ann Smeets, Ines Nevelsteen, Yannick Van Herck, Anne Deblander, Chantal Remmerie, Lieke Dullens, Maxime Van Houdt, Annouschka Laenen, Christine Desmedt, Patrick Neven. The effect of histological breast cancer subtype on progression free survival in patients with CDK4/6 inhibitors [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-05-05.

A decade of progress: advances in the third-line treatment of patients with metastatic colorectal cancer.

The treatment of metastatic colorectal cancer (mCRC) remains challenging. There has been substantial progress in understanding the molecular pathology of the disease that has led to meaningful advancements in treatment options with varying mechanisms of action, although treatment remains costly. Cytotoxic therapies, which are typically combined with targeted therapies, remain the mainstay of first- and second-line treatment for mCRC. While also relevant in earlier lines of therapy, molecular testing has become increasingly important to guide therapy across lines of therapy, for which treatment options are limited. A paucity of data exists in establishing clinical criteria for optimizing the sequencing of therapies in the third line and beyond. A customized approach should consider the efficacy of the therapy balanced with the patient's goals. Sequencing criteria should include a consideration for exposing patients to as many different modes of therapy as possible while preserving quality of life, avoiding serious toxicities, and accounting for the potential impact of cumulative toxicities from prior therapies.

Effectiveness and safety of a third-line rescue treatment for acute severe ulcerative colitis refractory to infliximab or ciclosporin (REASUC study).

The advent of new therapeutic agents and the improvement of supporting care might change the management of acute severe ulcerative colitis (ASUC) and avoid colectomy. To evaluate the colectomy-free survival and safety of a third-line treatment in patients with ASUC refractory to intravenous steroids and who failed either infliximab or ciclosporin. Multicentre retrospective cohortstudy of patients with ASUC refractory to intravenous steroids who had failed infliximab or ciclosporin and received a third-line treatment during the same hospitalisation. Patients who stopped second-line treatment due to disease activity or adverse events (AEs) were eligible. We assessed short-term colectomy-free survival by logistic regression analysis. Kaplan-Meier curves and Cox regression models were used for long-term assessment. Among 78 patients, 32 received infliximab and 46 ciclosporin as second-line rescue treatment. Third-line treatment was infliximab in 45 (58%), ciclosporin in 17 (22%), tofacitinib in 13 (17%) and ustekinumab in 3 (3.8%). Colectomy was performed in 29 patients (37%) during follow-up (median 21 weeks). Of the 78 patients, 32 and 18 were in clinical remission at, respectively, 12 and 52 weeks. At the last visit, 25 patients were still on third-line rescue treatment, while 12 had stopped it due to clinical remission. AEs were reported in 26 (33%) patients. Two patients died (2.6%), including one following colectomy. Third-line rescue treatment avoided colectomy in over half of the patients with ASUC and may be considered a therapeutic strategy.

Chemotherapy re-use versus anti-angiogenic monotherapy as the third-line treatment of patients with metastatic colorectal cancer: a real-world cohort study

BackgroundThere are various recommendations for third-line treatment in mCRC, however, there is no consensus on who is more suitable for particular strategy. Chemotherapy re-use in third-line setting is a common option in clinical practice. This study aimed to investigate the efficacy of third-line chemotherapy re-use by the comparison with that of anti-angiogenic monotherapy, and further find the population more suitable for third-line chemotherapy.MethodsUsing electronic medical records of patients with mCRC, a retrospective cohort study was conducted. A total of 143 patients receiving chemotherapy and 40 patients receiving anti-angiogenic monotherapy in third-line setting as control group were retrospectively collected. Baseline characteristics were analyzed using the χ² test or the Fisher’s exact test. ROC curve and surv_cutpoint function of ‘survminer’ package in R software were used to calculate the cut-off value. Survival curves were plotted with the Kaplan-Meier method and were compared using the log-rank test. The Cox proportional hazard regression model was used to analyze the potential risk factors.ResultsA total of 143 patients receiving chemotherapy and 40 patients receiving anti-angiogenic monotherapy in third-line setting were retrospectively collected. Chemotherapy rechallenge was recorded in 93 patients (93/143, 65.0%), and the remaining patients chose new chemotherapeutic drugs that had not been previously used, including irinotecan-based (22/50), oxaliplatin-based (9/50), raltitrexed (9/50), gemcitabine (5/50) and other agents (5/50). The ORR and DCR of third-line chemotherapy reached 8.8%, 61.3%, respectively (anti-angiogenic monotherapy group: ORR 2.6%, DCR 47.4%). The mPFS and mOS of patients receiving chemotherapy were 4.9 and 12.0 m, respectively (anti-angiogenic monotherapy group: mPFS 2.7 m, mOS 5.2 m). Subgroup analyses found that patients with RAS/RAF mutation, longer PFS (greater than 10.6 m) in front-line treatment or larger tumor burden had better prognosis with third-line chemotherapy rather than anti-angiogenic monotherapy.ConclusionsThird-line chemotherapy re-use was effective in mCRC. Those with more aggressive characteristics (RAS/RAF mutant, larger tumor burden) or better efficacy of previous chemotherapy (longer PFS) were more appropriate for third-line chemotherapy, rather than anti-angiogenic monotherapy.

Real-world outcomes of third-line immune checkpoint inhibitors versus irinotecan-based chemotherapy in patients with advanced gastric cancer: a Korean, multicenter study (KCSG ST22-06)

BackgroundImmune checkpoint inhibitor (ICI) or irinotecan-based chemotherapy is frequently used after failure of second-line paclitaxel plus ramucirumab treatment for patients with locally advanced unresectable or metastatic advanced gastric cancer (AGC). This study aimed to compare the efficacy between ICI and irinotecan-based chemotherapy as third-line treatment in patients with AGC.MethodsWe retrospectively reviewed patients with AGC, whose third-line treatment started between July 2019 and June 2021 at 17 institutions in Korea. The ICI group included patients who received nivolumab or pembrolizumab, and the irinotecan-based chemotherapy group included patients who received irinotecan or FOLFIRI (5-fluorouracil, leucovorin and irinotecan).ResultsA total of 363 patients [n = 129 (ICI) and n = 234 (irinotecan-based chemotherapy)] were analyzed. The median progression-free survival was 2.3 and 2.9 months in ICI and irinotecan-based chemotherapy groups, respectively (p = 0.802). The median overall survival (OS) was 5.5 and 6.0 months in ICI and irinotecan-based chemotherapy groups, respectively (p = 0.786). For all patients included in this study, multivariable analysis showed that weight loss, peritoneal metastasis, low serum sodium or albumin, and short duration of second-line treatment were associated with inferior OS (p < 0.05). ICI showed significantly longer OS than irinotecan-based chemotherapy in patients without peritoneal metastasis. Whereas ICI showed significantly shorter OS in patients without PD-L1 expression than irinotecan-based chemotherapy.ConclusionsNo significant difference in survival outcome was observed between ICI and irinotecan-based chemotherapy as third-line treatment for AGC patients. ICI might be preferred for patients without peritoneal metastasis and irinotecan-based chemotherapy for patients with tumors without PD-L1 expression.Trial registrationThis study was registered in the Clinical Trial Registry of Korea (https://cris.nih.go.kr: KCT 0007732).

A prospective phase II single-arm study and predictive factor analysis of irinotecan as third-line treatment in patients with metastatic gastric cancer.

Currently, there is no recommended standard third-line chemotherapy for metastatic gastric cancer. In this study, we aimed to evaluate irinotecan's efficacy and safety in treating metastatic gastric cancer after the failure of first- and second-line chemotherapy. Prospective single-arm, two-center, phase II trial. Patients were aged 18-70 years, with histologically confirmed gastric adenocarcinoma and an Eastern Cooperative Oncology Group performance status of 0-1, progressed during or within 3 months following the last administration of second-line chemotherapy and had no other severe hematologic, cardiac, pulmonary, hepatic, or renal functional abnormalities or immunodeficiency diseases. Eligible patients received 28-day cycles of irinotecan (180 mg/m2 intravenously, days 1 and 15) and were assessed according to the RECIST 1.1 criteria every two cycles. Patients who discontinued treatment for any reason were followed up every 2 months until death. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and toxicity. A total of 98 eligible patients were enrolled in this study. In the intention-to-treat population, the median OS was 7.17 months, the median PFS was 3.47 months, and the ORR and DCR were 4.08% and 47.96%, respectively. In the per-protocol population, the median OS was 7.77 months, the median PFS was 3.47 months, and the ORR and DCR were 4.82% and 50.60%, respectively. The incidence of grade 3 or 4 hematological and non-hematological toxicities was 19.4%, and none of the patients died owing to adverse events. Cox regression analysis revealed neutropenia and baseline thrombocyte levels were independently correlated with PFS and OS. Irinotecan monotherapy is an efficient, well-tolerated, and economical third-line treatment for patients with metastatic gastric cancer as a third-line treatment. ClinicalTrials.gov identifier: NCT02662959.

Cost-effectiveness analysis of elacestrant versus standard endocrine therapy for second-/third-line treatment of patients with HR+/HER2- advanced or metastatic breast cancer: a US payer perspective.

This study evaluated the cost-effectiveness of elacestrant (ELA) and standard-of-care (SOC) as second-/third-line treatment for pretreated estrogen receptor (ER)- positive/human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer (A/MBC) in the US. The 3 health states partitioned survival model (PSM) was conducted from the perspective of the US third-party payers. The time horizon for the model lasted 10 years. Effectiveness and safety data were derived from the EMERALD trial (NCT03778931). Costs were derived from the pricing files of Medicare and Medicaid Services, and utility values were derived from published studies. One-way sensitivity analysis as well as probabilistic sensitivity analysis were performed to observe model stability. ELA led to an incremental cost-effectiveness ratio (ICER) of $8,672,360/quality-adjusted life year (QALY) gained compared with SOC in the overall population and $2,900,560/QALY gained compared with fulvestrant (FUL) in the ESR1(estrogen receptor 1) mutation subgroup. The two ICERs of ELA were significantly higher than the willingness-to-pay (WTP) threshold values of $150,000/QALY. ELA was not cost-effective for the second-/third-line treatment of patients with ER+/HER2-A/MBC compared with SOC in the US.

Regorafenib alone or in combination with high/low-dose radiotherapy plus toripalimab as third-line treatment in patients with metastatic colorectal cancer: protocol for a prospective, randomized, controlled phase II clinical trial (SLOT).

https://clinicaltrials.gov/study/NCT05963490?cond=NCT05963490&rank=1, identifier NCT05963490.

1625P Multicenter, randomized, parallel group, phase II study to establish the efficacy and safety of CBP501, cisplatin, and nivolumab for ≥ third-line treatment of patients with exocrine pancreatic cancer and WBC &lt;10,000/mm3

1625P Multicenter, randomized, parallel group, phase II study to establish the efficacy and safety of CBP501, cisplatin, and nivolumab for ≥ third-line treatment of patients with exocrine pancreatic cancer and WBC &lt;10,000/mm3

Escalation Versus Induction/High-Efficacy Treatment Strategies for Relapsing Multiple Sclerosis: Which is Best for Patients?

After more than 2decades of recommending an escalating strategy for the treatment of most patients with multiple sclerosis, there has recently been considerable interest in the use of high-efficacy therapies in the early stage of the disease. Early intervention with induction/high-efficacy disease-modifying therapy may have the best risk-benefit profile for patients with relapsing-remitting multiple sclerosis who are young and have active disease, numerous focal T2 lesions on spinal and brain magnetic resonance imaging, and no irreversible disability. Although we have no curative treatment, at least seven classes of high-efficacy drugs are available, with two main strategies. The first strategy involves the use of high-efficacy drugs (e.g., natalizumab, sphingosine 1-phosphate receptor modulators, or anti-CD20 drugs) to achieve sustained immunosuppression. These can be used as a first-line therapy in many countries. The second strategy entails the use of one of the induction drugs (short-term use of mitoxantrone, alemtuzumab, cladribine, or autologous hematopoietic stem cell transplant) that are mainly recommended as a second-line or third-line treatment in patients with very active or aggressive multiple sclerosis disease. Early sustained immunosuppression exposes patients to heightened risks of infection and cancer proportionate to cumulative exposure, and induction drugs expose patients to similar risks during the initial post-treatment period, although these risks decrease over time. Their initial potential safety risks should now be revisited, taking account of long-term data and some major changes in their regimens: natalizumab with the long-term monitoring of John Cunningham virus; use of monthly courses of mitoxantrone with maximum cumulative doses of 36-72 mg/m2, followed by a safer disease-modifying drug; cladribine with only 2-weekly treatment courses required in years 1 and 2 and no systematic treatment for the following 2 years; alemtuzumab, whose safety and clinical impacts have now been documented for more than 6 years after the last infusion; and autologous haematopoietic stem cell transplant, which dramatically reduces transplantation-related mortality with a new regimen and guidelines. Escalation and induction/high-efficacy treatments need rigorous magnetic resonance imaging monitoring. Monitoring over the first few years, using the MAGNIMS score or American Academy of Neurology guidelines, considerably improves prediction accuracy and facilitates the selection of patients with relapsing-remitting multiple sclerosis requiring aggressive treatment.

Comparison of efficacy between immune checkpoint inhibitors and irinotecan-based chemotherapy as third-line treatment for patients with advanced gastric cancer: A Korean real-world multicenter study (KCSG ST22-06).

e16047 Background: Immune checkpoint inhibitor (ICI) or irinotecan-based chemotherapy are frequently used after paclitaxel plus ramucirumab as second-line treatment for patients with recurrent and/or metastatic gastric cancer (RMGC). This study aimed to compare the efficacy between ICI and irinotecan-based chemotherapy as third-line treatment in patients with RMGC. Methods: We retrospectively reviewed patients with RMGC, whose third-line treatment started between July 2019 and June 2021 at 17 centers in South Korea. The ICI group included patients who received nivolumab or pembrolizumab and the irinotecan-based chemotherapy group included those patients who received irinotecan or FOLFIRI. Results: A total of 363 patients (129 in the ICI group and 234 in the irinotecan-based chemotherapy group) were analyzed. The median progression-free survival (PFS) was 2.2 and 2.9 months in the ICI and irinotecan-based chemotherapy groups, respectively. The median overall survival (OS) was 5.5 months (95% CI, 3.6-7.4) in the ICI group and 6.0 months (95% CI, 4.8-7.0) in the irinotecan-based chemotherapy group [HR 0.97 (95% CI, 0.75-1.25); P=0.786]. Multivariable Cox-regression analysis showed that weight loss, peritoneal metastasis, low serum sodium, low serum albumin and short duration of second-line treatment were associated with inferior OS ( P&lt;0.05), meanwhile microsatellite instability-high (MSI-H)/mismatch repair-deficient (MMR-D) tumor was an independent prognostic factor for superior OS. The ICI group showed significantly longer OS than the irinotecan-based chemotherapy group in patients without peritoneal metastasis [HR 0.54 (95% CI 0.30-0.99); P=0.047)]. Whereas the irinotecan-based chemotherapy group showed significantly longer OS in patients without PD-L1 expression [HR 1.62 (95% CI 1.03-2.55); P=0.037] than the ICI group. Conclusions: No significant difference in survival outcome was observed between ICI and irinotecan-based chemotherapy as third-line treatment for patients with RMGC. ICI might be preferred for patients without peritoneal metastasis and irinotecan-based chemotherapy for patients with tumors without PD-L1 expression.

Synergistic antitumor activity of regorafenib and rosuvastatin in colorectal cancer.

Introduction: Colorectal cancer is one of the most prevalent life-threatening malignant tumors with high incidence and mortality. However, the efficacy of current therapeutic regimens is very limited. Regorafenib has been approved for second- or third-line treatment of patients who are refractory to standard chemotherapy diagnosed with metastatic colorectal cancer, but its clinical efficacy needs to be further improved. Accumulating evidence demonstrates that statins also possess potent anticancer activities. However, whether regorafenib and statins pose synergistic anticancer effects in colorectal cancer is still unclear. Methods: Sulforhodamine B (SRB) assays were applied to evaluate the anti-proliferative activity of regorafenib or/and rosuvastatin in vitro, and immunoblotting analysis were applied to detect the effects of regorafenib/rosuvastatin combined treatment on mitogen-activated protein kinase (MAPK) signaling and apoptosis-related proteins. MC38 tumors were applied to investigate the synergistic anticancer effects of regorafenib in combination with rosuvastatin in vivo. Results: We found that regorafenib in combination with rosuvastatin exerted significant synergistic inhibition against colorectal cancer growth in vitro and in vivo. Mechanistically, regorafenib and rosuvastatin combination synergistically suppressed MAPK signaling, a crucial signaling pathway promoting cell survival, as indicated by the reduction of phosphorylated MEK/ERK. In addition, regorafenib in combination with rosuvastatin synergistically induced the apoptosis of colorectal cancer in vitro and in vivo. Discussion: Our study demonstrated the synergistic anti-proliferative and pro-apoptotic effects of regorafenib/rosuvastatin combined treatment in colorectal cancer in vitro/vivo and might potentially be evaluated as a novel combination regimen for clinical treatment of colorectal cancer.

The efficacy and safety of nanoparticle albumin bound-paclitaxel-based regimen as second- or third-line treatment in patients with advanced esophageal squamous cell carcinoma.

There are limited reports on nanoparticle albumin bound-paclitaxel (nab-paclitaxel) regimens as second- or third-line treatments for advanced esophageal squamous cell carcinoma (ESCC). Additionally, its safety and efficacy in ESCC patients after failure of first-line programmed cell death protein-1 (PD-1) blockade plus chemotherapy have not been reported. In this study, we aimed to assess the efficacy and tolerability of nab-paclitaxel regimens as second- or later-line treatment in advanced ESCC. We retrospectively reviewed clinical data of advanced ESCC patients who participated in a randomized phase III clinical study and received serplulimab or placebo plus chemotherapy at our institution, and consecutive patients who received subsequent nab-paclitaxel-based regimens as second- or later-line treatment were included for data collection and analysis. A total of 39 patients were included, 25 (64.1%) received serplulimab plus chemotherapy and 14 (35.9%) received chemotherapy alone as first-line treatment. Treatment strategies included nab-paclitaxel monotherapy (7/39, 17.9%), or in combination with other chemotherapy (19/39, 48.7%), with anti-PD-1 antibodies (12/39, 30.8%) or with nimotuzumab (1/39, 2.6%). Overall, the objective response rate (ORR) and disease control rate (DCR) were 33.3% (13/39) and 61.5% (24/39), respectively. With a median follow-up of 9.7 months, the median progression-free survival and median overall survival were 5.0 and 7.9 months, respectively. The most common adverse events were neuropathy peripheral (30.8%), anemia (30.8%), neutrophil count decreased (23.1%), and nausea (20.5%). Nab-paclitaxel-based regimen could be a safe and effective option as second- or later-line treatment in patients with advanced ESCC, regardless of their previous exposure to PD-1 inhibitors.

Outcome comparison of pyrotinib with current standard of care in the second/third line setting in advanced non-small cell lung cancer patients with HER2 mutation.

Outcome comparison of pyrotinib with current standard of care in the second/third line setting in advanced non-small cell lung cancer patients with HER2 mutation.

Efficacy and Safety of TACE Combined with Regorafenib versus TACE in the Third-Line Treatment of Colorectal Liver Metastases.

The liver is the most common site of metastasis in colorectal cancer. In patients with unresectable colorectal liver metastases, the 5-year survival rate is less than 5%. Many patients with colorectal liver metastases require effective subsequent therapy after the failure of standard first-line/second-line therapy. The purpose of this study is to investigate the efficacy and safety of TACE combined with Regorafenib versus TACE in the third-line treatment of patients with colorectal liver metastases. The clinical data of 132 patients with colorectal liver metastases were collected. There were two groups: TACE + Regorafenib group (N = 63); TACE group (N = 69). TACE uses CalliSpheres® drug-loaded microspheres (loaded with irinotecan). Regorafenib is administered at a dose of 120 mg once daily. If the patient is severely intolerable, the regorafenib dose is adjusted to 80 mg once daily. Primary study endpoints were (1) to evaluate the tumor response, ORR, and DCR and (2) to evaluate OS and PFS in the two groups. Secondary study endpoints were (1) to compare the performance status, CEA, CA19-9 after treatment between the two groups and (2) to compare the incidence of adverse events between the two groups. There were significant differences in tumor response, ORR, DCR, OS, and PFS after treatment between the two groups. TACE combined with the Regorafenib group versus the TACE group: ORR (57.1% vs 33.3%), DCR (82.5% vs 68.1%), mOS (18.2 months vs 11.3 months), and mPFS (8.9 months vs 5.3 months). The performance status after treatment was better in the TACE + Regorafenib group than in the TACE group (P < 0.05). The CEA and CA19-9 negative rates after treatment were higher in the TACE + Regorafenib group than in the TACE group (P < 0.05). For the third-line treatment of colorectal liver metastases, the combination of TACE + Regorafenib had better tumor response, OS, and PFS than TACE TACE + Regorafenib combination could be considered as salvage therapy for colorectal liver metastases who failed the first- and second-line standard therapy.

A Phase II Multicenter Clinical Trial Assessing the Safety and Efficacy of Ixazomib Pomalidomide Dexamethasone Combination As Second or Third-Line Treatment for Patients with Triple Exposed Relapsed and Refractory Multiple Myeloma: Prespecified Interim Analysis (IPoD-790 trial)

Introduction: Despite significant improvement in the outcomes of early treatment lines in myeloma, most patients (Pts) invariably relapse. As triple and quadruple regimens are being introduced at the upfront setting, many Pts are either triple-exposed or triple-refractory early in their disease course. We report here the outcomes of a pre-specified interim analysis of the IPoD-790 clinical trial (NCT04790474), an all oral ixazomib (IXA) pomalidomide (POM) dexamethasone (DEX) (IPd) combination, in Pts with relapsed refractory multiple myeloma (RRMM) previously treated with bortezomib (BTZ) lenalidomide (LEN) and daratumumab (DARA). Methods: A phase 2, investigator initiated, open-label, single-arm, prospective, multicenter study evaluating the safety, tolerability and efficacy of IPd as a second or third-line combination treatment for Pts with RRMM who progressed after receiving BTZ, LEN and DARA during the first and second treatment lines. IXA is administered twice-weekly during the first 3 cycles. Pts receive IXA: 3 mg days (d) 1, 4, 8, 11 of 21-d Cycles (Cy) 1-3; 4mg d 1, 8, 15 of 28-d Cy 4-24. POM 4mg: d 1-14 Cy 1-3; d 1-21 Cy 4-24. DEX 20mg: d 1,2,8,9,15,16 Cy 1-3; d 1,2,8,9,15,16, 22,23 Cy 4-24. Treatment continues until disease progression (PD) or unacceptable toxicity. After completion of 24 treatment cycles, Pts continue POM DEX as standard of care. The primary endpoint is progression free survival (PFS) according to IMWG criteria. Results: Twenty-two Pts (out of the 60 Pts planned) enrolled between February 2021-May 2022. The median age was 71 (range: 53-88), median time from Myeloma diagnosis to study enrollment was 3.7 years; 58% had high risk FISH cytogenetics (t(4:14), +1q21, del17p); 10% had extramedullary disease at study enrollment; 32%, 9%, 73% and 86% of the Pts were refractory to BTZ, cyclophosphamide, LEN and DARA, respectively. Forty-five percent had previously undergone an auto-transplant. At the interim analysis cutoff date of 28-Jun-2022, after a median follow-up of 5.8 months (mo) (95% CI 4.5-7.1), 13 Pts discontinued the study treatment due to disease progression (PD) (n=9, 41%), death (n=2, 9%, 1 each: COVID-19 and cerebrovascular accident) and withdrawal of consent (n=2, 9%). Eighty-six percent of the Pts had at least one treatment emergent adverse event (TEAE) and 59% had a TEAE grade ≥3. TEAE that occurred in ≥10% include neutropenia 27% (23% ≥Gr 3), thrombocytopenia 27% (14% ≥Gr 3), rash 23%, diarrhea 14%, dyspnea 14%, fatigue 14%, COVID-19 14% and pneumonia 14% (14% ≥Gr 3). No Pts discontinued therapy due to an AE. Overall response rate was 53% (10/19 of evaluable Pts); 2 (10%) complete or very good partial response (CR/VGPR); 8 (42%) partial response (PR); 6 (32%) stable disease; 3 (16%) PD. Median time to response was 0.7 (range: 0.4-6) mo. The median PFS and overall survival (OS) were 6.9 [95% CI 2.0-12.0] and not-reached (NR), respectively [Figure 1A]. Median PFS was 10.4 vs 2.2 mo among Pts who achieved at least a PR vs non-responsive Pts, respectively (p=0.005). [Figure 1B]. Conclusions: IPd combination with twice-weekly ixazomib provided an all-oral safe and efficacious therapy in triple-exposed RRMM Pts, most of whom were refractory to both DARA and LEN. Study enrollment is ongoing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Trastuzumab-based regimens beyond progression: A crucial treatment option for HER2+ advanced/metastatic breast cancer

Upon its establishment for the treatment of metastatic breast cancer (mBC), continuing trastuzumab beyond disease progression was an important paradigm shift that became the recommendation by major guidelines. However, data supporting continuation of human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab beyond the second-line setting are limited, resulting in a lack of approval of, or access to, this therapeutic strategy in many countries. This study aimed to provide additional data on the continued use of trastuzumab and trastuzumab-based therapies in combination with chemotherapy (CT) as third-line treatment for patients with mBC. This open-cohort, retrospective, observational study used deidentified patient-level data from an electronic health record–derived database that included patients with mBC who initiated third-line treatment with trastuzumab-based therapy combined with CT (Tras + CT; n = 288) or CT alone (CT; n = 49). Patients who received Tras + CT had a longer weighted median overall survival vs those who received CT only: 20.6 months (95% CI, 18.3–26.4 months) vs 10.1 months (95% CI, 7.8–12.3 months), respectively (hazard ratio [HR], 0.29; 95% CI, 0.16–0.53). This study provides additional support for maintaining trastuzumab-based therapies for patients with HER2+ mBC beyond second-line treatment. This treatment option should be available for all patients with mBC worldwide.

Synergistic Antitumor Effects of Anlotinib Combined with Oral 5-Fluorouracil/S-1 via Inhibiting Src/AKT Signaling Pathway in Small-Cell Lung Cancer.

Background Small-molecule tyrosine inhibitor anlotinib which developed in China has been approved as a third-line treatment for patients with small-cell lung cancer (SCLC). Our previous clinical study found that anlotinib combined with S-1 has better short-term ORR than the single-agent anlotinib of SCLC and other small-molecule vascular targeted drug therapies in the treatment of SCLC. However, the molecular mechanism of those effect remains unclear. Methods SCLC cell line H446 was treated with either anlotinib, 5-FU alone, or combination. The cellular effects including cell viability, cell apoptosis, cell cycle, cell migration, and invasion were explored to evaluate the cell proliferation level. Western blot was performed to determine the protein levels of the combined action of the two drugs. The xenograft mouse model was established by injection of H446 cells into mouse, and the animals were randomized and assigned for the drug treatments. Body weights and tumor sizes were recorded. WB was conducted using tumor tissues. All data were collected and statistically analyzed using t-test to reveal the underlying molecular mechanism. Results When anlotinib was combined with 5-FU, the IC50 value of cells was significantly reduced. And apoptosis, cell cycle arrest, and cell motility rates were stronger when anlotinib combined with 5-FU than in the anlotinib or 5-FU alone. In H446 cell-derived xenograft mouse model, tumor volumes were significantly decreased in Anlo/5-FU combination group than anlotinib or 5-FU alone group. Western blot showed the decreasing expression of p-Src/p-AKT in the Anlo/5-FU group. Conclusion Our data revealed that the treatment of combination of antitumor angiogenesis agent anlotinib with chemotherapy drug 5-FU may have synergistic cytotoxicity to SCLC in vitro and in vivo. This treatment modality reduced cell proliferation and migration via Src/AKT pathway. This new strategy may be a promising treatment for SCLC but needs to be confirmed in future clinical trials.

Studies of the Efficacy of Low-Dose Apatinib Monotherapy as Third-Line Treatment in Patients with Metastatic Colorectal Cancer and Apatinib's Novel Anticancer Effect by Inhibiting Tumor-Derived Exosome Secretion.

Simple SummaryWe assessed the efficacy and safety of low-dose apatinib monotherapy as a third-line treatment in patients with metastatic colorectal cancer. The ORR and DCR were 4.0% (2/50) and 70% (35/50), and the median PFS and OS were 4.7 months and 10.1 months, which demonstrated comparable survival outcomes, significant improvements to the patient’s quality of life, and tolerable adverse reactions. We also disclosed a novel role of apatinib’s anticancer effect, i.e., inhibiting tumor-derived exosome release. Our results indicated that apatinib treatment inhibited exosome secretion through the regulation of MVB biogenesis, transport, and fusion by regulating LAMP2, RAB11, Snap23, and VAMP2. This novel regulatory mechanism provides a new perspective for the antitumor effect of apatinib in CRC treatment.Antiangiogenic therapy is an important treatment strategy for metastatic colorectal cancer (mCRC). We carried out a clinical study of low-dose apatinib (250 mg) monotherapy as a third-line treatment in patients with mCRC and assessed its efficacy and safety. It demonstrated that low-dose apatinib had comparable survival outcomes, significantly improved the patient quality of life, and caused tolerable adverse reactions. To further investigate the underlying mechanism of the effects of apatinib in CRC besides angiogenesis, we performed RNA-seq, and our results suggested that apatinib may have other potential antitumor mechanisms in CRC through multiple pathways, including exosomes secretion. In RKO and HCT116 cells, apatinib significantly reduced exosomes secretion by targeting multivesicular body (MVB) transport. Further studies have indicated that apatinib not only promoted the degradation of MVBs via the regulation of LAMP2 but also interfered with MVB transport by inhibiting Rab11 expression. Moreover, apatinib inhibited MVB membrane fusion by reducing SNAP23 and VAMP2 expression. In vivo, apatinib inhibited orthotopic murine colon cancer growth and metastasis and reduced the serum exosomes amount. This novel regulatory mechanism provides a new perspective for the antitumor effect of apatinib beyond angiogenesis inhibition.

Efficacy and safety of regorafenib in Japanese patients with advanced gastrointestinal stromal tumors

Regorafenib is an oral multi-kinase inhibitor that has been established as third-line treatment for patients after the failure of imatinib and sunitinib. However, since clinical data of regorafenib in the Japanese population are still lacking, the management of regorafenib is mainly based on the clinical experience of each oncologist. The aim of this study was to evaluate the efficacy and safety of regorafenib in a Japanese population. Thirty-three patients treated with regorafenib for metastatic and recurrent gastrointestinal stromal tumors were retrospectively enrolled.This study investigated the anti-tumor effect, including overall survival, progression-free survival, and safety, which was evaluated based on the incidence of adverse events. The median overall survival of patients treated with regorafenib was 23.8months and the 1-year overall survival rate was 80.0%, the median progression-free survival was 7.1months and the 1-year progression-free survival rate was 40.2%. The responses to regorafenib were partial response in 3 cases (9.1%), stable disease in 17 (51.5%), progressive disease in 10 (30.3%), and non-evaluable in 3 (9.1%). The disease control rate was 54.0%. Treatment-related adverse events were reported in all patients, with the most common being hand-foot syndrome (72.7%), followed by liver damage (36.4%) and diarrhea (27.3%), and six patients (20.0%) were discontinued due to adverse events. This is the first report of Japanese patients with gastrointestinal stromal tumors treated with regorafenib. Regorafenib showed efficacy and a manageable safety profile in Japanese patients with advanced gastrointestinal stromal tumors, which was comparable with previous studies.