Systemic Therapy For Metastatic Disease Research Articles

Abstract PO5-19-05: A Phase II Trial of Stereotactic Body Radiation Therapy and Fluoroestradiol Positron Emission Tomography in Patients with Oligoprogressive Estrogen Receptor Positive Metastatic Breast Cancer

Abstract Background: The term oligoprogression (OP) refers to a clinical scenario in which patients with diffuse metastatic disease on systemic therapy have a limited number of metastases that have progressed or are new whereas the majority of metastases are stable or improved. OP disease is increasingly being encountered in clinical practice due to improvements in systemic therapy. Treating OP disease with local ablative therapies may therefore prolong the time to more diffuse progression necessitating a change in systemic therapy and may therefore lead to improved overall survival in these patients. Only one study has evaluated the role of SBRT in patients with OP MBC. This trial accrued 47 patients with OP MBC, with 2/3 having triple negative disease. There was no difference in PFS between patients that received SBRT versus those that did not (4.2 months vs. 4.4 months, p=0.2). Whether ablative therapies are beneficial in subtypes of breast cancer that have many effective systemic therapies available, such as ER+ breast cancer, remains an open question and an unmet clinical need. Design: Phase II study for patients with OP ER+ MBC (1-4 new and/or progressing metastatic lesions). Eligible patients will receive stereotactic body radiation therapy (SBRT) to the OP lesions. SBRT will be delivered to each lesion in 3-5 fractions. Each patient’s systemic therapy regimen will be held during study therapy and will resume upon completion of study therapy. Patients will then be restaged at 12 weeks post-SBSRT. Patients that have at least stable disease at that time point will continue on their systemic therapy and then be re-staged 12 weeks later (24 weeks after SBRT). This study will also study the role of ER-targeted positron emission tomography (PET) imaging with 16α-18F-Fluoro-17β-Fluroestradiol (FES) in the OP ER+ patient population with FES PET scans obtained at baseline, and at each of the 2 follow-up imaging timepoints. A key secondary hypothesis is that the use of FES PET in addition to standard imaging at baseline and in follow-up will help confirm patients have OP disease and will help assess for new lesions on subsequent restaging. Eligibility: Key inclusion criteria: age≥18 yo; histologically confirmed ER+/HER2- metastatic breast cancer; the presence of metastatic breast cancer at the time of study entry with progression in 1-4 lesions (including new lesions); SBRT must be feasible for all progressing lesions. Key Exclusion Criteria: >2 lines of systemic therapy for metastatic disease; intracranial disease progression Objective: To determine whether using SBRT to treat OP lesions allows ER+ breast cancer patients to continue on their current systemic therapy for at least 24 weeks post SBRT. Objective: To assess whether FES-PET increases the number of lesions found prior to SBRT; To determine the impact of SBRT on patient quality of life; time to next line systemic therapy; PFS Statistical Methods Simon 2 stage optimal design with α=0.05 and 1-β=0.80. The null hypothesis is that the proportion of patients that remain on their original systemic therapy ≥24 weeks (2 restaging scans) post-treatment is 20%. The alternative hypothesis is that the proportion of patients that remain on their original systemic therapy after 2 restaging scans is 50%. In stage 1, 8 patients that proceed to SBRT will be enrolled. The study will be terminated if only 0 or 1 subjects remain on original systemic therapy after 2 restaging scans. However, if ≥2 patients remain on original systemic therapy after 2 restaging, then an additional 10 patients would be enrolled for a total of 18 patients. The null hypothesis will be rejected if ≥6 patients remain on their original systemic therapy after 2 restaging scans. Contact Information: Jose G. Bazan (jbazan@coh.org) Funding Source: City of Hope Comprehensive Cancer Center Citation Format: Jose Bazan, Joanne Mortimer, Yun-Rose Li. A Phase II Trial of Stereotactic Body Radiation Therapy and Fluoroestradiol Positron Emission Tomography in Patients with Oligoprogressive Estrogen Receptor Positive Metastatic Breast Cancer [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 PO5-19-05.

Abstract PO4-19-03: FES-PET/MRI for Tailored treatment of luminal A and lobular breast cancer: a prospective cohort study

Abstract Background: Breast cancer (BC) staging is essential to planning the most appropriate treatment pathway. Currently, BC management has become more tailored to the tumor’s and patient’s characteristics. However, BC imaging shows varying performance according to tumor subtypes. In particular, routine imaging may pose some challenges when evaluating luminal A BC (LumA) and lobular BC (Lob). LumA, due to low grade and proliferation index (< 20%) shows lower sensitivity on axillary US, reduced MRI enhancement, and low FDG-avidity on PET. Similarly, Lob, due to its peculiar single-cell growth pattern, exhibits inferior sensitivity on axillary MRI and FDG-avidity. LumA and Lob account for >50% of all BCs. Despite their favourable prognosis, metastases and recurrences still occur; this translates into a higher absolute number of events than in other subtypes. As a result, a concrete risk of disease underestimation and under-treatment exists. Two ongoing studies on FDG-PET/MRI imaging in our institution have already demonstrated that its sensitivity also decreases in LumA and Lob. Based on these premises, our hypothesis states that by combining the advantages of hybrid PET/MRI with the high accuracy of 16α -18F-fluoro-17-beta-estradiol(FES), a radiolabeled form of estrogen binding to functionally active ER, we could obtain a reliable, non-invasive, operator-independent, one-stage imaging method for staging LumA and ER-positive Lob. Trial design: This is a prospective cohort study where patients with LumA and ER-positive Lob will be enrolled in four cohorts undergoing: A) primary surgery; B) induction endocrine therapy; C) neoadjuvant chemotherapy, and D) systemic therapy for metastatic disease. FES PET/MRI examinations will be performed at baseline for local and systemic staging in all cohorts and a second exam after systemic therapy in cohorts C-D. Correlations between the FES PET/MRI parameters and pathology, gene expression, and FDG PET parameters, when available, will be investigated. Study aims will evaluate: 1) the performance of the FES PET/MRI in axillary staging compared with axillary surgery; 2) potential correlations between changes in FES uptake and changes in proliferation index after three weeks of endocrine therapy (ET); 3) the performance of the FES PET/MRI in systemic staging of patients undergoing systemic therapy in comparison with standard imaging; 4) biological determinants of tumor heterogeneity on pathological, imaging, and genomic levels. Statistics: The primary analysis in cohort A will test the sensitivity of the FES PET/MRI in detecting macrometastatic axillary nodes. Assuming that the probability that a patient has positive nodes is 33%, 119 patients (10% drop-out included) will provide 80% power to reject the null hypothesis about sensitivity at a 5% significance level if the true sensitivity is at least 50%. Results from the FES PET/MRI will be also compared with standard imaging in terms of sensitivity and number of lesions detected using the Mc-Nemar test for paired proportions and the Wilcoxon signed-rank test for paired data. The primary analysis in Cohort B will test the association between the FES-SUV change from pre-ET to post-ET and the Ki-67 change from core biopsy to post-ET in ER positive BC patients with a Ki-67 >10%. The association between these changes will be measured by the Pearson correlation index ρ. Α total of 52 patients (10% drop-out included) from Cohort B will provide 80% power to reject the null hypothesis about ρ at a 5% significance level if the true ρ is at least 0.4. No formal sample size was calculated for cohort C and D: results will be considered descriptive in nature, informing sample size considerations for future trials. We intent to recruit 20 and 30 patients, respectively. Accrual has not started yet. Project funded by AIRC (Associazione Italiana Ricerca sul Cancro) Next Gen Clinician Scientist ID 28378 Contact: Dr. Rosa Di Micco, dimicco.rosa@hsr.it Citation Format: Rosa Di Micco, Carla Canevari, Francesca Gallivanone, Nicole Rotmensz, Veronica Zuber, Sara Baleri, Giovanni Cisternino, Mario Rampa, Stefania Zambelli, Giulia Viale, Patrizia Zucchinelli, Manuela Morgante, Paola Scifo, Elena Venturini, Paola Magnani, Isabella Sassi, Vincenzo Bagnardi, Pietro Panizza, Giampaolo Bianchini, Arturo Chiti, Oreste Davide Gentilini. FES-PET/MRI for Tailored treatment of luminal A and lobular breast cancer: a prospective cohort study [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 PO4-19-03.

Abstract PS12-06: A phase 2 study of abemaciclib monotherapy for patients with retinoblastoma-positive (Rb+), triple-negative metastatic breast cancer

Abstract Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors can significantly extend survival when given in combination with endocrine therapy as treatment for hormone receptor-positive metastatic breast cancer. Preclinical studies suggest CDK4/6 inhibitor monotherapy might also be effective in a subset of triple-negative breast cancers (TNBCs), including those that express a functional retinoblastoma (RB) protein and/or those of the Luminal Androgen Receptor (LAR) subtype. Currently, the clinical activity of CDK4/6 inhibitor therapy in TNBC has not been reported. Methods: We conducted a single-arm phase II study of abemaciclib monotherapy in patients with locally advanced or metastatic TNBC. Key eligibility criteria included: (i) Measurable disease by RECIST 1.1; (ii) Between 1-3 prior lines of systemic therapy for advanced TNBC; (iii) RB-positive tumor (defined as ≥ 50% of tumor cells staining positive for RB by immunohistochemistry [archival or fresh sample] on central testing); (iv) ECOG PS 0/1. Patients were treated with abemaciclib 200 mg orally (28-day cycles) twice daily until disease progression, unacceptable toxicity, withdrawal of consent, or death. Tumor biopsies were mandatory at baseline and C2D1 if tumor tissue was safely accessible. The primary outcome was objective response rate (ORR). Key secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR: CR + PR + SD ≥ 24 weeks), and safety and tolerability. The study had a two-stage design. Thirteen patients were enrolled in the first stage, with the plan to enrol a further 25 patients if at least one objective response was observed. Results: One unconfirmed partial response was observed in stage 1, and a total of 27 patients were enrolled before the trial was closed early due to slow accrual. The median age was 61 years and patients had received a median of 2 prior lines of systemic therapy for metastatic disease. Twelve patients had received prior immunotherapy. After a median follow-up of 28.5 months, the confirmed ORR was 0% and the CBR was 15%, with 4 of 27 patients experiencing stable disease for ≥ 24 weeks. The median PFS was 1.94 months (95% CI: 1.8 – 11.5 months), and the median OS was 8.44 months (95% CI: 4.6 – 15.6 months). There was no significant difference in PFS or OS between patients with PD-L1-positive versus PD-L1-negative disease, or Androgen Receptor (AR) positive versus negative tumors by immunohistochemistry. The most common adverse events of grade 2 or higher were diarrhea (41%), neutropenia (41%), anemia (30%), and nausea (30%). RNA-sequencing of baseline biopsies has been performed to identify biomarkers associated with clinical benefit, and results will be presented at the meeting. Conclusions: Abemaciclib monotherapy did not show clinical activity in patients with Rb+ metastatic TNBC. This finding suggests that future trials of CDK4/6 inhibition as monotherapy in TNBC are not warranted. Citation Format: Shom Goel, Bojana Jovanović, Xiangying Chu, Melissa Hughes, Ayesha Mohammed-Abreu, Julie Kasparian, Timothy Erick, Molly DiLullo, Eileen Wrabel, Rinath Jeselsohn, Nabihah Tayob, Stuart Schnitt, Nancy Lin, Sara Tolaney. A phase 2 study of abemaciclib monotherapy for patients with retinoblastoma-positive (Rb+), triple-negative metastatic breast cancer [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 PS12-06.

A randomized phase III study comparing 2-weekly docetaxel, cisplatin and 5-FU (bDCF) with cisplatin and 5-FU (CF) in patients with metastatic or recurrent esophageal cancer: JCOG1314 (MIRACLE).

322 Background: For metastatic or recurrent esophageal cancer, 2-drug combination of cisplatin and 5-FU (CF) has long been a standard of care before the emergence of immune checkpoint inhibitors (ICIs). Previous phase I/II study of 3-drug combination, 2-weekly docetaxel plus CF (bDCF) showed promising antitumor activity (JCOG0807). We conducted JCOG1314, a randomized phase III study to confirm the survival superiority of bDCF over CF. Methods: Main eligibility criteria were metastatic or recurrent esophageal cancer; histologically proven squamous cell carcinoma or adenocarcinoma; age 20 to 75; no previous systemic therapy for metastatic disease. Patients were randomly assigned to CF arm (cisplatin 80 mg/m2 on day 1, and 5-FU 800 mg/m2 on days 1-5, every 28 days), or bDCF arm (docetaxel 30 mg/m2 on day 1 and day 15 in addition to CF, every 28 days). The primary endpoint was overall survival (OS). To detect a 3-month difference in median OS [hazard ratio (HR) = 0.73] with study-wise, one-sided alpha level of 5% and power of 75%, 240 patients were required. Results: A total of 240 patients were randomly assigned to bDCF (n = 121) and CF (n = 119) between September 2014 to April 2021. Patient background in bDCF/CF arm was median age, 65/64 years; ECOG performance status 0, 69%/75%; metastatic disease, 63%/67%, ≥2 metastatic organs, 59%/56%; squamous cell carcinoma, 94%/97%. As a data cut-off of April 2023, all 240 patients discontinued protocol treatment. The reasons for treatment discontinuation in bDCF/CF arm were disease progression, 58%/71%; adverse events (AEs), 35%/27%; refusal, 1%/1%; others, 7%/5%, respectively. With a median follow-up of 15.3 months (m), bDCF arm was not superior to CF arm in terms of OS with a median of 16.2 m versus 14.8 m [HR, 0.90; 95% confidence interval (CI), 0.68–1.19; p = 0.23], however, progression-free survival (PFS) in bDCF arm was favorable compared to CF arm with a median of 6.0 m versus 5.2 m (HR, 0.68; 95% CI, 0.52–0.88). Response rate in bDCF/CF arm was 52.8%/45.6%. Major grade 3 or 4 AEs observed in bDCF/CF arm were neutropenia (37.8%/27.1%); anorexia (25.2%/16.1%); fatigue (10.1%/15.3%); hyponatremia (13.4%/13.6%). No treatment related death was observed. Subsequent therapy in bDCF/CF arm was provided for 87%/89% of patients. Conclusions: JCOG1314 did not reach its primary objective, although bDCF was associated with significant increases in PFS. CF is still the standard therapy in patients with metastatic or recurrent esophageal cancer if ICIs are not applicable. Clinical trial information: jRCTs031180143 .

Cabozantinib (Cabometyx)


 CADTH recommends that Cabometyx in combination with Opdivo be reimbursed by public drug plans for the treatment of adults with advanced or metastatic renal cell carcinoma (RCC) who have had no prior systemic therapy for metastatic disease if certain conditions are met.
 Cabometyx in combination with Opdivo should be covered in patients aged 18 years and older with RCC that is not amenable to curative surgery or radiation therapy, or has spread to other organs; who have not received prior cancer treatment targeting the entire body for advanced RCC; and who are in relatively good health (i.e., have good performance status). Cabometyx in combination with Opdivo should not be reimbursed to treat patients who have active tumours in the brain or spinal cord from the cancer spreading or active autoimmune disease.
 Cabometyx in combination with Opdivo should be reimbursed if prescribed by a clinician with expertise in treating RCC in an outpatient oncology clinic or institution and the total drug cost of Cabometyx in combination with Opdivo does not exceed the total drug cost of the lowest-cost alternative combination regimen.

Comprehensive Systematic Review of Biomarkers in Metastatic Renal Cell Carcinoma: Predictors, Prognostics, and Therapeutic Monitoring.

Challenges remain in determining the most effective treatment strategies and identifying patients who would benefit from adjuvant or neoadjuvant therapy in renal cell carcinoma. The objective of this review is to provide a comprehensive overview of biomarkers in metastatic renal cell carcinoma (mRCC) and their utility in prediction of treatment response, prognosis, and therapeutic monitoring in patients receiving systemic therapy for metastatic disease. A systematic literature search was conducted using the PubMed database for relevant studies published between January 2017 and December 2022. The search focused on biomarkers associated with mRCC and their relationship to immune checkpoint inhibitors, targeted therapy, and VEGF inhibitors in the adjuvant, neoadjuvant, and metastatic settings. The review identified various biomarkers with predictive, prognostic, and therapeutic monitoring potential in mRCC. The review also discussed the challenges associated with anti-angiogenic and immune-checkpoint monotherapy trials and highlighted the need for personalized therapy based on molecular signatures. This comprehensive review provides valuable insights into the landscape of biomarkers in mRCC and their potential applications in prediction of treatment response, prognosis, and therapeutic monitoring. The findings underscore the importance of incorporating biomarker assessment into clinical practice to guide treatment decisions and improve patient outcomes in mRCC.

Addition of Metastasis-Directed Therapy to Standard of Care Systemic Therapy for Oligometastatic Breast Cancer (EXTEND): A Multicenter, Randomized Phase II Trial

Prior retrospective and prospective evidence have suggested a potential survival benefit of adding metastasis-directed therapy (MDT) to standard of care systemic therapy for oligometastatic breast cancer. This has led to the increased utilization of MDT in this setting despite the lack of randomized evidence to support this approach. Furthermore, the recent presentation of NRG-BR002 has questioned the value of MDT. Thus, we evaluated whether the addition of MDT to systemic therapy improves PFS in oligometastatic breast cancer. EXTEND (NCT03599765) is a phase II randomized basket trial for multiple solid tumors testing whether the addition of MDT improves PFS. The primary endpoint was pre-specified to be independently assessed and reported for the breast basket when a minimum of 6 months of follow-up had been reached. Patients with ≤5 metastases were randomized to standard of care systemic therapy with or without MDT. The choice of systemic therapy was at the discretion of the treating medical oncologist. Number of metastatic lesions and prior lines of systemic therapy for metastatic disease were used as stratification variables pre-randomization. The primary endpoint was progression-free survival (PFS) defined as time to randomization to date of clinical or radiographic progression or death. The study was designed to have 80% power to detect an improvement in median PFS from 18 to 36 months, with a type I error of 0.1. Between September 2018 to July 2022, 43 patients were randomized. 22 patients were assigned to the MDT arm, and 21 patients to the no MDT arm. Three patients were not evaluable. The MDT arm patients were older vs the no-MDT arm patients (median 61.5 years vs 48 years, p = 0.01). Otherwise, the arms were well-balanced. Overall, 8 patients had triple negative disease (18.6%), and 12 patients (30%) had de novo metastatic disease. Of those patients with de novo presentation randomized to MDT, all except one had the primary tumor treated with surgery and radiation. At a median follow-up of 19.4 months, 20 events were observed. Among the 40 evaluable patients, there were 5 deaths (3 in the MDT arm and 2 in the no MDT arm). There was no difference in PFS between the MDT and no MDT arms (median 15.6 v 24.9 months, p = 0.66). Similarly, there was no difference in the secondary endpoint of time to new metastatic lesion appearance between the MDT and no MDT arms (median 15.6 months vs not reached, p = 0.09). Two grade 3 toxicities were observed in the MDT arm, and 1 in the no MDT arm. Further analysis of correlative translational biomarkers, including immune markers and ctDNA, are ongoing. The addition of MDT to standard of care systemic therapy did not improve PFS or time to new metastatic lesion in patients with oligometastatic breast cancer. This data coupled with the recently presented NRG-BR002 results, suggests there is no benefit to MDT in an otherwise unselected oligometastatic breast cancer population.

Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study

There is a paucity of effective systemic therapy options for patients with advanced, chemotherapy-refractory colorectal cancer. We aimed to evaluate the efficacy and safety of fruquintinib, a highly selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, in patients with heavily pretreated metastatic colorectal cancer. We conducted an international, randomised, double-blind, placebo-controlled, phase 3 study (FRESCO-2) at 124 hospitals and cancer centres across 14 countries. We included patients aged 18 years or older (≥20 years in Japan) with histologically or cytologically documented metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine-tipiracil or regorafenib, or both. Eligible patients were randomly assigned (2:1) to receive fruquintinib (5 mg capsule) or matched placebo orally once daily on days 1-21 in 28-day cycles, plus best supportive care. Stratification factors were previous trifluridine-tipiracil or regorafenib, or both, RAS mutation status, and duration of metastatic disease. Patients, investigators, study site personnel, and sponsors, except for selected sponsor pharmacovigilance personnel, were masked to study group assignments. The primary endpoint was overall survival, defined as the time from randomisation to death from any cause. A non-binding futility analysis was done when approximately one-third of the expected overall survival events had occurred. Final analysis occurred after 480 overall survival events. This study is registered with ClinicalTrials.gov, NCT04322539, and EudraCT, 2020-000158-88, and is ongoing but not recruiting. Between Aug 12, 2020, and Dec 2, 2021, 934 patients were assessed for eligibility and 691 were enrolled and randomly assigned to receive fruquintinib (n=461) or placebo (n=230). Patients had received a median of 4 lines (IQR 3-6) of previous systemic therapy for metastatic disease, and 502 (73%) of 691 patients had received more than 3 lines. Median overall survival was 7·4 months (95% CI 6·7-8·2) in the fruquintinib group versus 4·8 months (4·0-5·8) in the placebo group (hazard ratio 0·66, 95% CI 0·55-0·80; p<0·0001). Grade 3 or worse adverse events occurred in 286 (63%) of 456 patients who received fruquintinib and 116 (50%) of 230 who received placebo; the most common grade 3 or worse adverse events in the fruquintinib group included hypertension (n=62 [14%]), asthenia (n=35 [8%]), and hand-foot syndrome (n=29 [6%]). There was one treatment-related death in each group (intestinal perforation in the fruquintinib group and cardiac arrest in the placebo group). Fruquintinib treatment resulted in a significant and clinically meaningful benefit in overall survival compared with placebo in patients with refractory metastatic colorectal cancer. These data support the use of fruquintinib as a global treatment option for patients with refractory metastatic colorectal cancer. Ongoing analysis of the quality of life data will further establish the clinical benefit of fruquintinib in this patient population. HUTCHMED.

Avelumab in Patients With Metastatic Colorectal Cancer.

Metastatic colorectal cancer (mCRC) is incurable, and median overall survival is less than 2½ years. Although monoclonal antibodies that block PD-1/PD-L1 interactions are active in microsatellite unstable/mismatch repair deficient tumors, a growing dataset shows that most patients with microsatellite stable/mismatch repair proficient tumors will not benefit from the blockade of PD-1/PD-L1 interactions. Here we present results from patients with mCRC (n = 22) treated with the anti-PD-L1 monoclonal antibody avelumab. Patients received treatment on a phase I, open-label, dose-escalation trial via a consecutive parallel-group expansion in colorectal cancer. Patients aged 18 years and older with mCRC measurable by RECIST v1.1 who had received at least 1 line of systemic therapy for metastatic disease enrolled. Patients with prior immune checkpoint inhibitor treatment were excluded. Patients received avelumab 10 mg/kg intravenously every 2 weeks. The primary endpoint was the objective response rate. Twenty-two participants received treatment from July 2013 to August 2014. There were no objective responses and median progression-free survival was 2.1 months (95% CI: 1.4-5.5 months). There were 5 grade 3 treatment-related adverse events: GGT elevation (n = 2), PRESS (n = 1), lymphopenia (n = 1), and asymptomatic amylase/lipase elevation (n = 1). As demonstrated with other anti-PD-1/PD-L1 monoclonal antibodies, avelumab is not active in unselected patients with mCRC (ClinicalTrials.gov Identifier: NCT01772004).

Effect of CBM588 in combination with cabozantinib plus nivolumab for patients (pts) with metastatic renal cell carcinoma (mRCC): A randomized clinical trial.

LBA104 Background: We have previously demonstrated that the live bacterial product CBM588 may augment clinical outcomes in pts with mRCC receiving 1st-line (1L) therapy with dual immune checkpoint inhibitors (ICIs; Dizman et al Nature Medicine 2022). As tyrosine kinase inhibitors (TKIs) in combination with ICIs also represent a 1L standard of care in mRCC, we sought to determine if CBM588 would augment clinical outcome with the TKI cabozantinib (cabo) with nivo. Methods: Eligible pts were ≥18 yrs old (Karnofsky performance status ≥70%) with histologically verified (clear-cell, papillary or sarcomatoid component) mRCC and no prior systemic therapy for metastatic disease. Patients were randomized 1:2 to receive either cabo/nivo at the standard dose/schedule (40mg PO QD and 480mg IV monthly, respectively) alone or with CBM588 dosed at 80mg PO BID. The primary endpoint was the relative abundance of Bifidobacterium spp. in stool specimens at baseline and after 12 weeks of treatment. Secondary endpoints included assessment of response rate, overall survival, progression-free survival (PFS), systemic immunomodulation, and toxicity. A two-group t-test with a one-sided type I error of 0.05 was used to assess the study's primary endpoint, hypothesizing an increase in Bifidobacterium spp. with CBM588 therapy. Results: A total of 30 (20:10 M:F) pts were recruited; median age was 65 (36-84) and 5 pts (17%) had sarcomatoid features and 2 pts (7%) had predominant papillary histology. 12 (40%), 12 (40%) and 6 pts (20%) had good, intermediate and poor risk, respectively. Metagenomic sequencing of paired stool specimens showed a significant decrease in diversity from baseline to week 12 in patients receiving cabo/nivo (P=0.02); no significant difference was observed in those treated with cabo/nivo+CBM588. No significant change in Bifidobacterium spp. was observed. RR was 63% in pts receiving cabo/nivo+CBM588 vs 33% in pts receiving cabo/nivo alone. Median PFS was not reached in pts receiving CBM588 vs 5.8 mos in pts receiving cabo/nivo along (P=0.03). Grade 3/4 toxicities were observed in 44% and 42% of patients on control and experimental arms, respectively. Conclusions: In the second prospective trial assessing the addition of CBM588 to ICI-based therapy in mRCC, a consistent result with improved PFS and RR was observed. Further translational efforts are underway to characterize the mechanism through which CBM588 augments clinical activity. Clinical trial information: NCT05122546 .

Tucatinib and trastuzumab for previously treated HER2-positive metastatic biliary tract cancer (SGNTUC-019): A phase 2 basket study.

4007 Background: Biliary tract cancer (BTC) is an aggressive malignancy with a poor prognosis, and current treatment options for advanced BTC are limited, with second-line therapy, FOLFOX and S-1 offering an objective response rate (ORR) of 5.0% and 7.5%, respectively. Up to 20% of BTCs overexpress human epidermal growth factor receptor 2 (HER2). Tucatinib (TUC) is a highly selective HER2-directed TKI approved for HER2-positive (HER2+) metastatic breast and colorectal cancer. Discussed here are the efficacy and safety results of TUC combined with Trastuzumab (Tras) in pts with previously treated HER2+ metastatic BTC. Methods: SGNTUC-019 (NCT04579380) is an open-label phase 2 basket study evaluating efficacy, safety, and tolerability of TUC and Tras in pts with HER2-altered solid tumors. Pts in the BTC cohort had been previously treated with and progressed after ≥1 line of systemic therapy for metastatic disease. Eligible pts had locally determined HER2+ (defined as HER2 overexpression determined by immunohistochemistry [IHC] 3+ or HER2 amplification determined by in situ hybridization assay or next-generation sequencing) metastatic BTC. Pts were treated on a 21-day cycle with TUC (300 mg orally twice a day) and Tras (8 mg/kg IV followed by 6 mg/kg every 3 wks). Disease status was determined based on RECIST v1.1 with assessments performed every 6 wks for 24 wks and every 12 wks thereafter. The primary endpoint is confirmed objective response rate (cORR) per investigator assessment. Secondary endpoints include overall survival (OS), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and safety. Results: Thirty pts were enrolled in the BTC cohort as of data cutoff date of 30 Nov 2022. The median duration of follow-up was 8.3 months. cORR was 46.7% (90% CI, 30.8, 63.0), with 14 responses including 1 complete and 13 partial responses. Median DOR was 6.0 months (90% CI, 5.5, not estimable). DCR was 76.7% (n=23; 90% CI, 60.6, 88.5), and median PFS was 5.5 months (90% CI, 3.9, 8.1). At data cutoff, 13 (43.3%) patients had died, and the 12-months OS rate was 53.8% (90% CI, 35.2, 69.1%). Overall, the most common treatment-emergent adverse events (TEAEs) reported were pyrexia (43.3%) and diarrhea (40.0%). Grade ≥3 TEAEs were reported in 18 (60.0%) of 30 pts; however, only 6 (20.0%) and 2 (6.7%) of these pts had Grade ≥3 TEAEs related to TUC and Tras, respectively. Two (6.7%) pts discontinued TUC due to TEAEs, cholangitis and liver disorder. No deaths were due to TEAEs. Conclusions: The combination of TUC and Tras was well tolerated in pts with previously treated HER2+ metastatic BTC. The observed antitumor activity supports the combination of TUC and Tras as a future chemotherapy-free treatment option for this population with historically poor outcomes. Clinical trial information: NCT04579380 .

Abstract 4347: A pivotal clinical trial of cResponse, a functional assay for cancer precision medicine

Abstract Precision cancer therapy has the potential to revolutionize treatment outcome. While genomic analysis has become central to cancer personalized medicine, recent studies have not shown that it drastically improves the patient’s survival as compared to standard drug selection. Additionally, genomic mutations may suggest several treatment protocols without elucidating which approach will yield the best clinical response. To advance cancer precision guidance, we have developed cResponse, a combined genomic-functional drug sensitivity platform to determine individualized patient treatment regimens. Fresh patient cancer samples are taken by biopsy or resection and sectioned into 250uM slices which when cultured in cResponse platform demonstrate similar architecture and tissue proliferation to those found in vivo. An initial clinical study showed that cResponse can preserve human cancer tissue in 3D culture together with its microenvironment, including endothelial and immune cells, at a high viability (&amp;gt;90%) with continued cell division for more than 7 days. On a cohort of 34 patients treated with neoadjuvant therapy or systemic therapy for metastatic disease, the assay was able to predict patient response to drug treatment with a sensitivity of 96% and a specificity of 77.7%. To further validate the capacity of the cResponse platform to predict patient response to cancer therapy, a follow up pivotal clinical study was established at 7 major cancer centers located in the UK with the goal of recruiting a total of 170 patients to provide a large statistical validation of the previous results. Here we report on the outcome of the first 50 patients recruited to the pivotal trial and describe the predictive results correlated to patient response. Citation Format: Seth Salpeter, Vered Bar, Guy Neev, Adi Zundelevich, Gil Rosen, Sandra Hanks, Naoise Costelloe, Jonathan Krell, Ravid Straussman. A pivotal clinical trial of cResponse, a functional assay for cancer precision medicine. [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 4347.

Efficacy, toxicities, and prognostic factors of stereotactic body radiotherapy for unresectable liver metastases

This study aims to determine the outcomes of stereotactic body radiotherapy (SBRT) for liver metastases in patients not eligible for surgery. This study included 31 consecutive patients with unresectable liver metastases who received SBRT between January 2012 and December 2017; 22 patients had primary colorectal cancer and nine patients had primary non-colorectal cancer. Treatments ranged from 24 Gy to 48 Gy in 3 to 6 fractions over 1 to 2 weeks. Survival, response rates, toxicities, clinical characteristics, and dosimetric parameters were evaluated. Multivariate analysis was performed to identify significant prognostic factors for survival. Among these 31 patients, 65% had received at least one prior regimen of systemic therapy for metastatic disease, whereas 29% had received chemotherapy for disease progression or immediately after SBRT. The median follow-up interval was 18.9 months; actuarial in-field local control rates at 1, 2, and 3 years after SBRT were 94%, 55%, and 42%, respectively. The median survival duration was 32.9 months; 1-year, 2-year, and 3-year actuarial survival rates were 89.6%, 57.1%, and 46.2%, respectively. The median time to progression was 10.9 months. Stereotactic body radiotherapy was well-tolerated, with grade 1 toxicities of fatigue (19%) and nausea (10%). Patients who received post-SBRT chemotherapy had significant longer overall survival (P=0.039 for all patients and P=0.001 for patients with primary colorectal cancer). Stereotactic body radiotherapy can be safely administered to patients with unresectable liver metastases, and it may delay the need for chemotherapy. This treatment should be considered for selected patients with unresectable liver metastases.

In brief: A new breast cancer indication for sacituzumab govitecan (Trodelvy).

Sacituzumab govitecan-hziy (Trodelvy – Gilead) has been approved for treatment of unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer in adults who received prior endocrine therapy and ≥2 additional systemic therapies for metastatic disease. It was previously approved for treatment-refractory metastatic triplenegative breast cancer and for treatment of locally advanced or metastatic urothelial cancer in adults who received platinum-based chemotherapy and a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor.

Trials in progress: TAM kinase inhibitor PF-07265807 and sasanlimab plus axitinib in patients with advanced or metastatic renal cell carcinoma—A phase 1, open-label, pharmacokinetic, safety and tolerability study.

TPS743 Background: Tumor-associated macrophage kinases (TAMK) are expressed on tumor cells during malignant transformation. Inhibition of AXL and MERTK, members of the TAMK family, may lower the immune activation threshold and promote antitumor immunity. PF-07265807 (ARRY-067) is a small-molecule inhibitor of MERTK and AXL showing antitumor activity in preclinical models as monotherapy or combined with anti-programmed cell death protein 1 (anti-PD-1) antibodies (ab). Sasanlimab is an anti-PD-1 ab with acceptable safety profile being tested (300 mg SC Q4W, Phase 3) in non-muscle invasive bladder cancer. Axitinib is a VEGF inhibitor approved (single agent and combined with anti-PD-1 inhibitors) for advanced renal cell carcinoma (RCC). This first-in-human Phase 1, open-label, multi-center study (NCT04458259) will evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of PF-07265807 in patients (pts) with advanced or metastatic solid tumors as a single agent and in combination with sasanlimab with or without axitinib. We describe here the dose escalation (Part 3) and dose expansion (Part 4) for the triplet combination of PF-07265807 + sasanlimab + axitinib. Methods: Eligible participants for the triplet cohorts are adult pts with confirmed unresectable advanced or metastatic clear cell RCC, with estimated creatinine clearance ≥30 mL/min and urinary protein &lt;2+ or ≥2+ but 24-h urine protein:creatinine ratio &lt;2 g/24 h. Pts for Part 4 need to have intermediate and poor risk RCC and no prior systemic therapy for metastatic disease. Other key eligibility criteria: measurable disease by RECIST 1.1 or non-measurable disease, ECOG PS 0–2, adequate bone marrow and liver function, and resolved acute effects of prior therapy. Each cycle is 21 days. Part 3 will determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) of PF-07265807 in triplet therapy using a Bayesian logistic regression model and the escalation with overdose control principle. After the MTD/RP2D is identified, Part 4 will further evaluate the safety and preliminary efficacy of PF-07265807 combined with sasanlimab and axitinib. Treatment with study drug will continue until disease progression, consent withdrawal, or unacceptable toxicity, whichever occurs first. Primary endpoints of Part 3 are incidence of dose-limiting toxicities, adverse events (AE), and laboratory (lab) abnormalities. For Part 4, the primary endpoints are objective response rate and complete response rate; secondary endpoints include disease control rate; time-to-event endpoints; AEs; lab abnormalities; concentrations of PF-07265807 and its metabolite, sasanlimab, and axitinib; and incidence and titer of anti-sasanlimab anti-drug antibodies response. The study started in late 2020 and is recruiting. Clinical trial information: NCT04458259 .

SAFFRON-103: a phase 1b study of the safety and efficacy of sitravatinib combined with tislelizumab in patients with locally advanced or metastatic non-small cell lung cancer

BackgroundSome patients with locally advanced/metastatic non-small cell lung cancer (NSCLC) respond poorly to anti-programmed cell death protein 1 (PD-1)/anti-programmed death-ligand 1 (PD-L1) treatments. Combination with other agents may improve the...

Clinicopathological and survival features of neuroendocrine tumors: A retrospective analysis of 153 cases, our current remarks on a heterogeneous tumor group, and still unmet future expectations

Neuroendocrine neoplasms (NENs) originate from the diffuse neuroendocrine cell system and constitute a heterogeneous group of tumors exhibiting diverse clinical and biological characteristics. NENs include well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). In the present study, we performed a retrospective analysis of patients diagnosed with NET to evaluate clinicopathological characteristics, treatment and outcomes. Data from 153 patients diagnosed with NET who were treated and followed up at three tertiary care centers from November 2002 to June 2021 were retrospectively evaluated. Clinicopathological and prognostic factors, treatment modalities and survival data were analyzed. Kaplan-Meier analysis was used to assess survival data and comparisons were performed using the logrank test. Median age (IQR) was 53 (18-80) years. 85.6% of the patients had gastro-entero-pancreatic (GEP)-NET. The primary tumor was resected in 95 patients (62.1%) and metastasectomy were performed in 22 patients (14.4%). Seventy-eight patients received systemic therapy for metastatic disease. Patients were followed up for a median of 22 (IQR = 33.8) months. The estimated one-year and three-year survival rate was 89.8% and 74.4%, respectively. Median progression-free survival (PFS) were 10.1, 8.5, and 4.2 months after first-, second- and third-line therapy, respectively. The number of systemic treatment options and diagnostic tools for NETs has significantly improved in the last few years. NET classification, which treatment will be more appropriate for which group of patients, the molecular basis of this disease and the development of treatment strategies are open-ended questions that still need to be investigated.

Lenvatinib (Lenvima) in Combination With Pembrolizumab (Keytruda)

&#x0D; CADTH recommends that Lenvima in combination with Keytruda be reimbursed by public drug plans for the treatment of adult patients with advanced or metastatic renal cell carcinoma (RCC) who have had no prior systemic therapy for metastatic disease if certain conditions are met.&#x0D; Lenvima in combination with Keytruda should only be covered in patients aged 18 years and older with advanced (that cannot be cured with surgery or radiation) or metastatic (that has spread to other organs) RCC who have not received prior systemic therapy for advanced RCC.&#x0D; Lenvima in combination with Keytruda should be reimbursed if prescribed under supervision in an outpatient oncology clinic or institution with expertise in delivering systemic therapy. Lenvima in combination with Keytruda should only be reimbursed when administered in combination and if cost is reduced.&#x0D;

InnovaTV 207: New combination dosing cohorts in the open label phase 2 study of tisotumab vedotin in solid tumors.

TPS6100 Background: Tisotumab vedotin (TV; TIVDAK) is a tissue factor (TF)-directed antibody-drug conjugate that has been granted accelerated approval in the US for treatment of adults with recurrent/metastatic (r/m) cervical cancer with disease progression on or after chemotherapy. TV remains investigational in other tumor types including squamous cell carcinoma of the head and neck (HNSCC) and squamous non-small cell lung cancer (sqNSCLC). This abstract presents the addition of Part D to innovaTV 207 (NCT03485209), a global, open label, multicenter phase 2 trial investigating the safety, tolerability, and activity of TV in solid tumors. Untreated patients (pts) with r/m HNSCC or sqNSCLC enrolled in Part D will receive either TV in combination with pembrolizumab (pembro) or TV + pembro and a platinum agent. Based on encouraging preliminary safety and efficacy results with 2.0 mg/kg TV once every 3 weeks (Q3W) in combination with pembro or carboplatin (carbo) in innovaTV 205 cervical cancer study cohorts, TV is being evaluated at 2.0 mg/kg Q3W in combination with pembro or pembro + carbo (or cisplatin). Methods: Up to 140 treatment-naive pts with r/m HNSCC or sqNSCLC will be enrolled in Part D of innovaTV 207. First, the All-Comers cohorts for HNSCC and sqNSCLC will each enroll up to 30 pts, regardless of PD-L1 expression, for Q3W dosing with 2.0 mg/kg TV in combination with 200 mg pembro and AUC 5 carbo. After enrollment in the HNSCC All-Comers Cohort is complete, up to 20 pts with HNSCC will be enrolled into a Cisplatin Safety Cohort for dosing with 2.0 mg/kg TV in combination with 200 mg pembro and 100 mg/m2 cisplatin. Completion of enrollment in the All-Comers Cohort for each tumor type will also be followed by enrollment of up to 30 pts with HNSCC (CPS ≥1) and 30 pts with sqNSCLC (TPS ≥1%) into PD-L1 Selected cohorts for dosing with TV in combination with 200 mg pembro. Response will be assessed every 6 weeks for the first 6 months, every 12 weeks for the next 6 months, and then every 6 months after that. Pts with HNSCC must have had no previous systemic therapy for metastatic disease (exception is systemic therapy given as part of multimodal treatment for locally advanced disease completed &gt; 6 months prior). Pts with NSCLC must have histologically or cytologically documented squamous cell NSCLC and must not have had any previous systemic therapy for metastatic disease or radiation therapy to the lung that is &gt; 30 Gy within 6 months of the first dose of study drug. The primary endpoint is investigator-determined confirmed ORR per RECIST v1.1. Secondary endpoints include confirmed and unconfirmed ORR per RECIST v1.1, disease control rate, duration of response, time to response, PFS, OS, safety and tolerability, pharmacokinetics, and immunogenicity. The trial opened in June 2018 and was amended to add Part D in November 2021. Part D enrollment will begin in early 2022; updates will be provided at the meeting. Clinical trial information: NCT03485209.

A phase I trial to evaluate the biologic effect of CBM588 (Clostridium butyricum) in combination with cabozantinib plus nivolumab for patients with metastatic renal cell carcinoma (mRCC).

TPS4606 Background: Combination therapy with the immune checkpoint inhibitor (ICI) nivolumab (nivo) and the tyrosine kinase inhibitor cabozantinib (cabo) is a new standard of care for first line treatment of patients with clear cell mRCC. However, despite the improved clinical benefit obtained with this regimen, a subgroup of patients still presents with progressive disease as best response (Choueiri et al NEJM 2021). There is now evidence supporting the role of the gut microbiome in mediating ICI activity (Routy et al Science 2018) and certain bacterial species, such as Bifidobacterium spp. in predisposing clinical response in patients with mRCC receiving ICIs (Salgia et al Eur Urol 2020). Moreover, recent evidence from a phase I clinical trial suggests that the addition of CBM588, a live probiotic comprised primarily of Clostridium butyricum, can enhance clinical response in patients with mRCC receiving nivolumab plus ipilimumab without incurring added toxicity (Meza et al ASCO, 2021). Herein we present the study design of an ongoing phase I study evaluating the biological effect of CBM588 in combination with cabozantinib plus nivolumab in patients with mRCC. Methods: This is an open label, randomized, single institution phase 1 trial for patients with confirmed mRCC with clear cell, papillary, or sarcomatoid components, who have not received prior systemic therapy for metastatic disease. A total of 30 eligible patient will be randomized 1:2 to receive either cabo/nivo at the standard dose/schedule (40mg PO QD and 480mg IV /4wks, respectively) alone or with CBM588 dosed at 80mg PO bid. The primary objective of the study is to determine the biologic effect of CBM588 with cabo/nivo in the modulation of the gut microbiome. This will be done by assessing the changes in Bifidobacterium spp. abundance and Shannon index (a measure of microbiome diversity) in stool specimens. Stool will be collected for bacteriomic profiling at baseline and after 12 weeks of treatment. Metagenomic sequencing will be performed using previously published methods (Dizman et al Cancer Med 2020). Secondary objectives include determining the effect of CBM588 on (1) clinical efficacy, through overall survival, response rate, and progression-free survival; (2) systemic immunomodulation, through assessment of changes in circulating Tregs, circulating cytokines/chemokines, etc; and (3) toxicities. A two-group t-test with a one-sided type I error of 0.05 will be used to assess the study primary endpoint. Clinical trial information: NCT05122546 .