Yung Lyou, MD from the City of Hope speaks about High-throughput global transcriptional profiling to identify the STAT3 signaling pathway as a potential biomarker for immune checkpoint inhibitor resistance in metastatic/advanced urothelial carcinoma.

Link to Poster -
https://meetinglibrary.asco.org/record/194788/poster

Context:
A major public health burden, with a median overall survival of 15 months, is advanced/metastatic urothelial carcinoma (UC). While an additional second-line treatment choice has been offered by immune checkpoint inhibitors (ICI), only 15-40% of patients can react. In order to further develop these therapies, there has been a great deal of work to establish the mechanisms of immunotherapy resistance and predictive biomarkers.
Methodology:

For study, pre-treatment genomic sequencing data derived from FFPE samples from the clinical IMVIGOR210 trial (n=298) was accessed. A single arm phase II clinical trial was briefly performed in which advanced/metastatic UC patients who were refractory to platinum chemotherapy received ICI atezolizumab. This research was published with extensive techniques (PMID: 28950298). Using standard QC steps, the raw sequencing information was pre-processed and matched to the human reference genome (hg38). To produce the gene level counts for differential gene expression, the resulting outputs were then normalized and processed (DGE). DGE research was conducted comparing atezolizumab with patients who had clinical benefit (CR, PR, SD) and non-clinical benefit (i.e. PD). The list of genes differentially expressed was then analyzed using different methods for gene ontology, pathway and systems biology (IPA, Enrichr, and X2Kweb). Using gene-gene correlations (i.e. PD-L1 and STAT3) and clinicopathologic characteristics, further subset analysis was performed (eg. gender, race, smoking history).

Outcomes:
Of the 298 patients in this study, 25 had CR, 43 had PR, 63 had SD, and 167 had PD based on atezolizumab clinical response. Subgroup review for patients with CR vs PD showed that approximately 847 genes with statistical significance were expressed differentially (p ⁇ 0.05). 'Primary immunodeficiency' and 'sirtuin signaling' were the IPA study for this list of differentially expressed genes located in the top signaling pathways. Further subset study of 39 genes (p ≤ 0.01) enriched in PD patients using Enrichr and X2kweb showed that there was an overrepresentation of STAT3 signaling genes (hypergeometric p-val 6.32x104).

Findings:
Our findings showed that there was differential gene expression in STAT3, primary immunodeficiency, and sirtuin signaling pathways when the transcriptional profiles of CR vs PD occurred. Of note, STAT3 signaling has been reported to modulate immune function and its expression is associated with poor prognosis in patients with urothelial carcinoma. These findings require a wider study to see whether a possible biomarker for ICI resistance is STAT3 signaling. This could mean that the STAT3 pathway, if validated, is a possible therapeutic target for overcoming ICI resistance and enhancing the effectiveness of these agents.

Sumanta (Monty) K. Pal, MD of the City of Hope speaks about A randomized, multi-arm comparison of targeted therapies for advanced papillary renal cell carcinoma.


PORTLAND, OR-The small molecule inhibitor cabozantinib was found to be most effective in treating patients with metastatic papillary kidney cancer in a SWOG Cancer Research Network trial that tested three targeted drugs, results that are expected to change medical practice.

These results will be discussed on Feb. 13, 2021, at 1 p.m. at ASCO's virtual 2021 Genitourinary Cancers Symposium. ET. The et. The results will be published in The Lancet simultaneously.



For metastatic papillary kidney cancer or metastatic pRCC, a rare subtype of kidney cancer, there are currently no successful therapies. One analysis of 38 patients showed that eight months after diagnosis was the average survival rate.



Sumanta Pal, MD, City of Hope's clinical professor of medical oncology, a comprehensive cancer center, and a researcher at SWOG, a cancer clinical trials group sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), said that there is hope for patients with metastatic papillary kidney cancer. MET gene mutations are a characteristic of this type of cancer, and new medicines that target the MET gene are available. Pal wanted to test three of them against the latest standard medication, sunitinib, a tyrosine receptor inhibitor.



Pal studied 147 qualifying patients with papillary kidney cancer in his S1500 report, the majority of whom had not undergone any previous treatment. One of four treatment classes, those who took sunitinib and those who took one of the three MET target medicines, cabozantinib, crizotinib, and savolitinib, were randomly assigned to patients.



Pal and his team decided to see how long it would take to spread or return patients to cancer, a metric known as progression-free survival. What they found: Patients receiving sunitinib had a median progression of 5.6 months before their cancer; patients receiving savolitinib and crizotinib had an average progression of much worse. Yet cabozantinib gave patients a median of 9.2 months prior to the progression of their cancer. In addition, 23 percent of patients had a substantial decrease in their cabozantinib tumor size. In comparison, with sunitinib, only 4 percent of patients saw this type of tumor response.



Building on the S1500 momentum, SWOG will lead the next crucial papillary kidney cancer study, one focusing on the possible synergies between targeted therapies such as cabozantinib and immune therapy. Pal will lead the research at the Huntsman Cancer Institute at the University of Utah with SWOG investigator Dr. Benjamin Maughan.



SWOG 1500, also referred to as PAPMET, was funded by NCI, designed and led under the leadership of Dr. Pal by the SWOG Cancer Research Network, and performed through the National Clinical Trials Network of NCI.



Via NCI grants CA180888, CA180819, CA180820, CA180821, CA180863, and CA180868, S1500 was also sponsored by the NIH; and in part by AstraZeneca plc/AB, Exelixis, Inc. and Pfizer, Inc. For the trial under each company's Cooperative Research and Development Agreement with the NCI, the companies given savolitinib, cabozantinib, crizotinib and sunitinib, respectively.

Prof. Michael Boyer of the Chris O’Brien Lifehouse and the University of Sydney discusses Pembrolizumab Plus Ipilimumab or Placebo for Metastatic Non–Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50%: Randomized, Double-Blind Phase III KEYNOTE-598 Study.


Link to Full Article -
https://ascopubs.org/doi/10.1200/JCO.20.03579


ABSTRACT -

Intent —
Pembrolizumab monotherapy is a normal first-line treatment with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of about 50 percent without actionable driver mutations for metastatic non-small-cell lung cancer (NSCLC). It is not clear if the addition of ipilimumab to pembrolizumab in this population increases efficacy compared to pembrolizumab alone.


FOR METHODS
In the randomized, double-blind, phase III KEYNOTE-598 trial (ClinicalTrials.gov identifier: NCT03302234), qualified patients with previously untreated metastatic NSCLC were randomly allocated 1:1 to ipilimumab 1 mg/kg or placebo every 6 weeks for up to 18 doses with PD-L1 TPS ⁇ 50% and no sensitizing EGFR or ALK aberrations; all participants received pembrolizumab 200 mg every 3 weeks for up to 18 doses. General survival and progression-free survival were the key endpoints.



OUTCOMES
Of the 568 participants, 284 were assigned to each group at random. The median overall survival for pembrolizumab-ipilimumab was 21.4 months, compared with 21.9 months for pembrolizumab-placebo (hazard ratio, 1.08; 95% CI, 0.85 to 1.37; P = .74). Pembrolizumab-ipilimumab median progression-free survival was 8.2 months versus 8.4 months for pembrolizumab-placebo (hazard ratio, 1.06; 95 percent CI, 0.86 to 1.30; P = .72). In 62.4 percent of pembrolizumab-ipilimumab recipients versus 50.2 percent of pembrolizumab-placebo recipients, Grade 3-5 adverse effects occurred and 13.1 percent versus 7.5 percent contributed to the death. The external data and safety control committee recommended that the research be halted for futility and that ipilimumab and placebo be discontinued by the participants.



Outcome
Adding ipilimumab to pembrolizumab does not boost efficacy and is associated with greater toxicity than first-line treatment with pembrolizumab monotherapy for metastatic NSCLC with PD-L1 TPS ⁇ 50% and no targetable aberrations of EGFR or ALK. These data do not support the use of pembrolizumab-ipilimumab in this population in place of monotherapy with pembrolizumab.

Cathy Eng, MD, FACP, FASCO from Vanderbilt-Ingram Cancer Center Vanderbilt University Medical Center speaks about the Editorial - BRAF Mutation in Colorectal Cancer: An Enigmatic Target.

Link to Full Article -
https://ascopubs.org/doi/full/10.1200/JCO.20.03043

Cytotoxic chemotherapy combined with biologic agents such as antivascular endothelial growth factor or antiepidermal growth factor has been our normal strategy for all patients for over a decade.1-3 Since then, research has advanced, including the importance of genomic alterations as potential predictive and prognostic markers in the treatment of colorectal cancer (CRC).4,55

The BRAF gene encodes the critical mechanism in the carcinogenesis of multiple cancers for a serine or threonine-protein kinase associated with the mitogen-activated protein kinase pathway.6,7 The BRAF mutation (MT) results in the constitutive activation of downstream kinases, resulting in cell proliferation and survival. BRAF MT occurs in 60% of all melanomas but is present in < 10% of all CRCs. The V600E subtype, typically found in female and right-side colon cancers, accounts for more than 90% of all BRAF MTs.


Compared to their wild-type counterparts, the majority of patients with BRAFV600E MT metastatic CRC (mCRC) undergo decreased progression-free survival (PFS) and overall survival (OS). Researchers observed a decline in OS for BRAFV600E stage II-IV CRC as early as 2005.9 The predicted median OS (mOS) for colorectal stage IV cancer is approximately 29-30 months.10-12 Standard combination chemotherapy for BRAFV600E MT mCRC, in stark contrast, results in an mOS of 12-14 months.12,13


Individualized treatment should be given for advances in precision medicine, including the implementation of molecular testing and the development of novel targeted agents. Orally selective BRAFV600E inhibitors such as vemurafenib, dabrafenib, and encorafenib are licensed by the Food and Drug Administration (FDA) for use in surgically unresectable or metastatic melanoma.14-16 A pilot phase II trial of vemurafenib reporting a disappointing response rate (RR) of only 5% quickly dampened high expectations of similar gain in refractory BRAFV600E mCRC.17


In order to test this hypothesis, Corcoran et al18 developed a non-randomized three-arm phase I/II trial of dabrafenib(D)+panitumumab(P)+/−trametini In order to test this hypothesis, Corcoran et al18 developed a non-randomized three-arm phase I/II trial of dabrafenib(D)+panitumumab(P)+/−trametini. Dabrafenib-panitumumab resulted in a 10 percent RR and a 3.5-month PFS (95 percent CI, 2.8 to 5.8 months); dabrafenib-panitumumab-trametinib resulted in a 21 percent improved RR and a 4.2-month PFS (95 percent CI, 4.0 to 5.6 months). Correlatives showed a decrease in the radiographic response of the BRAFV600E stage, suggesting the position of serial cell-free DNA (cfDNA). Also mentioned was the clonal evolution of acquired Kristen-Ras (KRAS) mutations.


Kopetz et al22 published the results of S1406, the first phase II randomized National Clinical Trials Network analysis of irinotecan + cetuximab +/− vemurafenib (VIC) in refractory BRAFV600E MT mCRC, in the first article preceding this editorial. Microsatellite instability-high (MSI-H) tumors were not excluded in this trial because S1406 followed the FDA approval of immune checkpoint approval PFS was the primary endpoint, allowing patients on the control arm to crossover. For the VIC combination of 4.2 months versus 2.0 months, the investigators registered superior PFS. A non-statistical difference in OS in 42 percent of patients was due to the crossover. As a clinician, I find the dismal PFS of 2.0 months in the control arm of irinotecan + cetuximab in BRAFV600E mCRC to be the most striking result.


In order to detect the presence of somatic mutations, correlative work from S1406 included next-generation sequencing, serial plasma collection, and circulating tumor DNA (ctDNA). Challenges persisted, however, in the collection of tissue and blood. It was shown in Figure 3 of the publication that only 34 percent of patients supplied both baseline and first ctDNA restaging. S1406 reveals the difficulties that occur in current and potential BRAFV600E MT trials to obtain correlatives. Due to tissue acquisition limitations in this population, ctDNA would likely act as our best correlative resource as most patients will have surgically unresectable disease. Strict serial collection of plasma should be required from all participating sites as a result of the traditionally short PFS.


The BEACON trial is a global three-arm, phase III randomized trial of cetuximab + encorafenib (CE) +/− binimetinib (CEB) versus standard chemotherapy (irinotecan + cetuximab-based) in previously treated BRAFV600E mCRC patients.22 The trial included a safety run in 30 patients with an outstanding RR of 56%, 7.5-month PFS, and 19.0-month OS, resulting in the FDA breakthrough. OS for the CE arm relative to control, PFS, length of reaction, and protection were secondary endpoints; in particular, the study was not able to compare the two investigational weapons. The primary endpoint was met with the superior OS for CEB 9.0 months versus 5.4 months (HR = 0.52; 95 percent CI, 0.39 to 0.70) after a median follow-up of 7.8 months. As part of their descriptive analysis, it was noted that the CE arm provided CEB with identical Kaplan-Meier curves with a comparable OS (8.4 months v 5.4 months; HR = 0.60; 95% CI, 0.45 to 0.79). The investigators also noted that if given earlier in care, promoting RR with CEB (one prior line versus heavily pretreated: 34 percent v 26 percent ).

Anne L. Angiolillo, MD, MS, director of the Leukemia and Lymphoma Program at Children’s National Medical Center speaks about the Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932.

Link To Study -
https://ascopubs.org/doi/abs/10.1200/JCO.20.00494

Abstract - 

PURPOSITY:
In order to optimize disease-free survival (DFS) thus reducing the burden of therapy in children with newly diagnosed NCI standard-risk (SR) B-acute lymphoblastic leukemia, AALL0932 tested two randomized maintenance approaches (B-ALL).



AND METHODS:
AALL0932 enrolled 9,229 patients with B-ALL; 2,364 patients with a mean risk (AR) were randomly assigned to vincristine/dexamethasone pulses every 4 (VCR/DEX4) or every 12 (VCR/DEX12) weeks and to a starting dose of 20 mg/m2 (MTX20) or 40 mg/m2 once-weekly oral methotrexate every 4 (VCR/DEX4) or every 12 (VCR/DEX12) weeks at the start of maintenance therapy (MTX40).



RESULTATIONS:
For all qualifying and evaluable SR B-ALL patients (n = 9,226), 5-year event-free survival and overall survival (OS) from registration were 92.0 percent (95 percent CI, 91.1 percent to 92.8 percent) and 96.8 percent (95 percent CI, 96.2 percent to 97.3 percent), respectively. For randomly allocated AR patients, the 5-year DFS and OS from the start of maintenance were 94.6 percent (95 percent CI, 93.3 percent to 95.9 percent) and 98.5 percent (95 percent CI, 97.7 percent to 99.2 percent), respectively. For patients randomly assigned to receive VCR/DEX4 (n = 1,186) versus VCR/DEX12 (n = 1,178), the 5-year DFS and OS were 94.1 percent (95 percent CI, 92.2 percent to 96.0 percent) and 98.3 percent (95 percent CI, 97.2 percent to 99.4 percent) v 95.1 percent (95 percent CI, 93.3 percent to 96.9 percent) and 98.6 percent (95 percent CI, 97.7 percent to 99.6 percent) respectively (P = 95.1 percent) v 95.1 percent (95 percent CI, 93.3 percent to 96.9 percent) For AR patients randomly assigned to receive MTX20 versus MTX40, the 5-year DFS and OS for AR patients were 95.1 percent (95 percent CI, 93.3 percent to 96.8 percent) and 98.8 percent (95 percent CI, 97.9 percent to 99.7 percent) versus 94.2 percent (95 percent CI, 92.2 percent to 96.1 percent) and 98.1 percent (95 percent CI, 97.0 percent to 99.2 percent) versus 94.2 percent (P = .92 and .89).



Observations:
Despite obtaining one-third of the vincristine/dexamethasone pulses previously used as standard of care in Children's Oncology Community (COG) studies, the NCI-SR AR B-ALL that obtained VCR/DEX12 had outstanding results. Compared with 20 mg/m2 once weekly, the higher starting dose of MTX of 40 mg/m2 once weekly did not boost the performance. In order to minimize the burden of therapy for patients and their families, the reduced frequency of vincristine/dexamethasone pulses has been introduced into frontline COG B-ALL trials.

Professor Thomas Powles, MD of Barts Cancer Centre, Queen Mary University of London speaks about Seattle Genetics and Astellas Announce PADCEV® (enfortumab vedotin-ejfv) Significantly Improved Overall Survival in Phase 3 Trial in Previously Treated Locally Advanced or Metastatic Urothelial Cancer.


Link to Press Release -
https://www.businesswire.com/news/home/20200918005101/en/

BOTHELL, Wash. & TOKYO—(BUSINESS WIRE)—Seattle Genetics, Inc. (Nasdaq: SGEN) and Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") today reported that their primary endpoint of overall survival relative to chemotherapy was reached by a phase 3 trial of PADCEV® (enfortumab vedotin-ejfv). Following a planned interim study, the findings were reviewed by an independent Data Management Committee. For adult patients with locally advanced or metastatic urothelial cancer who have previously been treated with platinum-based chemotherapy and a PD-1/L1 inhibitor, the global EV-301 clinical trial compared PADCEV with chemotherapy.

In the study, PADCEV significantly enhanced overall survival (OS), decreasing the risk of death by 30 percent (Hazard Ratio [HR]=0.70; [95 percent Confidence Interval (CI): 0.56, 0.89]; p=0.001). A secondary endpoint, PADCEV also dramatically improved progression-free survival (PFS) with a 39 percent decrease in disease progression or death risk (HR=0.61 [95 percent CI: 0.50, 0.75]; p<0.00001).


Adverse events were consistent with those reported in the U.S. for patients in the PADCEV arm of the study. Prescribing Details for more than 5% of patients with rash, hyperglycemia, reduced neutrophil count, weakness, anemia, and decreased appetite as the most common Grade 3 or greater adverse event(s). Data from EV-301 will be sent to the forthcoming scientific congress for presentation. The chance to obtain PADCEV will be given to patients in the chemotherapy arm of the study.



The findings will be filed with the U.S. As the confirmatory trial following the accelerated approval of the drug in 2019, the Food and Drug Administration (FDA). The aim of the EV-301 is also to help global registration.



About 580,000 individuals will be diagnosed with bladder cancer globally in 2020.1 Urothelial cancer accounts for 90% of all bladder cancers and can also be located in the renal pelvis (where urine collects inside the kidney), ureter (the tube that connects the kidneys to the bladder), and urethra.2 About 80% of individuals do not respond to platinum-positive PD-1 or PD-L1 inhibitors.



Concerning the EV-301 Trial

The EV-301 (NCT03474107) trial is a national, multicenter, open-label, randomized phase 3 trial designed to test PADCEV versus doctor's choice of chemotherapy (docetaxel, paclitaxel, or vinflunine) in approximately 600 locally advanced or metastatic urothelial cancer patients who have been previously treated with a platinum-based PD-1 or PD-L1 inhibitor. Compared to those treated with chemotherapy, the primary outcome is the overall survival of participants treated with PADCEV. Secondary endpoints include progression-free survival, response length, and overall response rate, as well as the measurement of criteria of safety/tolerability and quality of life.

Please visit www.clinicaltrials.gov for more information on the EV-301 clinical trial.

Kim Chi, MD, Vice President & Chief Medical Officer of BC Cancer speaks about TITAN: A final analysis with close to four years of follow-up data evaluating Erleada versus placebo in patients with metastatic castration-sensitive prostate cancer receiving hormone therapy (Abstract #11).

Link to Abstract-

https://meetinglibrary.asco.org/record/194577/abstract

Context:

APA or PBO applied to ADT in pts with mCSPC is evaluated by TITAN. Eligibility was made for Pts with high- and low-volume disease, prior docetaxel, prior localized disease therapy, and prior ADT ( ⁇ 6 mos). APA substantially improved the dual primary endpoints of overall survival (OS) (hazard ratio [HR] 0.67) and radiographic progression-free survival (rPFS) (HR 0.48) relative to PBOS (hazard ratio [HR] 0.67) and radiographic progression-free survival (rPFS) (HR 0.48) in the first interim study with 22.7 MB of median follow-up (Chi et al. NEJM. 2019). OS analysis was first scheduled on an interim basis at that time, while rPFS was final. TITAN was unblinded, allowing pts without advancement to cross over to APA, who were still receiving PBO. Here, the final review of TITAN's effectiveness and safety results is published.

Methodology:

To receive APA (240 mg QD) or PBO plus ADT, 1052 mCSPC pts is randomized at 1:1. The Kaplan-Meier process and Cox proportional hazards model evaluated time-to-event endpoints. A pre-planned OS sensitivity analysis was carried out, accounting for crossover using the weighted log-rank test of inverse likelihood censoring (IPCW). No formal statistical retesting was performed; without multiplicity adjustment, nominal p values were recorded. A mixed-effect repeated-measures model was used to test the improvement from the baseline in the Functional Evaluation of Cancer Therapy-Prostate (FACT-P) total score.

Outcomes:

405 OS events occurred with a median follow-up of 44 mos. 208 PBO pts (39.5 percent) crossed over to APA after unblinding. The median period of treatment was 39.3 mos for the APA group, 20.2 mos for the whole PBO group, and 15.4 mos for the crossover PBO/APA group. In comparison with the PBO group, OS was superior in the APA group despite crossover (Table). Survival rates of 48-mo were 65 percent (APA) vs 52 percent (PBO). APA vs PBO also preferred other endpoints (Table). Per total FACT-P, health-related quality of life (HRQoL) was preserved through the analysis in the APA community and was not different from the PBO group. Security has been consistent with past studies.

Findings:

The final study of TITAN showed that APA plus ADT offers an improvement in OS with a 35 percent reduction in risk of death in a large population of pts with mCSPC, which increased to 48 percent reduction after adjustment for pts that crossed from PBO to APA, with nearly 4 years of follow-up. In addition, other endpoints, including delaying castration resistance, had clear advantages with APA, and HRQoL continued to be maintained with a reasonable safety profile. Details on the clinical trial: NCT02489318