Background
The androgen receptor (AR) pathway‐associated gene nuclear receptor coactivator 2 (NCOA2) has an established oncogenic role in early prostate cancer and likewise is a driver of metastatic ...disease and castration‐resistant prostate cancer. However, its significance as a biomarker in metastatic castration‐resistant prostate cancer (mCRPC), both alone and in conjunction with co‐occurring AR alterations using a liquid biopsy approach has not been investigated.
Methods
Ninety‐one patients were included in this study, (n = 68 receiving an androgen receptor pathway inhibitor and n = 23 receiving taxane chemotherapy). Up to 30 ml of peripheral blood was collected before commencing treatment from each patient. Plasma cell‐free DNA, along with a matched germline sample, underwent targeted next‐generation sequencing using a validated, highly sensitive in‐house prostate cancer panel. Variants in AR and NCOA2 were identified and correlated with clinical outcomes.
Results
Plasma AR and NCOA2 aberrations were identified in 35% and 13% of the cohort, respectively, whilst 8% had concurrent AR and NCOA2 alterations. NCOA2 copy number gain and any NCOA2 aberration predicted for lower prostate‐specific antigen (PSA) response rates. Likewise, median overall survival was shorter for NCOA2 gain (10.1 vs. 18.3 months; p = .004), remaining significant after adjusting for covariates including circulating tumor DNA fraction and tumor suppressor gene alterations. Importantly, dual AR and NCOA2 aberrations were also associated with inferior outcomes, including no PSA responses in patients treated with AR pathway inhibitors (0% vs. 64%; p = .02).
Conclusions
These data highlight the importance of identifying multiple markers of AR pathway modulation in mCRPC and represent the first instance of the assessment of plasma NCOA2 status as a prognostic biomarker for standard‐of‐care therapies. Further assessment is warranted to determine if NCOA2 aberrations are a marker of primary resistance to AR pathway inhibitors.
BackgroundProgrammed cell death receptor-1 (PD-1)-blocking antibodies are approved to treat metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) cases ineligible for curative ...surgery or radiation. Notwithstanding, some patients experience inadequate responses or severe immune-related adverse events (AEs), indicating the need for improved therapies. Cosibelimab is a high-affinity programmed cell death-ligand 1 (PD-L1)-blocking antibody that activates innate and adaptive immunity by blocking PD-L1 interaction with PD-1 and B7-1 receptors. It is an unmodified immunoglobulin G1 subtype with a functional Fc domain capable of inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Here, we present results of the pivotal study of patients with metastatic CSCC from an open-label, multicenter, multiregional, multicohort, phase 1 trial of cosibelimab.MethodsIn this trial, participants with metastatic CSCC received cosibelimab 800 mg intravenously every 2 weeks. Primary endpoint was objective response rate (ORR) by independent central review using Response Evaluation Criteria in Solid Tumors, V.1.1. Secondary endpoints included duration of response (DOR) and safety.ResultsObjective response was observed in 37 of 78 participants (47.4% (95% CI: 36.0% to 59.1%)), with median follow-up of 15.4 months (range: 0.4 to 40.5) as of data cut-off. Median DOR was not reached (range: 1.4+ to 34.1+ months), with response ongoing in 73.0% of participants. Common treatment-emergent AEs (≥15%) were fatigue (26.9%), rash (16.7%), and anemia (15.4%). Eighteen participants (23.1%) experienced immune-related AEs (grade 3: n=2 (2.6%); no grade 4/5). No treatment-related deaths were reported.ConclusionsCosibelimab demonstrated clinically meaningful ORR and DOR and was associated with a manageable safety profile.Trial registration numberNCT03212404.
BackgroundCosibelimab is a high affinity, fully-human IgG1 monoclonal antibody that directly binds to programmed death ligand-1 (PD-L1) and blocks its interaction with the programmed death receptor-1 ...(PD-1) and B7.1 receptors to restore an anti-tumor immune response. Cosibelimab has the additional benefit of a functional Fc domain capable of inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against tumor cells. Study CK-301–101 is a global, multicenter, multicohort trial that is enrolling patients (pts) with select advanced cancers, including pivotal cohorts of pts with metastatic and locally advanced cutaneous squamous cell carcinoma (cSCC) and a cohort of pts with previously untreated advanced non-small cell lung cancer (NSCLC).MethodsEligible pts were aged ≥18 years with an Eastern Cooperative Oncology Group performance status of 0–1. The cSCC cohorts enrolled pts with histologically confirmed metastatic or locally advanced cSCC not amenable to local therapy. The NSCLC cohort enrolled previously untreated NSCLC pts with advanced disease and a PD-L1 tumor proportion score of at least 50%. Pts received a fixed dose of 800 mg cosibelimab administered intravenously every two weeks. Anti-tumor activity was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and were conducted every 8 weeks for the initial 32 weeks on study, and every 12 weeks thereafter.ResultsAs of August 2020, 114 pts (73M/41F, median age 66 years) with diverse tumor types have been enrolled and treated with cosibelimab. Among these pts, 103 (90%) experienced ≥1 treatment-emergent adverse event (AE), 42 (37%) experienced a grade ≥3 AE, and 6 (5%) experienced a grade ≥3 drug-related AE. The most common AEs were fatigue (25%), anemia (21%), rash (18%) and nausea (16%) and the most common drug-related AEs were fatigue (15%) and rash (14%). In 42 cSCC pts evaluable for response, ORR based on investigator assessment of tumor response was 55% (95% confidence interval CI: 39, 70), including 5 (12%) complete responses, with 20/23 (87%) responses ongoing and 10 responses ≥6 months in duration as of data cutoff. In 25 NSCLC pts evaluable for response, ORR based on investigator assessment was 44% (95% CI: 24, 65), with 5/11 (45%) responses ongoing and 10 responses ≥6 months in duration.ConclusionsCosibelimab has a predictable and manageable safety profile and demonstrated robust clinical activity in cSCC and NSCLC pts, including durable complete and partial responses. Updated results will be presented.Trial RegistrationNCT03212404Ethics ApprovalThe study was approved by an appropriate ethics committee for each participating institution. Informed consent was obtained for all subjects.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Effective treatments are needed for melanoma that progresses on inhibitors of programmed cell death protein-1 (PD-1) or its ligand (PD-L1). We conducted the phase II LEAP-004 study to evaluate the ...combination of the multikinase inhibitor lenvatinib and the PD-1 inhibitor pembrolizumab in this population (ClinicalTrials.gov identifier: NCT03776136).
Eligible patients with unresectable stage III-IV melanoma with confirmed progressive disease (PD) within 12 weeks of the last dose of a PD-1/L1 inhibitor given alone or with other therapies, including cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4) inhibitors, received lenvatinib 20 mg orally once daily plus ≤ 35 doses of pembrolizumab 200 mg intravenously once every 3 weeks until PD or unacceptable toxicity. The primary end point was objective response rate (ORR) per RECIST, version 1.1, by independent central review.
A total of 103 patients were enrolled and treated. The median study follow-up was 15.3 months. ORR in the total population was 21.4% (95% CI, 13.9 to 30.5), with three (2.9%) complete responses and 19 (18.4%) partial responses. The median duration of response was 8.3 months (range, 3.2-15.9+). ORR was 33.3% in the 30 patients with PD on prior anti-PD-1 plus anti-CTLA-4 therapy. The median progression-free survival and overall survival in the total population were 4.2 months (95% CI, 3.8 to 7.1) and 14.0 months (95% CI, 10.8 to not reached), respectively. Grade 3-5 treatment-related adverse events occurred in 47 (45.6%) patients, most commonly hypertension (21.4%); one patient died from a treatment-related event (decreased platelet count).
Lenvatinib plus pembrolizumab provides clinically meaningful, durable responses in patients with advanced melanoma with confirmed PD on prior PD-1/L1 inhibitor-based therapy, including those with PD on anti-PD-1 plus anti-CTLA-4 therapy. The safety profile was as expected. These data support lenvatinib plus pembrolizumab as a potential regimen for this population of high unmet need.
The combination of ipilimumab and nivolumab is a highly active systemic therapy for metastatic melanoma but can cause significant toxicity. We explore the safety and efficacy of this treatment in ...routine clinical practice, particularly in the setting of serine/threonine‐protein kinase B‐Raf (BRAF)‐targeted therapy. Consecutive patients with unresectable stage IIIC/IV melanoma commenced on ipilimumab and nivolumab across 10 tertiary melanoma institutions in Australia were identified retrospectively. Data collected included demographics, response and survival outcomes. A total of 152 patients were included for analysis, 39% were treatment‐naïve and 22% failed first‐line BRAF/MEK inhibitors. Treatment‐related adverse events occurred in 67% of patients, grade 3–5 in 38%. The overall objective response rate was 41%, 57% in treatment‐naïve and 21% in BRAF/MEK failure patients. Median progression‐free survival was 4.0 months (95% CI, 3.0–6.0) in the whole cohort, 11.0 months (95% CI, 6.0‐NR) in treatment‐naïve and 2.0 months (95% CI, 1.4–4.6) in BRAF/MEK failure patients. The combination of ipilimumab and nivolumab can be used safely and effectively in a real‐world population. While first‐line efficacy appears comparable to trial populations, BRAF‐mutant patients failing prior BRAF/MEK inhibitors show less response.
Background
This study investigated the safety and efficacy of an anti–CTLA‐4 monoclonal antibody (CS1002) as monotherapy and in combination with an anti–PD‐1 monoclonal antibody (CS1003) in patients ...with advanced/metastatic solid tumors.
Methods
The phase 1 study involved phase 1a monotherapy dose‐escalation (part 1) and phase 1b combination therapy dose escalation (part 2) and expansion (part 3). Various dosing schedules of CS1002 (0.3, 1, or 3 mg/kg every 3 weeks, or 3 mg/kg every 9 weeks) were evaluated with 200 mg CS1003 every 3 weeks in part 3.
Results
Parts 1, 2, and 3 included a total of 13, 18, and 61 patients, respectively. No dose‐limiting toxicities or maximum tolerated doses were observed. Treatment‐related adverse events (TRAEs) were reported in 30.8%, 83.3%, and 75.0% of patients in parts 1, 2, and 3, respectively. Grade ≥3 TRAEs were experienced by 15.4%, 50.0%, and 18.3% of patients in each part. Of 61 patients evaluable for efficacy, 23 (37.7%) achieved objective responses in multiple tumor types. Higher objective response rates were observed with conventional and high‐dose CS1002 regimens (1 mg/kg every 3 weeks or 3 mg/kg every 9 weeks) compared to low‐dose CS1002 (0.3 mg/kg every 3 weeks) in microsatellite instability‐high/mismatch repair‐deficient tumors, melanoma, and hepatocellular carcinoma (50.0% vs. 58.8%, 14.3% vs. 42.9%, and 0% vs. 16.7%).
Conclusion
CS1002, as monotherapy, and in combination with CS1003, had a manageable safety profile across a broad dosing range. Promising antitumor activities were observed in patients with immune oncology (IO)‐naive and IO‐refractory tumors across CS1002 dose levels when combined with CS1003, supporting further evaluation of this treatment combination for solid tumors.
Plain Language Summary
CS1002 is a human immunoglobulin (Ig) G1 monoclonal antibody that blocks the interaction of CTLA‐4 with its ligands and increases T‐cell activation/proliferation. CS1003, now named nofazinlimab, is a humanized, recombinant IgG4 monoclonal antibody that blocks the interaction between human PD‐1 and its ligands.
In this original article, we determined the safety profile of CS1002 as monotherapy and in combination with CS1003. Furthermore, we explored the antitumor activity of the combination in anti–programmed cell death protein (ligand)‐1 (PD‐L1)‐naive microsatellite instability‐high/mismatch repair‐deficient (MSI‐H/dMMR) pan tumors, and anti–PD‐(L)1‐refractory melanoma and hepatocellular carcinoma (HCC).
CS1002 in combination with CS1003 had manageable safety profile across a broad dosing range and showed promising antitumor activities across CS1002 dose levels when combined with CS1003. This supports further assessment of CS1002 in combination with CS1003 for the treatment of solid tumors.
This was a phase 1a/1b, dose‐escalation and dose‐expansion study evaluating the safety and efficacy of an anti–CTLA‐4 monoclonal antibody (CS1002) as monotherapy and in combination with an anti–PD‐1 monoclonal antibody (CS1003/nofazinlimab), in patients with advanced/metastatic solid tumors. Promising antitumor activities were observed in heavily pretreated patients with immune oncology (IO)‐naive and IO‐refractory tumors across CS1002 dose levels when combined with CS1003, which supports further assessment of CS1002 in combination with CS1003 for the treatment of solid tumors.
In 2014, a landmark study was published demonstrating that the expression of androgen receptor splice variant (AR-V) 7 was a negative predictive biomarker for response to abiraterone acetate and ...enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) patients. However, these results were not supported by the recently reported ARMOR3-SV phase III clinical trial, which employed an identical circulating tumour cell assay to assess AR-V7 expression. Therefore, the predictive utility of AR-V7 expression in mCRPC remains uncertain, as does any potential association between other AR-Vs and treatment response. To further investigate, we designed a highly sensitive and specific whole blood assay for detecting AR-V7 and AR-V9. We then examined for a correlation between baseline AR-V7/V9 status and treatment outcome in 37 mCRPC patients commencing abiraterone or enzalutamide. Of the patients, 24% (9/37) were AR-V–positive. Notably, prostate-specific antigen (PSA) response rates did not significantly differ between AR-V–positive (6/9) and AR-V–negative (18/28) patients (66% vs 64%, p=0.9). Likewise, median PSA progression-free survival was not significantly different between AR-V–positive and AR-V–negative patients (9.2 mo vs not reached; p=0.9). These data, which support the findings of the pivotal ARMOR3-SV clinical trial, suggest that baseline AR-V expression does not predict outcomes in mCRPC patients receiving abiraterone or enzalutamide.
Detection of androgen receptor splice variants (AR-Vs) in circulating tumour cells of advanced prostate cancer patients has been linked to resistance to abiraterone and enzalutamide. We designed a blood test to detect AR-Vs that can be performed more routinely than tests involving circulating tumour cells and found that patients with AR-Vs still benefit from these effective treatments.
We designed a whole blood assay for the detection of androgen receptor splice variant (AR-V) 7 and AR-V9. The presence of these AR-Vs does not predict for nonresponse to abiraterone and enzalutamide. Patients should not necessarily be excluded from such therapies if they express these AR-Vs.
Total plasma cell-free DNA (cfDNA) levels were recently shown to be prognostic in two large phase III trials of taxane chemotherapy in metastatic castration-resistant prostate cancer (mCRPC). ...However, whether cfDNA concentration is predictive of treatment outcomes with androgen receptor pathway inhibitors (ARPIs) is unknown. We quantified plasma cfDNA levels at baseline (n = 74) and 4 weeks on treatment (n = 56) in a prospective cohort of mCRPC patients treated with the ARPIs abiraterone acetate or enzalutamide. Elevated total cfDNA concentration (log10) at both baseline (hazard ratio HR 5.5, p < 0.001) and week 4 (HR 7.5, p < 0.001) was a significant negative prognostic factor for overall survival (OS), a finding maintained after adjustment for plasma circulating tumour DNA fraction. Unexpectedly, a rise in cfDNA concentration from baseline to week 4 was also associated with significantly improved OS (HR 0.14, p = 0.003). Conversely, patients with ≥29.8% decrease in cfDNA from baseline (optimal cut-point) had significantly shorter median OS than the rest of the cohort (10.5 vs 25.7 mo, p = 0.03). Collectively, our findings point to the potential prognostic utility of quantifying cfDNA in mCRPC and in particular suggest that dynamic changes in total cfDNA levels may be a novel early predictive biomarker for therapeutic outcome in ARPI-treated patients.
We measured the levels of total cell-free DNA (cfDNA) in the plasma of patients with metastatic prostate cancer prior to and 4 weeks after starting new hormonal drugs. We found that patients with higher levels of cfDNA or a higher proportion of tumour-derived DNA at baseline had worse outcomes on hormonal therapies. Similarly, higher levels of cfDNA at 4 weeks into therapy were also associated with worse outcomes. However, a rise in total cfDNA levels at 4 weeks compared with baseline was linked with better outcomes. Measuring changes in cfDNA concentration may be a useful and technically straightforward early way to predict how patients will respond to treatment in metastatic prostate cancer.
A higher total cell-free DNA (cfDNA) level is a poor prognosticator in advanced prostate cancer patients receiving novel hormonal therapies. Additionally, an early on-treatment rise in cfDNA levels predicts for better outcomes. Therefore, total cfDNA concentration may assist in prognostication and predicting treatment outcome.
The treatment paradigm for metastatic castration-resistant prostate cancer (mCRPC) has evolved significantly in recent years. Identifying predictive and/or prognostic biomarkers in the context of ...this rapidly expanding therapeutic armamentarium remains a pressing and unmet clinical need.
To develop a prognostic whole-blood gene signature for mCRPC patients.
As part of an ongoing prospective, multicentre biomarker research study (Australian Prostate Biomarker Alliance), we enrolled 115 mCRPC patients commencing chemotherapy (n = 34) or androgen receptor (AR) pathway inhibitors therapy (n = 81) and obtained pretreatment whole-blood samples in PAXgene RNA tubes. Gene expression was assessed using reverse transcription-polymerase chain reaction.
Gene transcripts correlating with overall survival (OS) at p < 0.10 in univariate Cox regression models were incorporated into a multigene signature. Kaplan-Meier survival estimates and multivariate analyses were used to assess association with clinical outcomes. Prognostic strength of the signature was estimated using a concordance probability estimate (CPE).
Based on univariate analysis for OS, the following genes were incorporated into a multigene signature: AR splice variant 7 (AR-V7), and three androgen-regulated genes: GRHL2, HOXB13, and FOXA1. The number of positive transcripts clearly stratified survival outcomes (median OS: not reached vs 24.8 mo vs 16.2 mo for 0, 1, and ≥2 transcripts, respectively; p = 0.0052). Notably, this multigene signature retained prognostic significance on multivariable analysis (hazard ratio, 2.1; 95% confidence interval, 1.1–4.0; p = 0.019). Moreover, CPE for this model was 0.78, indicating strong discriminative capacity. Limitations include short follow-up time.
Our data demonstrate the prognostic utility of a novel whole-blood AR-based signature in mCRPC patients commencing contemporary systemic therapies. Our pragmatic assay requires minimal processing, can be performed in most hospital laboratories, and could represent a key prognostic tool for risk stratification in mCRPC.
We found that expression of certain genes associated with the androgen receptor could help determine how long men with advanced prostate cancer survive after starting modern drug therapies.
We demonstrated that a whole-blood androgen receptor-based multigene signature was an important prognostic tool in a cohort of metastatic castration-resistant prostate cancer (mCRPC) patients receiving contemporaneous systemic treatment. This signature may have a valuable role in upfront risk stratification and prognostication of mCRPC patients.
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