Metastatic castration-resistant prostate cancer (mCRPC) remains a terminal diagnosis with an aggressive disease course despite currently approved therapeutics. The recent successful development of ...poly ADP-ribose polymerase (PARP) inhibitors for patients with mCRPC and mutations in DNA damage repair genes has added to the treatment armamentarium and improved personalized treatments for prostate cancer. Other promising therapeutic agents currently in clinical development include the radiotherapeutic 177-lutetium-prostate-specific membrane antigen (PSMA)-617 targeting PSMA-expressing prostate cancer and combinations of immunotherapy with currently effective treatment options for prostate cancer. Herein, we have highlighted the progress in systemic treatments for mCRPC and the promising agents currently in ongoing clinical trials.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
BackgroundLow-density lipoprotein receptor-related protein 1b (encoded by LRP1B) is a putative tumor suppressor, and preliminary evidence suggests LRP1B-mutated cancers may have improved outcomes ...with immune checkpoint inhibitors (ICI).MethodsWe conducted a multicenter, retrospective pan-cancer analysis of patients with LRP1B alterations treated with ICI at Duke University, Johns Hopkins University (JHU) and University of Michigan (UM). The primary objective was to assess the association between overall response rate (ORR) to ICI and pathogenic or likely pathogenic (P/LP) LRP1B alterations compared with LRP1B variants of unknown significance (VUS). Secondary outcomes were the associations with progression-free survival (PFS) and overall survival (OS) by LRP1B status.ResultsWe identified 101 patients (44 Duke, 35 JHU, 22 UM) with LRP1B alterations who were treated with ICI. The most common tumor types by alteration (P/LP vs VUS%) were lung (36% vs 49%), prostate (9% vs 7%), sarcoma (5% vs 7%), melanoma (9% vs 0%) and breast cancer (3% vs 7%). The ORR for patients with LRP1B P/LP versus VUS alterations was 54% and 13%, respectively (OR 7.5, 95% CI 2.9 to 22.3, p=0.0009). P/LP LRP1B alterations were associated with longer PFS (HR 0.42, 95% CI 0.26 to 0.68, p=0.0003) and OS (HR 0.62, 95% CI 0.39 to 1.01, p=0.053). These results remained consistent when excluding patients harboring microsatellite instability (MSI) and controlling for tumor mutational burden (TMB).ConclusionsThis multicenter study shows significantly better outcomes with ICI therapy in patients harboring P/LP versus VUS LRP1B alterations, independently of TMB/MSI status. Further mechanistic and prospective validation studies are warranted.
A high tumor mutational burden (TMB) (≥10 mut/Mb) has been associated with improved clinical benefit in non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI) and is a ...tumor agnostic indication for pembrolizumab across tumor types. We explored whether combining TMB with programmed cell death ligand 1 (PD-L1) and pretreatment neutrophil-lymphocyte ratio (NLR) was associated with improved outcomes in ICI-treated NSCLC.
We retrospectively analyzed patients treated with ICI with Foundation One genomic testing, including TMB. Optimal cutoff for prediction of response by TMB was determined by receiver operating characteristic analysis, and area under the curve (AUC) was calculated for all 3 biomarkers and combinations. Cox model was used to assess prognostic factors of overall survival (OS) and time to progression (TTP). Survival cutoffs calculated with Kaplan-Meier survival curves were TMB ≥10 mut/Mb, PD-L1 ≥50%, NLR <5, and combined biomarkers.
Data from 88 patients treated were analyzed. The optimal TMB cutoff was 9.24 mut/Mb (AUC, 0.62), improving to 0.74 combining all 3 biomarkers. Adjusted Cox model showed that TMB ≥10 mut/Mb was an independent factor of OS (hazard ratio HR, 0.31; 95% confidence interval; 0.14-0.69; P = .004) and TTP (HR, 0.46; 95% CI, 0.27-0.77; P = .003). The combination of high TMB with positive PD-L1 and low NLR was significantly associated with OS (P = .038) but not TTP.
TMB has modest predictive and prognostic power for clinical outcomes after ICI treatment. The combination of TMB, PD-L1, and NLR status improves this power.
We conducted a real-world analysis of 88 patients to assess the usefulness of tumor mutational burden (TMB), programmed cell death ligand 1, and pretreatment neutrophil-lymphocyte ratio (NLR) for response and prognosis to immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC). The 3 were modest biomarkers; TMB was the strongest, but combining all 3 improved prediction of treatment response.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The combination of ipilimumab plus nivolumab (I+N) has greatly improved outcomes in patients with intermediate or poor-risk untreated metastatic renal cell carcinoma (mRCC). However, little is known ...about the outcomes of patients with brain metastasis (BrM) treated with I+N. A search was performed to retrospectively identify all patients with mRCC treated with I+N in the Duke Cancer Institute and the Cleveland Clinic Taussig Cancer Center, followed by a chart review. Patients were included if they had BrM at the time of I+N initiation. Cohort characteristics are summarized with descriptive statistics. Kaplan-Meier method was used to estimate overall survival (OS) and global, intracranial, and extracranial progression-free survival (PFS) for the cohort and log rank test was used to compare OS and PFS between patient groups. Radiographic response was categorized by RECIST. Fisher’s exact test was used to correlate patient factors with radiographic response. From October 2017 to December 2020, 19 patients with BrM received I+N for mRCC with a median follow-up time of 27.1 months (range 15.0–35.6). By International Metastatic RCC Database Consortium (IMDC) risk criteria, 16% had favorable, 58% had intermediate, and 26% had poor-risk disease. 68% were systemic therapy naïve, and 77% of patients had clear cell histology. 95% had received local CNS directed therapy with surgery, radiotherapy, or both. The objective response rate was 44% (0% complete response) with three of six patients treated in the second line or greater setting experiencing a partial response. The median PFS was 7.6 months (95% CI 5.6 to 14.9). The median extracranial PFS was 8.5 months (95% CI 5.6 to 19.7), and median intracranial PFS was 14.7 months (95% CI 7.2 to not reached). No variables assessed were significantly associated with radiographic response (gender, IMDC risk, presence of bone metastasis, line of therapy, or presence of immune related adverse events). In our retrospective cohort of patients with mRCC with BrM, I+N, in combination with CNS-directed local therapy, appears to have clinical efficacy as previously described with responses seen beyond the first-line setting. Further investigation is warranted in this population given exclusion from prior clinical trials.
The identification of biomarkers to select patients with metastatic renal cell carcinoma (mRCC) most likely to respond to combination immunotherapy (IO) is needed. We sought to investigate an ...association of the baseline neutrophil-to-eosinophil ratio (NER) with outcomes to nivolumab plus ipilimumab for patients with mRCC.
We performed a retrospective review of patients with clear cell mRCC treated with nivolumab plus ipilimumab from Vanderbilt-Ingram Cancer Center and Duke Cancer Institute. Patients with prior receipt of immunotherapy and those without available baseline complete blood count with differential were excluded. Patients were divided into groups by the median baseline NER and analyzed for overall survival (OS), progression free survival (PFS), and objective response rate (ORR). Patients were also divided by median baseline neutrophil-to-lymphocyte ratio (NLR) and analyzed for clinical outcome. Further analyses of patients above/below the median NER and NLR were performed in subgroups of IMDC intermediate/poor risk, IMDC favorable risk, and treatment naïve patients.
A total of 110 patients were included: median age was 61 years and 75% were treatment naïve. The median NER (mNER) at baseline was 26.4. The ORR was 40% for patients with <mNER compared to 21.8% among patients with >mNER (OR 2.39, p = 0.04). The median PFS for patients with <mNER was significantly longer at 8.6 months (mo) compared to 3.2 mo for patients with >mNER (HR 0.50, p < 0.01). Median OS was not reached (NR) for patients with <mNER compared with 27.3 mo for patients with >mNER (HR 0.31, p < 0.01). The median NLR (mNLR) was 3.42. While patients with <mNLR showed improvement in OS (HR 0.42, p = 0.02), PFS and ORR did not differ compared with patients in the >mNLR group.
A lower baseline NER was associated with improved clinical outcomes (PFS, OS, and ORR) in patients with mRCC treated with nivolumab plus ipilimumab, and prospective validation of the baseline NER as a predictive biomarker for response to immunotherapy-based combinations in mRCC is warranted.
BackgroundImmunotherapy combinations including ipilimumab and nivolumab are now the standard of care for untreated metastatic renal cell carcinoma (mRCC). Biomarkers of response are lacking to ...predict patients who will have a favorable or unfavorable response to immunotherapy. This study aimed to use the OmniSeq transcriptome-based platform to develop biomarkers of response to immunotherapy.MethodsTwo cohorts of patients were retrospectively collected. These included an investigational cohort of patients with mRCC treated with immune checkpoint inhibitor therapy from five institutions, and a subsequent validation cohort of patients with mRCC treated with combination ipilimumab and nivolumab from two institutions (Duke Cancer Institute and Cleveland Clinic Taussig Cancer Center). Tissue-based RNA sequencing was performed using the OmniSeq Immune Report Card on banked specimens to identify gene signatures and immune checkpoints associated with differential clinical outcomes. A 5-gene expression panel was developed based on the investigational cohort and was subsequently evaluated in the validation cohort. Clinical outcomes including progression-free survival (PFS) and overall survival (OS) were extracted by retrospective chart review. Objective response rate (ORR) was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1.ResultsThe initial investigation cohort identified 86 patients with mRCC who received nivolumab (80%, 69/86), ipilimumab/nivolumab (14%, 12/86), or pembrolizumab (6%, 5/86). A gene expression score was created using the top five genes found in responders versus non-responders (FOXP3, CCR4, KLRK1, ITK, TIGIT). The ORR in patients with high gene expression (GEhigh) on the 5-gene panel was 29% (14/48), compared with low gene expression (GElow) 3% (1/38, χ2 p=0.001). The validation cohort was comprised of 62 patients who received ipilimumab/nivolumab. There was no difference between GEhigh and GElow in terms of ORR (44% vs 38.5%), PFS (HR 1.5, 95% CI 0.58 to 3.89), or OS (HR 0.96, 95% CI 0.51 to 1.83). Similarly, no differences in ORR, PFS or OS were observed when patients were stratified by tumor mutational burden (high=top 20%), PD-L1 (programmed death-ligand 1) expression by immunohistochemistry or RNA expression, or CTLA-4 (cytotoxic T-lymphocytes-associated protein 4) RNA expression. The International Metastatic RCC Database Consortium (IMDC) risk score was prognostic for OS but not PFS.ConclusionA 5-gene panel that was associated with improved ORR in a predominantly nivolumab monotherapy population of patients with mRCC was not predictive for radiographic response, PFS, or OS among patients with mRCC treated with ipilimumab and nivolumab.
Introduction
Two separate antiangiogenic tyrosine kinase inhibitors (TKIs) and immunotherapy (IO) combinations are FDA‐approved as front‐line treatment for metastatic renal cell carcinoma (mRCC). ...Little is known about off‐protocol and post‐front‐line experience with combination TKI–IO approaches.
Methods
We conducted a retrospective analysis of mRCC patients who received combination TKI–IO post‐first‐line therapy between November 2015 and January 2019 at MD Anderson Cancer Center and Duke Cancer Institute. Chart review detailed patient characteristics, treatments, toxicity, and survival. Independent radiologists, blinded to clinical data, assessed best radiographic response using RECIST v1.1.
Results
We identified 48 mRCC patients for inclusion: median age 65 years, 75.0% clear cell histology, 68.8% IMDC intermediate risk, and median two prior systemic therapies. TKI–IO combinations included nivolumab–cabozantinib (N +C; 24 patients), nivolumab–pazopanib (N+P; 13), nivolumab–axitinib (6), nivolumab–lenvatinib (2), and nivolumab–ipilimumab–cabozantinib (3). The median progression‐free survival was 11.6 months and the median overall survival was not reached. Response data were available in 45 patients: complete response (CR; n = 3, 6.7%), partial response (PR; 20, 44.4%), stable disease (SD; 19, 42.2%), and progressive disease (3, 6.7%). Overall response rate was 51% and disease control rate (CR+PR+SD) was 93%. Only one patient had a grade ≥3 adverse event.
Conclusion
To our knowledge, this is the first case series reporting off‐label use of combination TKI–IO for mRCC. TKI–IO combinations, particularly N+P and N+C, are well tolerated and efficacious. Although further prospective research is essential, slow disease progression on IO or TKI monotherapy may be safely controlled with addition of either TKI or IO.
Real world use of combination anti‐angiogenic tyrosine kinase inhibitor (TKI)—anti‐PD1 immunotherapy (IO) is feasible, well tolerated and efficacious for metastatic renal cell carcinoma in the second line setting and beyond. Although further prospective research is essential to define optimal use of salvage TKI‐IO, slow disease progression on IO or TKI monotherapy may be safely controlled with addition of either a TKI or IO.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
BackgroundImmune related adverse events (irAEs) and their associated morbidity/mortality are a key concern for patients receiving immune checkpoint inhibitors (ICIs). A prospective evaluation of the ...drivers of irAEs in a diverse pan-tumor cohort is needed to identify patients at greatest risk and to develop rational interception strategies.MethodsWe prospectively collected clinical data and blood samples from patients with solid tumors at a single institution who received ICIs as standard of care. Blood samples were collected at baseline and early on treatment (month 1 or 2). We analyzed 32 circulating cytokines with Luminex multiplex assay and utilized Cytometry by Time-of-Flight (CyTOF) in an enriched cohort to investigate mechanisms of irAEs. Grade 2 or higher irAEs by CTCAE v5.0 were analyzed to enrich for clinically meaningful toxicities. Multi-testing adjustment utilizing false discovery rate (fdr) was performed for the primary cytokine time to irAE Cox analysis at baseline and early treatment.Results104 patients were prospectively enrolled. Reported race was 64.4% white, 28.8% black, and 2.9% Asian. 22.1% received combination anti-PD1/CTLA-4 therapy while 77.9% anti-PD1/PDL1 (monotherapy or in combination with other therapies). IrAEs occurred in 37.5% of the total patients with median onset of 2.1 months: 65.2% in anti-PD1/CTLA-4 (median 1.2 months) and 29.6% in anti-PD1/PDL1 groups (median of 2.9 months). Reported race was not associated with irAE development. No individual cytokine at baseline was associated with subsequent development of an irAE. In the Cox model, early fold changes in interleukin (Il)-6, Il-17f, Il-13, and Il-25 were significantly associated with the development of an irAE (table 1, adjusted p<0.05) and stratified patients by optimal cutoffs utilizing max log-rank statistics (figure 1, p<0.05). In the subgroup analysis, Il-6, Il-17f, and Il-25 were also significantly upregulated (figure 2, p<0.05) in patients who developed specific irAEs. To identify the cellular populations underlying these cytokine changes, we performed CyTOF on 15 irAE patients matched with 15 non-irAE patients by regimen and tumor type. Higher baseline proportions of two CD8+ T cell populations (CCR3+ and CCR4+), known to secrete type 2 cytokines,1 2 were associated with irAEs, while on-treatment persistent elevation of CD8+CCR4+ and peripheral expansion of effector memory Th17+ cells were associated with irAEs (figure 3, p<0.05).ConclusionsIn a diverse, pan-tumor cohort, Il-6/Il-17f related Th17 and Il-13/Il-25 related CD8+ type 2 cytokine signatures are associated with the development of irAEs, serving as possible targets for monitoring and therapeutic interventions.AcknowledgementsThe Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, F. Hoffman-La Roche Ltd., and Genentech are members of the imCORE Network.ReferencesKondo T, Takiguchi M. Human memory CCR4+CD8+ T cell subset has the ability to produce multiple cytokines. International Immunology. 2009;21:523–532.Fuschiotti P, Larregina A, Ho J, Feghali-Bostwick C, Medsger T. IL-13-producing CD8+ T cells mediate dermal fibrosis in patients with systemic sclerosis. Arthritis Rheum. 2013;65:236–246.Ethics ApprovalThis study was approved by the Johns Hopkins institution’s Ethics Board #IRB00267960.Abstract 1245 Table 1Significant cytokines in the adjusted time to irAE Cox model. HRs are reported per unit increase in fold change and were adjusted for treatment regimen used (combination anti-PD1/CTLA-4 treatment vs. anti-PD-1/PD-L1 groups). Abbreviations: HR = hazard ratioAbstract 1245 Figure 1Kaplan-Meier Curves of cumulative irAE stratified by early treatment cytokine fold changes. (A) IL-6 at cutoff 0.81, (B) II-17f at cutoff 1.4, (C) II-13 at cutoff of 1.1, (D) II-25 at cutoff of 1.6, (E) combined cytokine status. High combined cytokine status was defined as ≥2 cytokines were high, an intermediate status was defined when at least one cytokine was high, and a low status was when all four cytokines were lowAbstract 1245 Figure 2transformed early treatment fold change between patients with no irAEs and specific types of irAEs: (A) II-6, (B) II-17f, (C) II-25Abstract 1245 Figure 3Proportion of cell populations. (A) Baseline, (B) On Treatment. Abbreviations: Tc_I = CD8+CCR3+,Tc_II = CD8+CCR4+, Thi7_EM = CD4+CD45RO+RORYT+Ki67+
We report a case using combination cabozantinib plus nivolumab to salvage disease control in a patient with refractory metastatic renal cell carcinoma. The patient had previously experienced disease ...progression from high‐dose interleukin‐2, sunitinib, pazopanib, cabozantinib, and nivolumab, all given sequentially. Combination cabozantinib plus nivolumab resulted in 22 months of disease control. Vascular endothelial growth factor inhibitors including cabozantinib have immunomodulatory effects when combined with immune checkpoint inhibitors, with multiple ongoing phase III trials exploring the cabozantinib plus nivolumab combination in the first‐line setting. To our knowledge, this is the first reported case of progression on nivolumab and cabozantinib when given as sequential monotherapies but stable disease on combination cabozantinib plus nivolumab.
This case report describes a patient with refractory metastatic renal cell carcinoma treated with combination cabozantinib/nivolumab.
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