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The Oncologist; doi:10.1002/onco.13608
Background To characterize outcomes of patients with isolated brain metastases managed with local therapy followed by immune checkpoint inhibitor (ICI) therapy. Materials and Methods Patients from 4 medical centers were included if they presented with isolated brain metastases treated with local therapy, and received adjuvant treatment with ICI. Results Eleven patients with median size of largest brain metastasis of 3.9 cm, treated with surgical resection (n=8) and/or stereotactic radiosurgery (SRS; n=6) were included. Ipilimumab/nivolumab was the adjuvant ICI used in 4 patients, of which 1 recurred (25%) and none died, compared with 3 of 7 (43%) who recurred and 2 of 7 (29%) who died following adjuvant treatment with ICI monotherapy. All recurrences were intracranial. Conclusion Patients with isolated brain metastases treated with surgery or SRS appeared to benefit from adjuvant ICI, particularly with combination therapy. Recurrences in this setting appear to largely occur intracranially.
The Oncologist; doi:10.1002/onco.13609
Background The combination of everolimus (EVE) and exemestane (EXE) is approved for the treatment of metastatic hormone receptor‐positive breast cancer (mHRBC) patients who progress on non‐steroidal aromatase inhibitor (NSAI) therapy. However, none of the subjects enrolled in the trial that led to this approval (BOLERO‐2) had previously received CDK4/6 inhibitors (CDK4/6is), which have since become a frontline standard of care for mHRBC. As such, the clinical benefit of EVE + EXE in patients who have previously received CDK4/6is remains unknown. Methods Adult mHRBC patients at our institution who progressed on a NSAI + CDK4/6i or NSAI therapy alone and were treated with at least one cycle of EVE + EXE between 2012 and 2018 were analyzed. Collected data included patient demographics, treatment history, adverse events, and clinical outcomes. Primary objectives were to compare progression‐free survival (PFS) and overall survival (OS) between patients who received prior NSAI + CDK4/6i therapy versus a NSAI alone. Results Among 43 patients, 17 had prior CDK4/6i exposure. With the exception of de novo metastatic disease, patient and disease characteristics were comparable across treatment cohorts. There was no significant difference in PFS (median 3.6 vs 4.2 months) or OS (median 15.6 vs 11.3 months) between patients who had received prior CDK4/6is and those who had not, respectively. Conclusion Prior exposure to CDK4/6i therapy did not impact survival outcomes for mHRBC patients taking EVE + EXE. However, there was a trend towards improved OS in the CDK4/6i cohort that should be evaluated in larger cohorts. Implications for Practice The use of CDK4/6 inhibitors in combination with a non‐steroidal aromatase inhibitor has become a standard frontline therapy in metastatic hormone receptor‐positive breast cancer. An approved subsequent line of therapy is everolimus plus exemestane however the original data supporting this therapy predated prior of approval CDK4/6 inhibitors. As such, the clinical benefit of everolimus and exemestane in patients previously treated with a CDK4/6i was unknown. This retrospective cohort study offers real world data demonstrating prior CDK4/6 inhibitor exposure does not impact survival outcomes for everolimus plus exemestane.
The Oncologist; doi:10.1002/onco.13607
Background The prognostic implication of wild type APC (APC‐WT) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) is not well defined. Methods APC prognostic value was evaluated retrospectively in two independent cohorts of patient with MSS mCRC with a confirmatory analysis from a public data set from Memorial Sloan Kettering Cancer Center (MSKCC). Results In comparison to the APC‐mutant (APC‐MT) population (n=255), APC‐WT patients (n = 86) tended to be younger (59% of age 50), right‐sided (41.7% vs. 27%), BRAF‐V600E mutated (23.3% vs. 0.8%), and KRAS WT (65.1% vs. 49.8%). Alternative WNT pathway alterations, RNF43 and CTNNB1 were over‐represented in the APC‐WT vs APC‐MT population (7% vs 0.4% and 4.7% vs 0.4%, respectively). APC‐WT patients had a worse overall survival (OS) than APC‐MT patients (22.6 vs 45.6 months, p
The Oncologist; doi:10.1002/onco.13611
Background 5‐fluorouracil/leucovorin/oxaliplatin (FOLFOX) has activity in pancreatic NETs (pNETs), but its use is limited, partly due to toxicities. pNETs can often become aggressive over time. We evaluated the efficacy of FOLFOX in patients with aggressive pNETs who had progressed after capecitabine/temozolomide among other treatments. Methods Retrospective study of all patients with well‐differentiated metastatic pNETs treated at an academic cancer center between 1/2008 and 6/2019 who received FOLFOX and had received cap/tem in the past. Primary endpoint was objective response rate. Results 31 patients met criteria. 25 received FOLFOX and 6 received FOLFOX with bev. Patients were heavily pre‐treated, having received a median of 3 prior lines of systemic therapy prior to FOLFOX (range 1 – 8). 3 (9.7%) patients had G1 tumors, 16 (51.6%) had G2, 6 (19.4%) had G3, and grade was unspecified in 6 (19.4%). 14 (45.2%) exhibited a best response of PR per RECIST 1.1 criteria, 15 (48.4%) SD, and 2 (6.4%) PD; ORR was 45.2% and DCR was 93.5%. Median PFS was 6 months (95% CI 5.0‐7.0) and median OS was 16 months from onset of study treatment (95% CI 11.3 – 20.7); 67 months from date of diagnosis (95% CI 49.8 – 84.2). Median duration of treatment was 3 months, and median duration of response was 2 months. Toxicity profile was consistent with known adverse events associated with this regimen. Conclusions FOLFOX is active in aggressive, heavily pretreated pNETs who have progressed on prior cap/tem chemotherapy; response durations are relatively short. Implications for Practice FOLFOX chemotherapy has robust activity in patients with aggressively progressive, heavily pretreated pancreatic NETs, a setting where few, if any, other options are likely to be effective. Durations of response, however, are relatively short, and new treatments are urgently needed for patients with aggressive transformation of pancreatic NETs.
The Oncologist; doi:10.1002/onco.13597
Background Carcinoma of unknown primary origin (CUP) accounts for 2%–5% of newly diagnosed advanced malignancies, with chemotherapy as the standard of care. CUPISCO (NCT03498521) is an ongoing randomized trial using comprehensive genomic profiling (CGP) to assign patients with CUP to targeted or immunotherapy treatment arms based on genomic profiling. We performed a retrospective analysis of CUP cases referred for CGP to determine how many were potentially eligible for enrollment into an experimental CUPISCO arm. Materials and Methods Centrally reviewed adenocarcinoma and undifferentiated CUP specimens in the FoundationCore database were analyzed using the hybrid capture‐based FoundationOne CDx assay (mean coverage, >600×). Presence of genomic alterations, microsatellite instability (MSI), tumor mutational burden (TMB), genomic loss of heterozygosity (gLOH), and programmed death‐ligand 1 (PD‐L1) positivity were determined. Results A total of 96 of 303 patients (31.7%) could be matched to an experimental CUPISCO arm. Key genomic alterations included ERBB2 (7.3%), PIK3CA (6.3%), NF1 (5.6%), NF2 (4.6%), BRAF (4.3%), IDH1 (3.3%), PTEN, FGFR2, EGFR (3.6% each), MET (4.3%), CDK6 (3.0%), FBXW7, CDK4 (2.3% each), IDH2, RET, ROS1, NTRK (1.0% each), and ALK (0.7%). Median TMB was 3.75 mutations per megabyte of DNA; 34 patients (11.6%) had a TMB greater or equal to 16 mutations per megabyte. Three patients (1%) had high MSI, and 42 (14%) displayed high PD‐L1 expression (tumor proportion score ≥50%). gLOH could be assessed in 199 or 303 specimens; 19.6% had a score of >16%. Conclusions Thirty‐two percent of patients would have been eligible for targeted therapy in CUPISCO. Future studies, including additional biomarkers such as PD‐L1 positivity and gLOH, may identify a greater proportion potentially benefiting from CGP‐informed treatment. Clinical trial identification number. NCT03498521 Implications for Practice The findings of this retrospective analysis of carcinoma of unknown primary origin (CUP) cases validate the experimental treatment arms being used in the CUPISCO study (NCT03498521), an ongoing randomized trial using comprehensive genomic profiling to assign patients with CUP to targeted or immunotherapy treatment arms based on the presence of pathogenic genomic alterations. The findings also suggest that future studies including additional biomarkers and treatment arms, like programmed death‐ligand 1 positivity and genomic loss of heterozygosity, may identify a greater proportion of patients with CUP potentially benefiting from comprehensive genomic profiling‐informed treatment.
The Oncologist; doi:10.1002/onco.13605
The Oncologist; doi:10.1002/onco.13603
The Oncologist; doi:10.1002/onco.13601
Background Genomic biomarkers that predict response to anti‐PD1 therapy in prostate cancer are needed. Frameshift mutations are predicted to generate more neoantigens than missense mutations; therefore, we hypothesized that the number or proportion of tumor frameshift mutations would correlate with response to anti‐PD1 therapy in prostate cancer. Methods To enrich for response to anti‐PD1 therapy, we assembled a multi‐center cohort of 65 men with mismatch repair‐deficient (dMMR) prostate cancer. Patient characteristics and outcomes were determined by retrospective chart review. Clinical somatic DNA sequencing was used to determine tumor mutational burden (TMB), frameshift mutation burden (FSB) and frameshift mutation proportion (FSP), which were correlated to outcomes on anti‐PD1 treatment. We subsequently utilized data from a clinical trial of pembrolizumab in patients with non‐prostatic dMMR cancers of various histologies as a biomarker validation cohort. Results Nineteen of 65 patients with dMMR metastatic castration‐resistant prostate cancer were treated with anti‐PD1 therapy and demonstrated a PSA50 response rate of 65% and a median progression‐free survival (PFS) of 24 (95%CI, 16‐54) weeks. Tumor FSP, more than overall TMB, correlated most strongly with prolonged PFS and overall survival (OS) on anti‐PD1 treatment, and with density of CD8+ tumor infiltrating lymphocytes. High FSP similarly identified patients with longer PFS as well as OS on anti‐PD1 therapy in a validation cohort. Conclusions Tumor FSP correlated with prolonged efficacy of anti‐PD1 treatment among patients with dMMR cancers, and may represent a new biomarker of immune checkpoint inhibitor sensitivity. Implications for Practice Given the modest efficacy of immune checkpoint inhibition (ICI) in unselected patients with advanced prostate cancer, biomarkers of ICI sensitivity are needed. To facilitate biomarker discovery, we assembled a cohort of patients with DNA mismatch repair‐deficient (dMMR) prostate cancer as these patients are enriched for responses to ICI. We observed a high response rate to anti‐PD1 therapy in these patients, however these responses were not durable in most patients. Notably, we identified tumor frameshift mutation proportion (FSP) as a novel biomarker that was associated with prolonged response to anti‐PD1 therapy in this cohort. This finding was validated in a separate cohort of patients with non‐prostatic dMMR cancers of various primary histologies. This works suggests that FSP predicts response to anti‐PD1 therapy in dMMR cancers, which should be validated prospectively in larger independent cohorts.
The Oncologist; doi:10.1002/onco.13599
The Oncologist; doi:10.1002/onco.13572