A phase 2, single-arm trial evaluating 131I-PSMA-1095 targeted radioligand therapy for metastatic castration-resistant prostate cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) remains uniformly lethal. Prostate specific membrane antigen (PSMA) is a transmembrane glycoprotein overexpressed in prostate cancer. 131I-PSMA-1095 (also known as 131I-MIP-1095) is a PSMA-targeted radioligand which selectively delivers therapeutic radiation to cancer cells and the tumor microenvironment. METHODS: We conducted a single-arm, phase 2 trial to assess efficacy and tolerability of 131I-PSMA-1095 in mCRPC patients who had exhausted all lines of approved therapy. All patients underwent 18F-DCFPyL PET and 18F-FDG PET to determine PSMA-positive tumor volume, and patients with >50% PSMA-positive tumor volume were treated with up to four doses of 131I-PSMA-1095. The primary endpoint was the response rate of prostate specific antigen (PSA). Secondary endpoints included rates of radiographic response and adverse events. Overall and radiographic progression-free survival were also analyzed. RESULTS: Eleven patients were screened for inclusion and nine patients received 131I-PSMA-1095. The median baseline PSA was 162 µg/l, and six patients demonstrated a >50% PSA decrease. One patient demonstrated a confirmed radiographic response. Median overall survival was 10.3 months, and median progression-free survival was 5.4 months. Four patients experienced adverse events of grade 3 or higher, the most frequent being thrombocytopenia and anemia. CONCLUSION: 131I-PSMA-1095 is highly active against heavily-pretreated PSMA-positive mCRPC, significantly decreasing tumor burden as measured by PSA. Adverse events, mainly hematologic toxicity, were not infrequent, likely related to off-target irradiation. This hematologic toxicity, as well as a higher logistical burden associated with use, could represent relative disadvantages of 131I-PSMA-1095 compared to 177Lu-PSMA-617.

Osimertinib is associated with improved outcomes in pre-treated non-small cell lung cancer leptomeningeal metastases: A systematic review and meta-analysiss.

Purpose: Leptomeningeal metastasis (LM) is a severe complication of non-small cell lung cancer (NSCLC). In patients with NSCLC LM harboring epidermal growth factor receptor (EGFR) mutations, osimertinib is favored over alternative EGFR tyrosine kinase inhibitors (TKIs). However, the efficacy of osimertinib relative to other EGFR-TKIs is not well established for patients with LM. We aimed to compare the efficacy of EGFR-TKIs in EGFR-mutated NSCLC LM. Methods: This systematic review and meta-analysis performed according to PRISMA guidelines included studies of adult patients with EGFR-mutated NSCLC and a diagnosis of LM who received an EGFR-TKI for the treatment of LM. We searched Medline ALL, Embase, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science Core Collection. The evaluation of biases was done by using the Ottawa-Newscastle scale. The hazard ratio was used as the parameter of interest for overall survival (OS) and central nervous system-specific progression-free survival (PFS). Results: 128 publications were included with 243 patients and 282 lines of EGFR-TKI for NSCLC LM that met inclusion criteria. The median PFS in patients receiving any EGFR-TKI was 9.1 months, and the median OS was 14.5 months. In univariate analyses of the entire cohort, osimertinib treatment demonstrated significantly prolonged PFS, but not OS, compared to other EGFR-TKIs. Osimertinib demonstrated significantly prolonged PFS and OS in the subset of patients who were previously treated with EGFR-TKIs, but not in EGFR-TKI naïve patients. Conclusion: Osimertinib is associated with improved outcomes compared to other EGFR-TKIs, particularly in patients previously treated with EGFR-TKIs. An important limitation is that most patients were derived from retrospective reports. These results highlight the need for prospective studies for this difficult-to-treat patient population.

Clinical variables associated with immune checkpoint inhibitor outcomes in patients with metastatic urothelial carcinoma: a multicentre retrospective cohort study.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) are indicated for metastatic urothelial cancer (mUC), but predictive and prognostic factors are lacking. We investigated clinical variables associated with ICI outcomes. METHODS: We performed a multicentre retrospective cohort study of 135 patients who received ICI for mUC, 2016-2021, at three Canadian centres. Clinical characteristics, body mass index (BMI), metastatic sites, neutrophil-to-lymphocyte ratio (NLR), response and survival were abstracted from chart review. RESULTS: We identified 135 patients and 62% had received ICI as a second-line or later treatment for mUC. A BMI ≥25 was significantly correlated to a higher overall response rate (ORR) (45.4% vs 16.3%, p value=0.020). Patients with BMI ≥30 experienced longer median overall survival (OS) of 24.8 vs 14.4 for 25≤BMI<30 and 8.5 months for BMI <25 (p value=0.012). The ORR was lower in the presence of bone metastases (16% vs 41%, p value=0.006) and liver metastases (16% vs 39%, p value=0.013). Metastatic lymph nodes were correlated with higher ORR (40% vs 20%, p value=0.032). The median OS for bone metastases was 7.3 versus 18 months (p value <0.001). Patients with liver metastases had a median OS of 8.6 versus 15 months (p value=0.006). No difference for lymph nodes metastases (13.5 vs 12.7 months, p value=0.175) was found. NLR ≥4 had worse OS (8.2 vs 17.7 months, p value=0.0001). In multivariate analysis, BMI ≥30, bone metastases, NLR ≥4, performance status ≥2 and line of ICI ≥2 were independent factors for OS. CONCLUSIONS: Our data identified BMI and bone metastases as novel clinical biomarkers that were independently associated with ICI outcomes in mUC. External and prospective validation are warranted.

The role of CRAF in cancer progression: from molecular mechanisms to precision therapies.

The RAF family of kinases includes key activators of the pro-tumourigenic mitogen-activated protein kinase pathway. Hyperactivation of RAF proteins, particularly BRAF and CRAF, drives tumour progression and drug resistance in many types of cancer. Although BRAF is the most studied RAF protein, partially owing to its high mutation incidence in melanoma, the role of CRAF in tumourigenesis and drug resistance is becoming increasingly clinically relevant. Here, we summarize the main known regulatory mechanisms and gene alterations that contribute to CRAF activity, highlighting the different oncogenic roles of CRAF, and categorize RAF1 (CRAF) mutations according to the effect on kinase activity. Additionally, we emphasize the effect that CRAF alterations may have on drug resistance and how precision therapies could effectively target CRAF-dependent tumours. Here, we discuss preclinical and clinical findings that may lead to improved treatments for all types of oncogenic RAF1 alterations in cancer.

The Clinical, Genomic, and Transcriptomic Landscape of BRAF Mutant Cancers.

BACKGROUND: BRAF mutations are classified into four molecularly distinct groups, and Class 1 (V600) mutant tumors are treated with targeted therapies. Effective treatment has not been established for Class 2/3 or BRAF Fusions. We investigated whether BRAF mutation class differed according to clinical, genomic, and transcriptomic variables in cancer patients. METHODS: Using the AACR GENIE (v.12) cancer database, the distribution of BRAF mutation class in adult cancer patients was analyzed according to sex, age, primary race, and tumor type. Genomic alteration data and transcriptomic analysis was performed using The Cancer Genome Atlas. RESULTS: BRAF mutations were identified in 9515 (6.2%) samples among 153,834, with melanoma (31%), CRC (20.7%), and NSCLC (13.9%) being the most frequent cancer types. Class 1 harbored co-mutations outside of the MAPK pathway (TERT, RFN43) vs. Class 2/3 mutations (RAS, NF1). Across all tumor types, Class 2/3 were enriched for alterations in genes involved in UV response and WNT/ß-catenin. Pathway analysis revealed enrichment of WNT/ß-catenin and Hedgehog signaling in non-V600 mutated CRC. Males had a higher proportion of Class 3 mutations vs. females (17.4% vs. 12.3% q = 0.003). Non-V600 mutations were generally more common in older patients (aged 60+) vs. younger (38% vs. 15% p < 0.0001), except in CRC (15% vs. 30% q = 0.0001). Black race was associated with non-V600 BRAF alterations (OR: 1.58; p < 0.0001). CONCLUSIONS: Class 2/3 BRAFs are more present in Black male patients with co-mutations outside of the MAPK pathway, likely requiring additional oncogenic input for tumorigenesis. Improving access to NGS and trial enrollment will help the development of targeted therapies for non-V600 BRAF mutations.

Analysis of the Circulating Metabolome of Patients with Cutaneous, Mucosal and Uveal Melanoma Reveals Distinct Metabolic Profiles with Implications for Response to Immunotherapy.

Cutaneous melanoma (CM) patients respond better to immune checkpoint inhibitors (ICI) than mucosal and uveal melanoma patients (MM/UM). Aiming to explore these differences and understand the distinct response to ICI, we evaluated the serum metabolome of advanced CM, MM, and UM patients. Levels of 115 metabolites were analyzed in samples collected before ICI, using a targeted metabolomics platform. In our analysis, molecules involved in the tryptophan-kynurenine axis distinguished UM/MM from CM. UM/MM patients had higher levels of 3-hydroxykynurenine (3-HKyn), whilst patients with CM were found to have higher levels of kynurenic acid (KA). The KA/3-HKyn ratio was significantly higher in CM versus the other subtypes. UM, the most ICI-resistant subtype, was also associated with higher levels of sphingomyelin-d18:1/22:1 and the polyamine spermine (SPM). Overall survival was prolonged in a cohort of CM patients with lower SPM levels, suggesting there are also conserved metabolic factors promoting ICI resistance across melanoma subtypes. Our study revealed a distinct metabolomic profile between the most resistant melanoma subtypes, UM and MM, compared to CM. Alterations within the kynurenine pathway, polyamine metabolism, and sphingolipid metabolic pathway may contribute to the poor response to ICI. Understanding the different metabolomic profiles introduces opportunities for novel therapies with potential synergic activity to ICI, to improve responses of UM/MM.

Intrathecal trastuzumab versus alternate routes of delivery for HER2-targeted therapies in patients with HER2+ breast cancer leptomeningeal metastases.

BACKGROUND: Patients with HER2+ breast cancer (BC) frequently develop leptomeningeal metastases (LM). While HER2-targeted therapies have demonstrated efficacy in the neoadjuvant, adjuvant, and metastatic settings, including for parenchymal brain metastases, their efficacy for patients with LM has not been studied in a randomized controlled trial. However, several single-armed prospective studies, case series and case reports have studied oral, intravenous, or intrathecally administered HER2-targeted therapy regimens for patients with HER2+ BC LM. METHODS: We conducted a systematic review and meta-analysis of individual patient data to evaluate the efficacy of HER2-targeted therapies in HER2+ BC LM in accordance with PRISMA guidelines. Targeted therapies evaluated were trastuzumab (intrathecal or intravenous), pertuzumab, lapatinib, neratinib, tucatinib, trastuzumab-emtansine and trastuzumab-deruxtecan. The primary endpoint was overall survival (OS), with CNS-specific progression-free survival (PFS) as a secondary endpoint. RESULTS: 7780 abstracts were screened, identifying 45 publications with 208 patients, corresponding to 275 lines of HER2-targeted therapy for BC LM which met inclusion criteria. In univariable and multivariable analyses, we observed no significant difference in OS and CNS-specific PFS between intrathecal trastuzumab compared to oral or intravenous administration of HER2-targeted therapy. Anti-HER2 monoclonal antibody-based regimens did not demonstrate superiority over HER2 tyrosine kinase inhibitors. In a cohort of 15 patients, treatment with trastuzumab-deruxtecan was associated with prolonged OS compared to other HER2-targeted therapies and compared to trastuzumab-emtansine. CONCLUSIONS: The results of this meta-analysis, comprising the limited data available, suggest that intrathecal administration of HER2-targeted therapy for patients with HER2+ BC LM confers no additional benefit over oral and/or IV treatment regimens. Although the number of patients receiving trastuzumab deruxtecan in this cohort is small, this novel agent offers promise for this patient population and requires further investigation in prospective studies.

Inhibition of the MNK1/2-eIF4E Axis Augments Palbociclib-Mediated Antitumor Activity in Melanoma and Breast Cancer.

Aberrant cell-cycle progression is characteristic of melanoma, and CDK4/6 inhibitors, such as palbociclib, are currently being tested for efficacy in this disease. Despite the promising nature of CDK4/6 inhibitors, their use as single agents in melanoma has shown limited clinical benefit. Herein, we discovered that treatment of tumor cells with palbociclib induces the phosphorylation of the mRNA translation initiation factor eIF4E. When phosphorylated, eIF4E specifically engenders the translation of mRNAs that code for proteins involved in cell survival. We hypothesized that cancer cells treated with palbociclib use upregulated phosphorylated eIF4E (phospho-eIF4E) to escape the antitumor benefits of this drug. Indeed, we found that pharmacologic or genetic disruption of MNK1/2 activity, the only known kinases for eIF4E, enhanced the ability of palbociclib to decrease clonogenic outgrowth. Moreover, a quantitative proteomics analysis of melanoma cells treated with combined MNK1/2 and CDK4/6 inhibitors showed downregulation of proteins with critical roles in cell-cycle progression and mitosis, including AURKB, TPX2, and survivin. We also observed that palbociclib-resistant breast cancer cells have higher basal levels of phospho-eIF4E, and that treatment with MNK1/2 inhibitors sensitized these palbociclib-resistant cells to CDK4/6 inhibition. In vivo we demonstrate that the combination of MNK1/2 and CDK4/6 inhibition significantly increases the overall survival of mice compared with either monotherapy. Overall, our data support MNK1/2 inhibitors as promising drugs to potentiate the antineoplastic effects of palbociclib and overcome therapy-resistant disease.

The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor-resistant ER+ breast cancer with mitotic aberrations.

Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are standard first-line treatments for metastatic ER+ breast cancer. However, acquired resistance to CDK4/6i invariably develops, and the molecular phenotypes and exploitable vulnerabilities associated with resistance are not yet fully characterized. We developed a panel of CDK4/6i-resistant breast cancer cell lines and patient-derived organoids and demonstrate that a subset of resistant models accumulates mitotic segregation errors and micronuclei, displaying increased sensitivity to inhibitors of mitotic checkpoint regulators TTK and Aurora kinase A/B. RB1 loss, a well-recognized mechanism of CDK4/6i resistance, causes such mitotic defects and confers enhanced sensitivity to TTK inhibition. In these models, inhibition of TTK with CFI-402257 induces premature chromosome segregation, leading to excessive mitotic segregation errors, DNA damage, and cell death. These findings nominate the TTK inhibitor CFI-402257 as a therapeutic strategy for a defined subset of ER+ breast cancer patients who develop resistance to CDK4/6i.

Clinical Activity of Mitogen-Activated Protein Kinase-Targeted Therapies in Patients With Non-V600 BRAF-Mutant Tumors.

PURPOSE: Non-V600 mutations comprise approximately 35% of all BRAF mutations in cancer. Many of these mutations have been identified as oncogenic drivers and can be classified into three classes according to molecular characteristics. Consensus treatment strategies for class 2 and 3 BRAF mutations have not yet been established. METHODS: We performed a systematic review and meta-analysis with published reports of individual patients with cancer harboring class 2 or 3 BRAF mutations from 2010 to 2021, to assess treatment outcomes with US Food and Drug Administration-approved mitogen-activated protein kinase (MAPK) pathway targeted therapy (MAPK TT) according to BRAF class, cancer type, and MAPK TT type. Coprimary outcomes were response rate and progression-free survival. RESULTS: A total of 18,167 studies were screened, identifying 80 studies with 238 patients who met inclusion criteria. This included 167 patients with class 2 and 71 patients with class 3 BRAF mutations. Overall, 77 patients achieved a treatment response. In both univariate and multivariable analyses, response rate and progression-free survival were higher among patients with class 2 compared with class 3 mutations, findings that remain when analyses are restricted to patients with melanoma or lung primary cancers. MEK ± BRAF inhibitors demonstrated greater clinical activity in class 2 compared with class 3 BRAF-mutant tumors than BRAF or EGFR inhibitors. CONCLUSION: This meta-analysis suggests that MAPK TTs have clinical activity in some class 2 and 3 BRAF-mutant cancers. BRAF class may dictate responsiveness to current and emerging treatment strategies, particularly in melanoma and lung cancers. Together, this analysis provides clinical validation of predictions made on the basis of a mutation classification system established in the preclinical literature. Further evaluation with prospective clinical trials is needed for this population.

Pegylated Liposomal Doxorubicin and Kidney-Limited Thrombotic Microangiopathy in a Kidney Transplant Recipient: A Case Report.

A 64-year-old man with Kaposi sarcoma in clinical remission after treatment with pegylated liposomal doxorubicin and a history of deceased-donor kidney transplantation 4 years prior presented with a slowly progressive increase in his serum creatinine level, well-controlled hypertension, stable subnephrotic-range proteinuria, and bland urinary sediment. An allograft kidney biopsy demonstrated thrombotic microangiopathy, without clinical or laboratory features of systemic involvement. Based on the timing of drug initiation preceding thrombotic microangiopathy, complete recovery after drug withdrawal, and the absence of other etiologies, it was concluded that pegylated liposomal doxorubicin was the likely cause of kidney-limited thrombotic microangiopathy. When pegylated liposomal doxorubicin was resumed, the patient developed hypertension and kidney allograft dysfunction. A new kidney biopsy was not performed because of the overall risk benefit. The case highlights the importance of recognizing novel etiologies of thrombotic microangiopathy in kidney transplant patients with malignancy. Although Kaposi sarcoma has not been linked to thrombotic microangiopathy, pegylated liposomal doxorubicin has been increasingly associated with drug-induced thrombotic microangiopathy. To our knowledge, this is the first case report that etiologically links pegylated liposomal doxorubicin to kidney-limited thrombotic microangiopathy in a kidney transplant patient.

Melanomas with concurrent BRAF non-p.V600 and NF1 loss-of-function mutations are targetable by BRAF/MEK inhibitor combination therapy.

Although combination BRAF/MEK inhibition has produced significant survival benefits for BRAF p.V600 mutant melanomas, targeted therapies approved for BRAF non-p.V600 mutant melanomas remain limited. Through the analysis of 772 cutaneous melanoma exomes, we reveal that BRAF non-p.V600 mutations co-occurs more frequently with NF1 loss, but not with oncogenic NRAS mutations, than expected by chance. We present cell signaling data, which demonstrate that BRAF non-p.V600 mutants can signal as monomers and dimers within an NF1 loss context. Concordantly, BRAF inhibitors that inhibit both monomeric and dimeric BRAF synergize with MEK inhibition to significantly reduce cell viability in vitro and tumor growth in vivo in BRAF non-p.V600 mutant melanomas with co-occurring NF1 loss-of-function mutations. Our data suggest that patients harboring BRAF non-p.V600 mutant melanomas may benefit from current FDA-approved BRAF/MEK inhibitor combination therapy currently reserved for BRAF p.V600 mutant patients.

HSP90 inhibitors induce GPNMB cell-surface expression by modulating lysosomal positioning and sensitize breast cancer cells to glembatumumab vedotin.

Transmembrane glycoprotein NMB (GPNMB) is a prognostic marker of poor outcome in patients with triple-negative breast cancer (TNBC). Glembatumumab Vedotin, an antibody drug conjugate targeting GPNMB, exhibits variable efficacy against GPNMB-positive metastatic TNBC as a single agent. We show that GPNMB levels increase in response to standard-of-care and experimental therapies for multiple breast cancer subtypes. While these therapeutic stressors induce GPNMB expression through differential engagement of the MiTF family of transcription factors, not all are capable of increasing GPNMB cell-surface localization required for Glembatumumab Vedotin inhibition. Using a FACS-based genetic screen, we discovered that suppression of heat shock protein 90 (HSP90) concomitantly increases GPNMB expression and cell-surface localization. Mechanistically, HSP90 inhibition resulted in lysosomal dispersion towards the cell periphery and fusion with the plasma membrane, which delivers GPNMB to the cell surface. Finally, treatment with HSP90 inhibitors sensitizes breast cancers to Glembatumumab Vedotin in vivo, suggesting that combination of HSP90 inhibitors and Glembatumumab Vedotin may be a viable treatment strategy for patients with metastatic TNBC.

Development of a Metastatic Uveal Melanoma Prognostic Score (MUMPS) for Use in Patients Receiving Immune Checkpoint Inhibitors.

Metastatic uveal melanoma (mUM) is a rare disease. There are limited data on prognostic clinical factors for overall survival (OS) in patients with mUM treated with immune checkpoint inhibitors (ICI). Retrospective and non-randomized prospective studies have reported response rates of 0-17% for anti-PD1/L1 ± anti-CTLA4 ICI in mUM, indicating a potential benefit only in a subset of patients. This study evaluates the characteristics associated with ICI benefit in patients with mUM. We performed a single-center retrospective cohort study of patients with mUM who received anti-PD1/L1 ± anti-CTLA4 ICI between 2014-2019. Clinical and genomic characteristics were collected from a chart review. Treatment response and clinical progression were determined by physician assessment. Multivariable Cox regression models and Kaplan-Meier log-rank tests were used to assess differences in clinical progression-free survival (cPFS) and OS between groups and identify clinical variables associated with ICI outcomes. We identified 71 mUM patients who received 75 lines of ICI therapy. Of these, 54 received anti-PD1/L1 alone, and 21 received anti-PD1/L1 + anti-CTLA4. Patient characteristics were: 53% female, 48% were 65 or older, 72% received one or fewer lines of prior therapy. Within our cohort, 53% of patients had developed metastatic disease <2 years after their initial diagnosis. Bone metastases were present in 12% of patients. The median cPFS was 2.7 months, and the median OS was 10.0 months. In multivariable analyses for both cPFS and OS, the following variables were associated with a good prognosis: ≥2 years from the initial diagnosis to metastatic disease (n = 25), LDH < 1.5 × ULN (n = 45), and absence of bone metastases (n = 66). We developed a Metastatic Uveal Melanoma Prognostic Score (MUMPS). Patients were divided into 3 MUMPS groups based on the number of the above-mentioned prognostic variables: Poor prognosis (0-1), Intermediate prognosis (2) and Good prognosis (3). Good prognosis patients experienced longer cPFS (6.0 months) and OS (34.5 months) than patients with intermediate (2.3 months cPFS, 9.4 months OS) and poor prognosis disease (1.8 months cPFS, 3.9 months OS); p < 0.0001. We developed MUMPS-a prognostic score based on retrospective data that is comprised of 3 readily available clinical variables (time to metastatic diagnosis, presence of bone metastases, and LDH). This MUMPS score has a potential prognostic value. Further validation in independent datasets is warranted to determine the role of this MUMPS score in selecting ICI treatment management for mUM.

Genomic Landscape of Malignant Peripheral Nerve Sheath Tumor‒Like Melanoma.

Malignant peripheral nerve sheath tumor (MPNST)-like melanoma is a rare malignancy with overlapping characteristics of both neural sarcoma and melanoma. Although the genomics of cutaneous melanoma has been extensively studied, those of MPNST-like melanoma have not. To characterize the genomic landscape of MPNST-like melanoma, we performed a single-center, retrospective cohort study at a tertiary academic cancer center. Consecutive patients with a confirmed histologic diagnosis of MPNST-like melanoma were screened, and those whose tissues were locally available were included in this analysis. Archival tissue from six patients (eight samples) was submitted for whole-exome and transcriptome sequencing analysis. We compared these data with available genomic studies of cutaneous melanoma and MPNST. NF1 was altered (mutated, deleted, or amplified) in 67% of patients. Genes related to cell cycle regulation were frequently altered, with frequent deletion of ZNF331, which, to the best of our knowledge, has not been previously described in cutaneous melanoma. The serine protease inhibitor SERPINB4 was deleted in 100% of the patients. We show that MPNST-like melanoma presents overlapping genomic features with cutaneous melanoma and MPNST, but it is unique by the frequency of loss of function of ZNF331 and SERPINB4.

Biologic subtypes of melanoma predict survival benefit of combination anti-PD1+anti-CTLA4 immune checkpoint inhibitors versus anti-PD1 monotherapy.

PURPOSE: Anti-programmed cell death protein 1 (PD1)±anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) immune checkpoint inhibitors (ICIs) are standard therapeutic options for metastatic melanoma. We assessed whether biologic subtype according to primary tumor type or genomic subtype can function as predictive biomarkers for anti-PD1±anti-CTLA4 ICI in patients with advanced melanoma. METHODS: We performed a single-center retrospective cohort analysis of patients who received anti-PD1±anti-CTLA4 ICI for advanced melanoma between 2012 and 2019. Primary tumor type, BRAF and NRAS mutation status, and other covariates were abstracted from chart review. Log-rank tests and multivariable Cox regression models were used to assess differences in clinical progression-free (cPFS) and overall survival (OS). RESULTS: We identified 230 patients who received 249 lines of anti-PD1±anti-CTLA4 ICI for unresectable or metastatic disease. Of these patients, 74% were cutaneous, 11% mucosal, 8% unknown primary and 7% acral. BRAF and NRAS mutations were identified in 35% and 28% of patients, respectively. In multivariable analyses of the entire cohort, acral or mucosal primary tumor type, >3 metastatic sites, elevated LDH were predictive of shorter cPFS and OS. Combination ICI therapy was associated with longer cPFS (HR 0.57, 95% CI 0.38 to 0.86, p=0.007) and OS (HR 0.42, 95% CI 0.28 to 0.65, p<0.001). Combination ICI was significantly associated with longer OS in unknown primary and mucosal melanoma. There was a non-significant trend toward longer OS with anti-PD1+anti-CTLA4 in cutaneous melanoma, but not in acral melanoma. In multivariable analyses, combination ICI was associated with longer OS in NRAS (HR 0.24, 95% CI 0.10 to 0.62, p=0.003, n=69) and BRAF V600E/K (HR 0.47, 95% CI 0.24 to 0.90, p=0.024, n=86) mutant melanoma but not BRAF/NRAS wild-type (n=94) melanoma. CONCLUSIONS: In our cohort, primary melanoma tumor type and genomic subtype were independent predictive markers of cPFS and OS for patients with metastatic melanoma receiving anti-PD1 ICI. Primary tumor type and genomic subtype-including NRAS-should be further evaluated in prospective clinical trials to determine their value as predictive markers. Biologic subtypes may facilitate clinical decision-making when recommending combination ICI treatment (anti-PD1±anti-CTLA4) versus anti-PD1 alone for patients with metastatic melanoma.

Clinical impact of COVID-19 on patients with cancer treated with immune checkpoint inhibition.

BACKGROUND: Patients with cancer who are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more likely to develop severe illness and die compared with those without cancer. The impact of immune checkpoint inhibition (ICI) on the severity of COVID-19 illness is unknown. The aim of this study was to investigate whether ICI confers an additional risk for severe COVID-19 in patients with cancer. METHODS: We analyzed data from 110 patients with laboratory-confirmed SARS-CoV-2 while on treatment with ICI without chemotherapy in 19 hospitals in North America, Europe and Australia. The primary objective was to describe the clinical course and to identify factors associated with hospital and intensive care (ICU) admission and mortality. FINDINGS: Thirty-five (32%) patients were admitted to hospital and 18 (16%) died. All patients who died had advanced cancer, and only four were admitted to ICU. COVID-19 was the primary cause of death in 8 (7%) patients. Factors independently associated with an increased risk for hospital admission were ECOG ≥2 (OR 39.25, 95% CI 4.17 to 369.2, p=0.0013), treatment with combination ICI (OR 5.68, 95% CI 1.58 to 20.36, p=0.0273) and presence of COVID-19 symptoms (OR 5.30, 95% CI 1.57 to 17.89, p=0.0073). Seventy-six (73%) patients interrupted ICI due to SARS-CoV-2 infection, 43 (57%) of whom had resumed at data cut-off. INTERPRETATION: COVID-19-related mortality in the ICI-treated population does not appear to be higher than previously published mortality rates for patients with cancer. Inpatient mortality of patients with cancer treated with ICI was high in comparison with previously reported rates for hospitalized patients with cancer and was due to COVID-19 in almost half of the cases. We identified factors associated with adverse outcomes in ICI-treated patients with COVID-19.

Increasing Referrals of Patients With Gastrointestinal Cancer to a Cancer Rehabilitation Program: A Quality Improvement Initiative.

BACKGROUND: People with cancer are at risk for initial, late, and long-term effects of cancer and its treatments. Cancer rehabilitation (CR) focuses on prevention/treatment of these sequelae and optimization of physical, social, and vocational functioning. Our center has a multidisciplinary impairment-driven outpatient CR program, but referrals of patients with GI cancer were low. AIMS: We aimed (for 2019, relative to 2018) (1) to increase CR referrals of patients with GI cancer by 50% and (2) to increase the proportion of referrals coming from oncologists. Balancing measures included inappropriate referrals and cancellations. METHODS: A rapid cycle improvement approach was used to optimize GI referrals to the CR program. Barriers to CR referral were identified through a literature review and informal interviews of GI clinicians. Barriers included (a) knowledge of CR program existence, (b) awareness of the referral process, (c) time, and (d) lack of CR program exposure. The team used Plan-Do-Study-Act (PDSA) cycles every 2 months from January to December 2019 to address barriers. A p-chart was used to analyze the results. RESULTS: PDSA cycles included CR program advertisement, a presentation to GI staff, nurse-led patient identification, patient-facing posters, and clinician thank-you emails. The p-chart showed a 100% relative increase in referral numbers and an improvement in the percentage of patients referred by oncologists from 51% to 75%. There was no significant change in inappropriate referrals or cancellations. CONCLUSION: Through PDSA cycles, we improved the total number of patients with GI cancer and percentage referred by an oncologist to a CR program. Future work will assess sustainability.