Advanced Solid Organ Malignancies Research Articles

Genomic Landscape of Advanced Solid Tumors in Middle East and North Africa Using Circulating Tumor DNA in Routine Clinical Practice

Introduction: Next-generation sequencing (NGS) of tumor DNA can detect actionable drivers and help guide therapy for patients with advanced-stage cancers. While tissue-based genotyping is considered a standard of care, blood-based genotyping is emerging as a valid alternative. Tumor genomic profiles may vary by region, and data from the Middle East and North Africa (MENA) are not widely available. This study elucidates the genomic landscape of advanced solid cancers in patients from the MENA region by retrospectively analyzing results from NGS circulating tumor DNA (ctDNA) testing. Methods: In routine clinical practice, 926 plasma samples from 767 patients with advanced cancers from the MENA region were profiled using a comprehensive NGS assay (Guardant360®). We conducted a pan-cancer analysis and sub-analyses focusing on lung, breast, and colorectal cancers. Results: In the pan-cancer group, TP53 (58.5%), EGFR (20.4%), and KRAS (18.9%) were the most frequently mutated genes. EGFR (10.2%), FGFR1 (4.9%), and PIK3CA (4.9%) showed the most amplifications, while fusions were observed in 2.7% of patients, including ALK, FGFR2, and RET. For lung adenocarcinoma, EGFR (30.5%), KRAS (19.3%), and ERBB2 (4.6%) were the most frequently identified alterations among the genes recommended for evaluation by the National Comprehensive Cancer Network (NCCN). In patients with breast cancer, PIK3CA (35.3%), ESR1 (21.7%), and BRCA1/2 (13.3%) had the most prevalent alterations among NCCN-recommended genes. In colorectal cancer, KRAS (39.0%), NRAS (8.0%), and BRAF (V600E, 4.0%) were the most observed mutations among genes recommended by the NCCN. Comparing this cohort to publicly available Western and Eastern datasets also indicated similarities (including PIK3CA in breast cancer) and variances (including EGFR in lung adenocarcinoma) in key genes of interest in the analyzed cancer types. Conclusion: Overall, our findings provide insight into the genomic landscape of individuals with advanced solid organ malignancies from the MENA region and support the role of ctDNA in guiding therapeutic decisions.

Five-year survival and clinical correlates among patients with advanced non-small cell lung cancer, melanoma and renal cell carcinoma treated with immune check-point inhibitors in Australian tertiary oncology centres.

There is robust trial evidence for improved overall survival (OS) with immunotherapy in advanced solid organ malignancies. The real-world long-term survival data and the predictive variables are not yet known. Our aim was to evaluate factors associated with 3-year and 5-year OS for patients treated with immune checkpoint inhibitors (ICIs). We performed a retrospective study of patients who received ICIs as management of advanced solid organ malignancies in two tertiary Australian oncology centres from 2012-2017. Data pertaining to clinical characteristics, metastatic disease burden, immune-related adverse events (IRAEs) and tumour responses were collected and their relationship to survival examined. In this analysis of 264 patients, 202 (76.5%) had melanoma, 46 (17.4%) had non-small cell lung cancer (NSCLC), 12 (4.5%) had renal cell carcinoma (RCC) and 4 (1.5%) had mesothelioma. The 5-year OS rates were 42.1% in patients with melanoma, 19.6% with NSCLC, 75% with RCC, and none of the mesothelioma patients were alive at 5 years. In multivariate analysis, an ECOG score of 0 (Hazard ratio [HR] 0.39; 95% confidence interval [CI] 0.23-0.66; p < 0.001) and the occurrence of IRAE's of any grade (HR 0.61; 95% CI 0.37-0.95; p=0.05) were associated with better 5-year survival. The presence of bone metastases (HR 1.62; 95% CI 1.03-2.82; p=0.05) and liver metastases (HR 1.76; 95% CI 1.07-2.89; p=0.03) were associated with worse 5-year survival. These results support the long-term benefits of immunotherapy that in some patients, extend to at least 5 years. ECOG performance status of 0 and the occurrence of irAEs are associated with better long-term survival. Survival is significantly influenced by metastatic site and cancer type. These predictive clinical correlates aid discussions and planning in the delivery of ICIs to patients.

Impact of travel distance on outcomes for clinical trial patients: the Kinghorn Cancer Centre experience.

Geographic isolation and travel distance to specialist care is a known social determinant of health and contributes to poorer oncology survival outcomes. To compare survival and toxicity outcomes for patients travelling long distances (>50 km) for treatment on clinical trials with local patients (<10 km and 10-50 km). We performed a retrospective cohort study based at the Kinghorn Cancer Centre, a comprehensive cancer care centre in metropolitan Sydney. We included adult patients with advanced solid-organ malignancies who were enrolled on therapeutic clinical trials between July 2015 and December 2017. Outcome measures included overall survival, progression-free survival, rates of grade 3-4 toxicity and unplanned hospital admissions for the duration of the clinical trial. We included 173 patients, of whom 27% lived within 10 km, 29% lived between 10 and 50 km and 44% lived further than 50 km. We did not identify significant differences between survival or toxicity outcomes between patients travelling long distances and local patients. All patients should be considered for clinical trial referral based on clinical parameters and preference, regardless of geographic proximity. In the meantime, improving access to clinical trials for rural and regional patients continues to be a priority.

Recruitment, outcomes, and toxicity trends in phase I oncology trials: Six-year experience in a large institution.

BackgroundWith the rapid influx of novel anti‐cancer agents, phase I clinical trials in oncology are evolving. Historically, response rates on early phase trials have been modest with the clinical benefit and ethics of enrolment debated. However, there is a paucity of real‐world data in this setting.AimTo better understand the changing landscape of phase I oncology trials, we performed a retrospective review at our institution to examine patient and trial characteristics, screening outcomes, and treatment outcomes.Methods and resultsWe analyzed all consecutive adult patients with advanced solid organ malignancies who were screened across phase I trials from January 2013 to December 2018 at a single institution. During this period, 242 patients were assessed for 28 different trials. Median age was 64 years (range 30–89) with an equal sex distribution. Among 257 screening visits, the overall screen failure rate was 18%, resulting in 212 patients being enrolled onto a study. Twenty‐six trials (93%) involved immunotherapeutic agents or molecular targeted agents either alone or in combination, with only two trials of cytotoxic agents (7%). Twenty‐two (13.4%) of the 209 treated patients experienced a total of 33 grade 3 or higher treatment‐related adverse events. There was one treatment‐related death (0.5%). Of 190 response‐evaluable patients, 7 (4%) had a complete response, 34 (18%) a partial response, and 59 (31%) experienced stable disease for a disease control rate of 53%. The median overall survival for our cohort was 8.0 (95% CI: 6.8–9.2) months.ConclusionThe profile of phase I trials at our institution are consistent with the changing early drug development landscape. Response rates and overall survival in our cohort are superior to historically reported rates and comparable to contemporaneous studies. Severe treatment‐related toxicity was relatively uncommon, and treatment‐related mortality was rare.

Racial Disparities in Utilization of Palliative Care Among Patients Admitted With Advanced Solid Organ Malignancies

There is increasing recognition of the importance of early incorporation of palliative care services in the care of patients with advanced cancers. Hospice-based palliative care remains underutilized for black patients with cancer, and there is limited literature on racial disparities in use of non-hospice-based palliative care services for patients with cancer. The primary objective of this study is to describe racial differences in the use of inpatient palliative care consultations (IPCC) for patients with advanced cancer who are admitted to a hospital in the United States. This retrospective cohort study analyzed 204 175 hospital admissions of patients with advanced cancers between 2012 and 2014. The cohort was identified through the National Inpatient Dataset. International Classification of Disease, Ninth Revision codes were used to identify receipt of a palliative care consultation. Of this, 57.7% of those who died received IPCC compared to 10.5% who were discharged alive. In multivariable logistic regression models, black patients discharged from the hospital, were significantly less likely to receive a palliative care consult compared to white patients (odds ratio [OR] black: 0.69, 95% CI: 0.62-0.76). Death during hospitalization was a significant modifier of the relationship between race and receipt of palliative care consultation. There are significant racial disparities in the utilization of IPCC for patients with advanced cancer.

Association between PD-L1 status and immune checkpoint inhibitor response in advanced malignancies: a systematic review and meta-analysis of overall survival data.

Targeting the programmed death ligand 1 (PD-L1) pathway has become standard for many advanced malignancies. Whether PD-L1 expression predicts response is unclear. We assessed the association between PD-L1 expression and immunotherapy response using stratified meta-analysis. We performed a systematic review of randomized clinical trials published prior to October 2018 comparing overall survival (OS) in patients with advanced solid organ malignancies treated with immunotherapy or standard treatment. Pooled hazard ratios were calculated among patients with high and low PD-L1 levels independently. Differences between the two estimates were assessed using meta-analysis of study-level differences. Our primary analysis assessed a 1% threshold while secondary analyses utilized 5, 10 and 50%. 14 eligible trials reporting on 8887 patients were included. While there was a significant OS benefit for immunotherapy compared with standard treatment for all patients, the magnitude of benefit was significantly larger among those with high PD-L1 expression (P=0.006). This finding persisted regardless of threshold used and across subgroup analyses according to PD-L1 assay type, tumor histology, line of therapy, type of inhibitor and study methodology. PD-L1 levels have important predictive value in determining the response to immunotherapy. However, patients with low PD-L1 levels also experience improved survival with immunotherapy compared with standard treatment.

Analysis of Heterogeneity in Survival Benefit of Immunotherapy in Oncology According to Patient Demographics and Performance Status: A Systematic Review and Meta-Analysis of Overall Survival Data.

Immunotherapy (IO) has become standard of care (SOC) for many advanced malignancies, although identifying patients likely to benefit remains difficult. We sought to assess whether demographic factors are associated with response to IO, compared with SOC systemic therapy, using stratified meta-analysis. A systematic review of MEDLINE, PubMed, Embase, and Scopus from inception to October 2, 2018. Randomized controlled trials comparing IO to SOC in patients with advanced solid organ malignancies were included if results were stratified by age, performance status (PS), or race, assessing overall survival (OS). Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for each group using random-effects models independently. We identified 21 eligible randomized controlled trials, including 20 stratified by age, 17 by PS, and 4 by race. Patients with PS 0 (HR, 0.74; 95% CI, 0.63-0.86) and PS≥1 (HR, 0.75; 95% CI, 0.68-0.83) had similar OS benefits from IO compared with SOC (P=0.80). There was no difference on the basis of patient race (white vs. nonwhite) (P=0.46). IO demonstrated an OS benefit for younger (below 65 y: HR, 0.73; 95% CI, 0.65-0.82) and older (65 y and above: HR, 0.79; 95% CI, 0.71-0.88) patients with no difference between age groups (P=0.27). Among prespecified subgroup analyses, there was significant effect modification in 2 subgroups: younger patients in the first-line setting (P=0.03) and those receiving anti-CTLA-4 drugs (P=0.05). When examining OS using stratified meta-analysis, we did not demonstrate significant differences in IO efficacy according to patient age, PS or race, though data on race were sparse.

Association Between Smoking and Survival Benefit of Immunotherapy in Advanced Malignancies: A Systematic Review and Meta-Analysis.

Smoking is associated with an increased tumor mutational burden. As tumor mutational burden has been shown to correlate with response to immunotherapy (IO), we hypothesized that a history of smoking may be associated with better response to IO. We utilized a systematic review with stratified meta-analysis of randomized clinical trials of IO versus standard of care in patients with advanced solid organ malignancies. Among 9 relevant studies, we found no significant difference in the benefit of IO, compared with other systemic therapies, between ever smokers (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.58-1.04; P=0.09) and never smokers (HR, 0.75; 95% CI, 0.67-0.86; P<0.0001) (test for difference P=0.83). We also observed no significant difference between current (HR, 0.92; 95% CI, 0.63-1.34; P=0.66; I=67%) and never smokers (HR, 0.74; 95% CI, 0.59-0.93; P=0.01; I=46%) (test for difference P=0.35). Stratified meta-analysis demonstrates that smoking status is not significantly associated with the response to IO in the treatment of advanced solid organ malignancies.

Final results of a phase I study of amrubicin and cyclophosphamide in patients with advanced solid organ malignancies: HOG LUN 07-130.

7594 Background: Relapsed small cell lung cancer (SCLC) has limited treatment options. Anthracyclines and cyclophosphamide have shown synergy in a wide variety of tumors. Amrubicin (AMR) and cyclos...

A phase 1 Bayesian dose selection study of bortezomib and sunitinib in patients with refractory solid tumor malignancies

Background:This phase 1 trial utilising a Bayesian continual reassessment method evaluated bortezomib and sunitinib to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and recommended doses of the combination.Methods:Patients with advanced solid organ malignancies were enrolled and received bortezomib weekly with sunitinib daily for 4 weeks, every 6 weeks. Initial doses were sunitinib 25 mg and bortezomib 1 mg m−2. Cohort size and dose level estimation was performed utilising the Escalation with Overdose Control (EWOC) adaptive method. Seven dose levels were evaluated; initially, sunitinib was increased to a goal dose of 50 mg with fixed bortezomib, then bortezomib was increased. Efficacy assessment occurred after each cycle using RECIST criteria.Results:Thirty patients were evaluable. During sunitinib escalation, DLTs of grade 4 thrombocytopenia (14%) and neutropenia (6%) at sunitinib 50 mg and bortezomib 1.3 mg m−2 were seen. Subsequent experience showed tolerability and activity for sunitinib 37.5 mg and bortezomib 1.9 mg m−2. Common grade 3/4 toxicities were neutropenia, thrombocytopenia, hypertension, and diarrhoea. The recommended doses for further study are bortezomib 1.9 mg m−2 and sunitinib 37.5 mg. Four partial responses were seen. Stable disease >6 months was noted in an additional six patients.Conclusion:Bortezomib and sunitinib are well tolerated and have anticancer activity, particularly in thyroid cancer. A phase 2 study of this combination in thyroid cancer patients is planned.

A phase I study of amrubicin (AMR) and cyclophosphamide in patients with advanced solid organ malignancies: Correlative analysis of a trial from the Hoosier Oncology Group.

e17517 Background: AMR is an anthracycline with activity against small cell lung cancer (SCLC). Amrubicinol (AMR-OH) is an active metabolite of AMR. NAD(P)H quinone oxidoreductase 1(NQO1) participates in the metabolism of AMR and AMR-OH. NQO1 single nucleotide polymorphisms (SNPs) have been suggested as a contributing factor to AMR efficacy in Japanese patients (pts). We therefore analyzed NQO1 polymorphisms from a phase I study evaluating the combination of AMR and cyclophosphamide and their correlation with response and toxicity. Methods: Blood samples were collected from pts prior to therapy. Genomic DNA was extracted and genotyping conducted for the C to T point mutation at base pair 609 of exon 6, which codes for a proline to serine substitution in NQO1 protein. Results: Genotyping data was available for all 36 pts; CC genotype (normal enzyme activity) was detected in 23 pts (64%), CT genotype (reduced enzyme activity) in 13 pts (36%). TT genotype (associated with loss of NQO1 activity) was not detected in our pt population. Response data was available for 34 pts. No significant association (or correlation) between CC or CT polymorphisms and response or ≥ grade 4 toxicity was noted at 95% confidence level (p > 0.05). Conclusions: No correlation was noted in our study between NQO1 polymorphisms and response or toxicity to AMR. Exploratory objectives of the phase I study also include analysis of topoisomerase IIA amplifications by FISH and correlation with response to AMR. These studies are currently underway and will be presented at the ASCO Meeting.

A phase I study of amrubicin (AMR) and cyclophosphamide in patients with advanced solid organ malignancies: A trial from the Hoosier Oncology Group.

7082 Background: AMR is a synthetic anthracycline with activity in small cell lung cancer (SCLC). Cyclophosphamide is an alkylating agent commonly combined with anthracyclines in diseases such as b...

Sorafenib (Nexavar®, BAY 43-9006)-induced Hand-foot Skin Reaction with Facial Erythema

Sorafenib (Nexavar®, BAY 43-9006) is a novel, orally administered multi-kinase inhibitor that has recently been approved for the treatment of metastatic renal cell carcinoma. It is also used to delay disease progression in patients with advanced solid organ malignancies and metastatic melanoma. Sorafenib is associated with a relatively high incidence of dermatologic adverse events. The commonly occurring dermatologic adverse events associated with sorafenib include hand-foot skin reaction, facial erythema, splinter subungual hemorrhages, alopecia, pruritus and xerosis. We report here on a case of a 50-year-old man who was diagnosed with metastatic hepatocellular carcinoma. He developed both facial erythema and hand-foot skin reaction after the administration of sorafenib.

Effects of a monoclonal anti-αvβ3 integrin antibody on blood vessels—A pharmacodynamic study

The integrin alphavbeta3 is an adhesion molecule expressed by proliferating endothelial cells and antibodies blocking this integrin inhibit angiogenesis in preclinical models. MEDI-522 is a second generation humanized anti-alphavbeta3 antibody designed for antiangiogenic therapy. The purpose of this study was to examine potential effects of this agent on blood vessels. In a phase I dose escalation study, MEDI-522 was administered by weekly infusions to 25 adult patients with advanced solid organ malignancies. As a surrogate angiogenesis assay, a wound was created by punch biopsy of the arm skin. This wound site was re-biopsied after a 7-day interval. Dual-label immunofluorescence experiments followed by computer-assisted image analysis were conducted to analyze the vasculature. Sequential pretreatment and 4-week treatment skin biopsy pairs were available on 4 patients, who had received 6 or 10 mg/kg of MEDI-522. MEDI-522 was detected in the dermal blood vessels as well as the dermal interstitium both in intact and wounded skin sites following treatment. No statistically significant difference was found between pretreatment and treatment samples of skin for vascular area, endothelial cell proliferation and apoptosis, or beta3 integrin levels. Phosphorylated focal adhesion kinase (pFAK) was significantly diminished in skin wound vessels during MEDI-522 treatment compared to the pretreatment samples. MEDI-522 was detectable both in quiescent and in angiogenically active skin blood vessels as well as in the dermal interstitial space. The levels of pFAK were reduced during MEDI-522 treatment, suggesting a modulating effect on this signaling molecule.