Martin E. Gore

Olaratumab is a platelet-derived growth factor receptor-α (PDGFRα)-targeting monoclonal antibody blocking PDGFRα signaling. PDGFRα expression is associated with a more aggressive phenotype and poor ovarian cancer outcomes. This randomized, open label phase II study evaluated olaratumab plus liposomal doxorubicin compared with liposomal doxorubicin alone in advanced ovarian cancer patients. Patients with platinum-refractory or platinum-resistant advanced ovarian cancer were randomized 1:1 to receive liposomal doxorubicin (40 mg/m2, intravenous infusion) administered every 4 weeks with or without olaratumab (20 mg/kg, IV infusion) every 2 weeks. Patients were stratified based on prior response to platinum therapy (refractory vs resistant). The primary efficacy endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, duration of response, and safety. A total of 123 patients were treated (62 olaratumab+liposomal doxorubicin; 61 liposomal doxorubicin). Median PFS was 4.2 months for olaratumab+liposomal doxorubicin and 4.0 months for liposomal doxorubicin (stratified hazard ratio [HR] = 1.043; 95% confidence interval [CI] 0.698–1.558; p = 0.837). Median OS was 16.6 months and 16.2 months in the olaratumab+liposomal doxorubicin and liposomal doxorubicin arms, respectively (HR = 1.098; 95% CI 0.71–1.71). In the platinum-refractory subgroup, median PFS was 5.5 months (95% CI 1.6–9.2) and 3.7 months (95% CI 1.9–9.2) in the olaratumab+liposomal doxorubicin (n = 15) and liposomal doxorubicin arms (n = 16), respectively (HR = 0.85; 95% CI 0.38–1.91). Overall, 59.7% (olaratumab+liposomal doxorubicin) and 65.6% (liposomal doxorubicin) of patients reported grade ≥ 3 adverse events regardless of causality. The most common treatment-emergent adverse events (all grades) regardless of causality were fatigue related (61%), nausea (57%), and constipation (52%) with olaratumab+liposomal doxorubicin and nausea (64%), fatigue related (62%), and mucositis (46%) with liposomal doxorubicin. The addition of olaratumab to liposomal doxorubicin did not result in significant prolongation of PFS or OS in platinum-resistant or platinum-refractory ovarian cancer. ClinicalTrials.gov identifier: NCT00913835 ; registered June 2, 2009.

Hormonal therapy is used as a treatment option in high-grade ovarian carcinoma (HGOC), but the role and choice of treatment remains unclear. Agents used include tamoxifen and aromatase inhibitors. Our aim was to evaluate the efficacy of tamoxifen (T) and letrozole (L) in HGOC in clinical practice and investigate factors influencing clinical outcome. A retrospective review of patients with relapsed HGOC treated with either tamoxifen or letrozole at the Royal Marsden Hospital between 2007 and 2012 was performed. The primary endpoint of the study was objective response rate (ORR). Secondary endpoints included CA125 response, clinical benefit rate (CBR) and duration of response. Platinum-sensitivity and ER-status were evaluated as predictors of treatment response. 97 patients were included (43 T, 54 L); median age 63 years (20–92); 91% high-grade serous; median number of lines of prior chemotherapy 3 (1–8); 60% platinum-resistant, 40% platinum-sensitive; 52% ER + ve, 1% ER-ve, 47% unknown. 14 patients (6 T, 8 L) achieved a partial response, with ORR (RECIST) of 14% (T) and 15% (L). The CBR for ≥3 months was 65% (22/43) for tamoxifen and 56% (22/54) for letrozole. There was no significant difference in ORR (p = 0.99) or CBR (p = 0.14) between tamoxifen and letrozole. 22 patients (23%) had a CA-125 response with hormonal therapy (10 T – 23% and 12 L – 22%). ORR did not differ by platinum sensitivity (p = 0.42); or ER-status (positive vs unknown, p = 0.12). Responders to letrozole had longer durations of response than responders to tamoxifen (26 vs 11.5 months, p = 0.03), but equivalent disease stability duration (9.6 vs 7.2 months respectively, p = 0.11). Within the constraints of a retrospective study, we identified that patients treated with letrozole had a significantly longer duration of response than those treated with tamoxifen. Treatment with either tamoxifen or letrozole is a rational treatment option for patients with ER + ve HGOC, with equivalent ORR, CBR and disease stability.

Objective: To assess the efficacy and safety of sorafenib dose escalation in metastatic renal cell carcinoma ( mRCC ). Patients and Methods: Intra‐patient dose escalation may enhance the clinical benefit of targeted anticancer agents in metastatic disease. In this non‐randomised, open‐label, Phase 2b study, treatment‐naïve patients with mRCC were initially treated with the standard oral sorafenib dose [400 mg twice daily ( BID )]. Two dose escalations were planned, each 200 mg BID after 28 days at the prior level. Dose reductions, interruptions, or delayed escalations were used to manage adverse events ( AE s). The primary endpoint was objective response rate ( ORR ) in the modified intent‐to‐treat ( mITT ) population, which comprised patients with ≥6 months of treatment including ≥4 months of therapy at their highest tolerated dose. Secondary endpoints included progression‐free survival ( PFS ) and safety. Results: In all, 83 patients received sorafenib. The dose received for the longest duration was 400, 600, and 800 mg BID in 48.2%, 15.7%, and 24.1% of patients, respectively. The ORR was 44.4% [ n = 8/18; 95% confidence interval ( CI ) 21.5–69.2] and 17.9% ( n = 12/67; 95% CI 9.6–29.2) in the mITT and ITT populations, respectively. The median (95% CI ) PFS was 7.4 (6.0–11.7) months ( ITT ). The most common AE s of any grade were hand–foot skin reaction (66.3%) and diarrhoea (63.9%). Conclusion: Sorafenib demonstrated clinical benefit in treatment‐naïve patients with mRCC . However, relatively few patients could sustain doses of >400 mg BID . There was evidence that, where tolerated, escalation from the standard sorafenib dose may have enhanced clinical benefit. However, this study does not support dose escalation for most patients with treatment‐naïve mRCC . Alternative protocols for sorafenib dose escalation could be explored.

Renal cell carcinoma accounts for 90 % of renal neoplasms and metastatic disease is common. One third of newly diagnosed cases will have synchronous metastases at diagnosis and further 25–50 % will develop metachronous disease. This study presents two new cases of gallbladder metastasis from renal cell carcinoma (RCC) from our institution and reviews the published literature. The final cohort included 52 evaluable patients. M/F ratio was 2:1 and median age was 62.5 years. Most patients were diagnosed incidentally after follow-up or staging imaging for RCC. Of the patients with available histology, all except one were clear cell type (n = 39) and 92 % were polypoid. Thirty-six patients demonstrated metachronous gallbladder metastasis with median disease-free interval (DFI) from nephrectomy of 4 years. The most frequent site of metastasis was the contralateral kidney (46.7 %) followed by the pancreas and lung. The median disease-free interval (DFS) after cholecystectomy was 37 months. Three- and five-year OS rates were 74 and 62 %, respectively. Age younger than 45 years (p = 0.008) and DFI <24 months (p = 0.049) were associated with decreased OS. RCC metastasis to the gallbladder is associated with an unusual pattern of concomitant metastasis. Symptoms are not common. Simple cholecystectomy is associated with increased OS and nil local or port site recurrence. Young age and short DFI are associated with decreased OS.

Introduction: Ovarian cancer has the highest mortality rate of the gynaecological malignancies and approximately two thirds of affected women have Stage III/IV disease at diagnosis. Survival rates have been improved by cytoreductive surgery and adjuvant platinum-based chemotherapy but cure rates have not. Tumours exhibiting folate receptor alpha positivity have reduced responsiveness to cytotoxic chemotherapy and the degree of receptor expression is associated with tumour grade. Areas Covered: Farletuzumab (MORAb-003) is a humanized mAb with high affinity for folate receptor α (FRα), a 38 kDa GPI-anchored protein that is overexpressed in greater than 90% of epithelial ovarian cancers (EOC). The authors examine the published pharmacokinetic, safety, and clinical efficacy data from the Phase I, Phase II, Phase III studies of farletuzumab. Expert Opinion: The benefits of farletuzumab treatment observed in Phase I and II trials did not carry though to Phase III. It is possible that patient selection and serum biomarkers may be helpful in identifying patients that may derive benefit.

Background: We report final results with extended follow-up from a global, expanded-access trial that pre-regulatory approval provided sunitinib to metastatic renal cell carcinoma (mRCC) patients, ineligible for registration-directed trials. Methods: Patients ⩾18 years received oral sunitinib 50 mg per day on a 4-weeks-on–2-weeks-off schedule. Safety was assessed regularly. Tumour measurements were scheduled per local practice. Results: A total of 4543 patients received sunitinib. Median treatment duration and follow-up were 7.5 and 13.6 months. Objective response rate was 16% (95% confidence interval (CI): 15–17). Median progression-free survival (PFS) and overall survival (OS) were 9.4 months (95% CI: 8.8–10.0) and 18.7 months (95% CI: 17.5–19.5). Median PFS in subgroups of interest: aged ⩾65 years (33%), 10.1 months; Eastern Cooperative Oncology Group performance status ⩾2 (14%), 3.5 months; non-clear cell histology (12%), 6.0 months; and brain metastases (7%), 5.3 months. OS was strongly associated with the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model (n=4065). The most common grade 3/4 treatment-related adverse events were thrombocytopenia (10%), fatigue (9%), and asthenia, neutropenia, and hand–foot syndrome (each 7%). Conclusion: Final analysis of the sunitinib expanded-access trial provided a good opportunity to evaluate the long-term side effects of a tyrosine kinase inhibitor used worldwide in mRCC. Efficacy and safety findings were consistent with previous results.

[18F]fluciclatide, a peptide ligand with high affinity for αvβ3/αvβ5 integrins, is a proposed biomarker of tumor angiogenesis. The study rationale was to perform a preliminary evaluation of the relationship between tumor [18F]fluciclatide uptake and perfusion by [15O]H2O PET. Patients with non-small cell lung cancer and melanoma underwent dynamic imaging with arterial sampling following injection of [15O]H2O and [18F]fluciclatide. Quantification was performed using a one-tissue compartmental model for [15O]H2O and a two-tissue model for [18F]fluciclatide at volume-of-interest level, and SUV at voxel level. Tumor binding potential (k3/k4 ratio) of [18F]fluciclatide tumor was 5.39 ± 1.46, consistent with previous studies in breast cancer metastases. Voxel-by-voxel maps of [18F]fluciclatide delivery strongly correlated with [15O]H2O-based perfusion (p < 10−4 tumor, 1,794 ± 1,331 voxels). Interestingly, this correlation was lost when retention of [18F]fluciclatide at late time-points was compared with perfusion (p > 0.15). Our study suggests tumor [18F]fluciclatide retention is unrelated to tumor perfusion, supporting use of late (60-min) imaging protocols in patients.