Phase II Study of Panitumumab Monotherapy in Chemotherapy‐Naïve Frail or Elderly Patients with Unresectable RAS Wild‐Type Colorectal Cancer: OGSG 1602

Lessons Learned

• Panitumumab monotherapy showed favorable efficacy and feasibility in the treatment of frail or elderly patients with RAS wild‐type unresectable colorectal cancer.
• It is especially effective for left‐sided tumors; therefore, panitumumab as first‐line treatment could be an additional therapeutic option for frail elderly patients, particularly in those who are unsuitable for upfront oxaliplatin‐based or irinotecan‐based combination regimens.

BackgroundFirst‐line panitumumab monotherapy is expected to be well tolerated and improve survival in patients ineligible for intensive chemotherapy. However, its safety and efficacy in chemotherapy‐naïve frail or elderly patients with unresectable RAS wild‐type (WT) colorectal cancer (CRC) have not been studied. The aim of this phase II trial was to evaluate the efficacy and safety of panitumumab as first‐line treatment.MethodsWe conducted a multicenter phase II study on patients aged ≥76 years or ≥65 years considered unsuitable for intensive chemotherapy. Panitumumab 6 mg/kg of intravenous infusion was administered every 2 weeks. The primary endpoint was disease control rate (DCR). Secondary endpoints included progression‐free survival (PFS), overall survival (OS), response rate (RR), time to treatment failure (TTF), and incidence of grade 3 or 4 toxicities.ResultsThirty‐six patients (median age: 81 [range, 67–88] years) were enrolled between February 2017 and August 2018. Two patients were excluded from the analysis of efficacy: one from lack of image examination at baseline and the other from lack of a measurable lesion. Thirty‐three (91.6%) patients had a performance status (PS) of 0 or 1, whereas two (5.6%) patients and one (2.8%) patient had a PS of 2 and 3, respectively. Twenty‐eight patients (77.8%) had left‐sided CRC, whereas eight (22.2%) had right‐sided CRC. The RR was 50.0% (95% confidence interval [CI], 32.4–67.6), including three patients (8.8%) who had complete responses. A total of 26.5% had stable diseases, resulting in a DCR of 76.5% (90% CI, 61.5–87.7). The RR of patients with left‐ and right‐sided tumors was 65.4% (95% CI, 44.3–82.8) and 0.0% (95% CI, 0.0–36.9), respectively. Major grade 3 or 4 nonhematologic toxicities were rash (n = 6, 16.7%), hypomagnesemia (n = 4, 11.1%), fatigue (n = 3, 8.3%), paronychia (n = 2, 5.6%), and hyponatremia (n = 2, 5.6%). The only grade 3 hematologic toxicity was neutropenia (n = 1, 2.8%).ConclusionPanitumumab monotherapy showed favorable efficacy and feasibility in frail or elderly patients with RAS WT unresectable CRC. Survival analysis including OS, PFS, and TTF is currently in progress.     

First‐line pembrolizumab vs chemotherapy in metastatic non‐small‐cell lung cancer: KEYNOTE‐024 Japan subset

This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE‐024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a programmed death ligand 1 (PD‐L1) tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum‐based chemotherapy (four to six cycles). The primary end‐point was progression‐free survival; secondary end‐points included overall survival and safety. Of 305 patients randomized in KEYNOTE‐024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). Median progression‐free survival was 41.4 (95% confidence interval [CI], 4.2‐42.5) months with pembrolizumab and 4.1 (95% CI, 2.8‐8.3) months with chemotherapy (hazard ratio [HR], 0.27 [95% CI, 0.11‐0.65]; one‐sided, nominal P = .001). Median overall survival was not reached (NR) (95% CI, 22.9‒NR) and 21.5 (95% CI, 5.2‐35.0) months, respectively (HR, 0.39 [95% CI, 0.17‐0.91]; one‐sided, nominal P = .012). Treatment‐related adverse events occurred in 21/21 (100%) pembrolizumab‐treated and 18/19 (95%) chemotherapy‐treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3‐5 events. Immune‐mediated adverse events and infusion reactions occurred in 11 pembrolizumab‐treated patients (52%) and four chemotherapy‐treated patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3‐5 events. Consistent with results from KEYNOTE‐024 overall, first‐line pembrolizumab improved progression‐free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a PD‐L1 tumor proportion score of 50% or higher. The trial is registered with Clinicaltrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT02142738","term_id":"NCT02142738"}}NCT02142738.     

Precision medicine‐based therapies in advanced colorectal cancer: The University of California San Diego Molecular Tumor Board experience

Treatment for advanced colorectal cancer is often limited by complex molecular profiles, which promote resistance to systemic agents and targeted monotherapies. Recent studies suggest that a personalized, combinatorial approach of matching drugs to tumor alterations may be more effective. We implemented a precision medicine strategy by forming a Molecular Tumor Board (MTB), a multidisciplinary team of clinicians, scientists, bioinformaticians and geneticists. The MTB integrated molecular profiling information and patient characteristics to develop N‐of‐One treatments for 51 patients with advanced colorectal cancer. All patients had metastatic disease and 63% had received ≥ 3 prior therapy lines. Overall, 34/51 patients (67%) were matched to ≥ 1 drug recommended by the MTB based on individual tumor characteristics, whereas 17/51 (33%) patients received unmatched therapies. Patients who received matched therapy demonstrated significantly longer progression‐free survival (hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.21–0.81; P = 0.01) and a trend towards higher clinical benefit rates (41% vs. 18%, P = 0.058) (all multivariate) compared to patients receiving unmatched therapy. The MTB facilitated personalized matching of drugs to tumor characteristics, which was associated with improved progression‐free survival in patients with advanced colorectal cancer.     

Pembrolizumab plus pemetrexed‐platinum for metastatic nonsquamous non–small‐cell lung cancer: KEYNOTE‐189 Japan Study

Pembrolizumab plus pemetrexed‐platinum significantly improved overall survival (OS) and progression‐free survival (PFS) with manageable safety compared with placebo plus pemetrexed‐platinum in patients with previously untreated metastatic nonsquamous non–small‐cell lung cancer (NSCLC) without EGFR/ALK alterations in the global, randomized, double‐blind, phase 3 KEYNOTE‐189 study. We present results of Japanese patients enrolled in the KEYNOTE‐189 global and Japan extension studies. Patients were randomized 2:1 to intravenous pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for up to 35 cycles. All patients received pemetrexed 500 mg/m² plus the investigator’s choice of cisplatin or carboplatin Q3W for four cycles, followed by maintenance pemetrexed 500 mg/m² Q3W (all intravenous). Co–primary endpoints were OS and PFS. Forty Japanese patients enrolled (pembrolizumab, n = 25; placebo, n = 15). At data cutoff (20 May 2019; median time from randomization to data cutoff, 18.5 [range, 14.7‒38.2] months), the median OS was not reached in the pembrolizumab plus pemetrexed‐platinum arm; the median OS was 25.9 (95% confidence interval [CI], 11.9‒29.0) months in the placebo plus pemetrexed‐platinum arm (hazard ratio [HR] .29; 95% CI, .07‒1.15). The median (95% CI) PFS was 16.5 (8.8‒21.1) compared with 7.1 (4.7‒21.4) months (HR, .62; 95% CI, .27‒1.42), respectively. There were no grade 5 adverse events (AE). Grade 3/4 AE occurred in 72% vs 60% of patients in the pembrolizumab vs placebo arms; 40% vs 20% had immune‐mediated AE, and 4% vs 0% had infusion reactions. Efficacy and safety outcomes were similar to those from the global study and support first‐line therapy with pembrolizumab plus pemetrexed‐platinum in Japanese patients with nonsquamous NSCLC without EGFR/ALK alterations.     

Real‐World Clinical Outcomes in Biological Subgroups of Breast Cancer in the Hospital District of Southwest Finland

BackgroundComparing breast cancer survival trends globally, Finland is among the top three countries in Europe. However, outcome data on breast cancer subgroups in the Finnish population are limited. This retrospective, registry‐based study aimed to assess patient characteristics and clinical outcomes of different breast cancer subgroups in early (EBC) and metastatic breast cancer (MBC) in a real‐life clinical setting.Materials and MethodsThe study consisted of 6,977 adult, female patients with breast cancer diagnosed in Southwest Finland during 2005–2018. Patients were divided into four mutually exclusive groups: human epidermal growth factor receptor 2 positive (HER2+), triple negative, HER2−/hormone receptor positive (HR+), and HER2 and/or HR status unknown, and further into patients with EBC and MBC. Overall survival (OS) was assessed as a clinical outcome, as well as the following real‐world (rw) clinical outcomes: disease‐free survival (rwDFS), progression‐free survival (rwPFS), and distant recurrence‐free interval (rwDRFI).ResultsWithin EBC, 5‐year survival was the highest (88%) in HER2−/HR+, followed by 85% in HER2+, and 75% in triple negative. The rwDFS varied significantly in EBC (5‐year rwDFS HER2 ‐/HR+, HER2+, triple negative: 87%, 80%, 71% respectively). In MBC, median survival was 2 years for both HER2−/HR+ and HER2+ and markedly shorter for triple negative (0.8 years). Independent predictors of mortality were age (hazard ratio [HR], 1.1), other subgroups than HER2−/HR+ (HR, 1.2–1.9), metastatic disease (HR, 9.8), and other malignancies (HR, 2.7).ConclusionThis registry‐based study demonstrates significant differences in breast cancer outcomes on the subgroup level, as well as poorer outcomes compared with clinical trials, giving complementary insight on clinical characteristics in an unselected patient population.Implications for PracticeThis retrospective, registry‐based study assessed the clinical outcomes of different breast cancer subgroups in 6,977 adult, female patients with breast cancer diagnosed in Southwest Finland during 2005–2018. Results demonstrated significant variation in the survival between subgroups in both early breast cancer and metastatic breast cancer, as well as differences between unselected patients representing the standard of care and randomized clinical trials. Although, according to the global comparison of survival trends, the net survival of patients with breast cancer in Finland is generally high, there is great variation between subgroups. These real‐life breast cancer data provide tools to further evaluate medical need in different breast cancer subgroups.     

Modified FOLFOXIRI With or Without Cetuximab as Conversion Therapy in Patients with RAS/BRAF Wild‐Type Unresectable Liver Metastases Colorectal Cancer: The FOCULM Multicenter Phase II Trial

PurposeThis trial evaluated the addition of cetuximab to a modified FOLFOXIRI (mFOLFOXIRI: 5‐fluorouracil/folinic acid, oxaliplatin, irinotecan) as conversion therapy in a two‐group, nonrandomized, multicenter, phase II trial in patients with initially technically unresectable colorectal liver‐limited metastases (CLM) and BRAF/RAS wild‐type.Patients and MethodsPatients were enrolled to receive cetuximab (500 mg/m²) plus mFOLFOXIRI (oxaliplatin 85 mg/m², irinotecan 165 mg/m², folinic acid 400 mg/m², 5‐fluorouracil 2,800 mg/m² 46‐hour infusion, every 2 weeks) (the cetuximab group) or the same regimen of mFOLFOXIRI alone (the control group), in a 2:1 ratio allocation. The primary endpoint was the rate of no evidence of disease (NED) achieved. Secondary endpoints included resection rate, objective response rate (ORR), survival, and safety.ResultsBetween February 2014 and July 2019, 117 patients were registered for screening at six centers in China, and 101 of these were enrolled (67 cetuximab group, 34 control group). The rate of NED achieved was 70.1% in the cetuximab group and 41.2% in the control group (difference 29.0%; 95% confidence interval [CI], 9.1%–48.8%; p = .005). Patients in the cetuximab group had improved ORR (95.5% vs. 76.5%; difference 19.1%; 95% CI, 17.4%–36.4%; p = .010) compared with those in control group. Progression‐free survival and overall survival showed the trend to favor the cetuximab group. The incidence of grade 3 and 4 adverse events was similar in the two groups.ConclusionAddition of cetuximab to mFOLFOXIRI improved the rate of NED achieved. This combination could be an option of conversion regimen for molecularly selected patients with initially technically unresectable CLM.Implications for PracticeThis trial evaluated the addition of cetuximab to a modified FOLFOXIRI as conversion therapy in a phase II trial in patients with initially technically unresectable colorectal liver‐limited metastases and BRAF/RAS wild‐type. The rate of no evidence of disease achieved was 70.1% in the cetuximab plus modified FOLFOXIRI group and 41.2% in the modified FOLFOXIRI group. Objective response rates, overall survival, and progression‐free survival were improved in the cetuximab group when compared with the modified FOLFOXIRI group. Addition of cetuximab to modified FOLFOXIRI increased the rate of no evidence of disease achieved, and this combination could be an option of conversion regimen for molecularly selected patients with initially technically unresectable colorectal liver‐limited metastasis.     

Prognostic impact of circulating tumor cells detected with the microfluidic “universal CTC‐chip” for primary lung cancer

Detecting rare circulating tumor cells (CTCs) in the bloodstream is extremely challenging. We had previously developed a novel polymeric microfluidic device, “CTC‐chip,” for capturing CTCs and have shown high capture efficiency in lung cancer cell lines by conjugating Abs against epithelial cell adhesion molecules (EpCAM). This study aimed to optimize the EpCAM‐chip and clarify the prognostic impact of CTCs in lung cancer patients. Of 123 patients with pathologically proven lung cancer, both progression‐free survival (P = .037) and cancer‐specific survival (P = .0041) were predominantly poor when CTCs were detected before treatment. After classification into surgical and chemotherapy groups, progression‐free survival was worse in CTC‐positive patients in both groups (surgery, P = .115; chemotherapy, P = .012), indicating that the detection of baseline CTCs is a risk factor for recurrence and progression. Furthermore, we recovered captured CTCs using micromanipulators and undertook mutation analysis using PCR. Thus, the EpCAM‐chip is a highly sensitive system for detecting CTCs that contributes to the prediction of recurrence and progression and enables genetic analysis of captured CTCs, which could open new diagnostic, therapeutic, and prognostic options for lung cancer patients.     

EMA Review of Daratumumab (Darzalex) for the Treatment of Adult Patients Newly Diagnosed with Multiple Myeloma

The use of daratumumab in combination with established regimens for the treatment of newly diagnosed multiple myeloma has recently been authorized by the European Medicines Agency based on results from three separate phase III randomized, active controlled, open‐label studies that have confirmed enhanced efficacy and tolerability in both transplant‐ineligible (MMY3008 and MMY3007) and transplant‐eligible (MMY3006) patients, without compromising transplant ability. Trial MMY3008 showed an improvement in progression‐free survival (PFS) when daratumumab was added to lenalidomide and dexamethasone compared with lenalidomide and dexamethasone; the median PFS had not been reached in the daratumumab arm and was 31.9 months in the control arm (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.43–0.73; p < .0001). Trial MMY3007 showed an improvement in PFS when daratumumab was added to bortezomib, melphalan, and prednisone compared with bortezomib, melphalan, and prednisone; PFS had not been reached in the daratumumab arm and was 18.1 months in the control arm (HR, 0.5; 95% CI, 0.38–0.65; p < .0001). In trial MMY3006, daratumumab added to bortezomib, thalidomide, and dexamethasone was compared with bortezomib, thalidomide, and dexamethasone as induction and consolidation treatment prior to autologous stem cell transplant. The stringent complete response rate at day 100 after transplant in the daratumumab group was 29% compared with 20% in the control group (odds ratio, 1.60; 1.21–2.12 95% CI; p = .0010). Overall adverse events were manageable, with an increased rate of neutropenia and infections in the daratumumab arms. Regulatory assessment of efficacy and safety results from trials MMY3006, MMY3007, and MMY3008 confirmed a positive benefit‐risk ratio leading to an approval of the extensions of indication.Implications for PracticeA set of extensions of indication was recently approved for daratumumab (Darzalex) in the setting of newly diagnosed multiple myeloma in combination with established regimens. Results of the MMY3006, MMY3007, and MMY3008 trials have shown enhanced efficacy and a favorable side effect profile of several daratumumab‐based combinations in patients both ineligible and eligible for transplant, without compromising transplant ability. The combinations of daratumumab with either lenalidomide and low‐dose dexamethasone or bortezomib, melphalan, and prednisone were approved for transplant‐ineligible patients. The combination of daratumumab with bortezomib, thalidomide, and dexamethasone was approved for transplant‐eligible patients. These combinations are expected to improve the survival outlook for patients with multiple myeloma, without an unacceptable risk of increase in adverse events, and updated information on progression‐free survival and overall survival is expected from the above trials.     

Phase I/II Study of Cisplatin plus Nab‐Paclitaxel with Concurrent Thoracic Radiotherapy for Patients with Locally Advanced Non‐Small Cell Lung Cancer

Lessons Learned

• The combination of cisplatin plus nab‐paclitaxel with concurrent thoracic radiotherapy in unresectable stage III non‐small cell lung cancer is a promising therapeutic strategy.
• Further investigation is warranted.

BackgroundWe conducted a phase I/II trial of cisplatin plus nab‐paclitaxel with concurrent thoracic radiotherapy for locally advanced non‐small cell lung cancer (NSCLC) to determine the recommended dose (RD) of nab‐paclitaxel and to evaluate the safety and efficacy of this regimen.MethodsIn the phase I study, escalating doses of weekly nab‐paclitaxel were administered together with cisplatin at 75 mg/m² every 3 weeks and concurrent radiotherapy. In the phase II study, nab‐paclitaxel was administered at the RD.ResultsIn the phase I study, whereas no dose‐limiting toxicity (DLT) was observed with nab‐paclitaxel at 50 or 60 mg/m², one of six patients experienced DLT (esophagitis of grade 3) at 70 mg/m², determined as the RD. Twenty‐four patients at RD were evaluable for safety and efficacy in phase II. Common toxicities included esophagitis (87.5%) and leukopenia (79.2%). Pneumonitis and treatment‐related deaths were not observed, but 20 patients (83.3%) experienced radiation pneumonitis, with one case of grade 3 and four of grade 2, after completion of concurrent chemoradiotherapy. The 2‐year overall survival and progression‐free survival rates were 73.9% and 56.5% (95% confidence interval [CI], 34.3%–74.7%), respectively.ConclusionConcurrent chemoradiation with nab‐paclitaxel at 70 mg/m² and cisplatin at 75 mg/m² every 3 weeks showed encouraging feasibility and activity for locally advanced NSCLC.     

Current status of first‐line treatment with pembrolizumab for non–small‐cell lung cancer with high PD‐L1 expression

It is not clear whether pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum‐based chemotherapy (COMB) should be selected for patients with advanced non–small‐cell lung cancer (NSCLC) exhibiting high PD‐L1 expression (tumor proportion score ≥ 50%). We performed a retrospective, multicenter study of 300 patients with NSCLC exhibiting high PD‐L1 expression who received MONO or COMB as first‐line treatment between December 2018 and January 2020. We reviewed the medical records of all consecutive patients with no driver mutations, and assessed the patient characteristics, therapeutic regimens, treatment periods, and adverse events. In total, 166 (55%; median age: 74 years) and 134 (45%; median age: 68 years) patients received MONO and COMB, respectively. Patients were younger and had better performance status (0–1) in the COMB group (p < 0.01). With a median follow‐up time of 10.6 (range: 0.1–20.6) months, the median progression‐free survival was 7.1 months with MONO and 13.1 months with COMB. The objective response rate was 42.2% with MONO and 67.9% with COMB. With respect to treatment discontinuation, 36 out of 166 (21.7%) and 28 out of 134 (20.1%) patients discontinued MONO and COMB, respectively. In conclusion, COMB may be a promising option for first‐line treatment for NSCLC with high PD‐L1 expression and good performance status.     

68Ga‐DOTATATE Positron Emission Tomography‐Computed Tomography Quantification Predicts Response to Somatostatin Analog Therapy in Gastroenteropancreatic Neuroendocrine Tumors

BackgroundSomatostatin analogs (SSAs) are the frontline antitumor therapy in advanced well‐differentiated gastroenteropancreatic neuroendocrine tumors (GEP‐NETs). A subset of patients demonstrate early disease progression on SSA therapy, yet the currently known predictors for treatment failure lack specificity to affect therapeutic decision. SSAs target tumor somatostatin receptors, the level of which can be quantitatively assessed with ⁶⁸Ga‐DOTATATE positron emission tomography‐computed tomography (PET/CT). We investigated the ability of ⁶⁸Ga‐DOTATATE PET/CT to predict response to SSA therapy.Materials and MethodsThe records of 108 consecutive patients with well‐differentiated grade 1–2 GEP‐NETs on SSA monotherapy who received ⁶⁸Ga‐DOTATATE PET/CT scans were retrospectively reviewed to obtain baseline characteristics, ⁶⁸Ga‐DOTATATE maximum standardized uptake value (SUVmax), and progression‐free survival (PFS) data. The optimal SUVmax cutoff for patient stratification was obtained with receiver operating characteristic curve analysis. PFS in the high versus low SUVmax groups was compared with Kaplan‐Meier survival analysis. The effects of baseline characteristics and SUVmax on PFS were examined with univariate and multivariate Cox regression.Results ⁶⁸Ga‐DOTATATE SUVmax predicted therapeutic failure with sensitivity and specificity of 39% and 98%, respectively. SUVmax of <18.35 was associated with shorter PFS, which was reproduced in the subgroup analysis of SSA‐naïve patients. Low SUVmax was the only predictor of early treatment failure (hazard ratio, 6.85) in multivariate analysis, as well as in the subgroup analysis of grade 2 GEP‐NETs.ConclusionLow SUVmax on ⁶⁸Ga‐DOTATATE PET/CT independently predicts early failure on SSA monotherapy in patients with well‐differentiated grade 1–2 GEP‐NET. Patients with lack of expected benefit from SSA therapy can be readily identified using routine ⁶⁸Ga‐DOTATATE PET/CT with very high specificity.Implications for PracticeBased on ⁶⁸Ga‐DOTATATE positron emission tomography‐computed tomography imaging, clinicians can better inform patients on the expected benefit of somatostatin analog therapy for gastroenteropancreatic neuroendocrine tumors, especially when access to the therapy is difficult, and offer proactive discussion on alternative management options.     

Sunitinib and Evofosfamide (TH‐302) in Systemic Treatment‐Naïve Patients with Grade 1/2 Metastatic Pancreatic Neuroendocrine Tumors: The GETNE‐1408 Trial

BackgroundSunitinib (SUN)‐induced hypoxia within the tumor could promote the activation of the prodrug evofosfamide (EVO), locally releasing the cytotoxic DNA alkylator bromo‐isophosphoramide mustard. SUNEVO, a phase II, open‐label, single‐arm trial, investigated the potential synergy of SUN plus EVO in advanced progressive pancreatic neuroendocrine tumors (panNETs).MethodsSystemic treatment‐naïve patients with advanced or metastatic, unresectable, grade 1/2 panNETs with a Ki67 ≤20%, received EVO 340 mg/m² on days 8, 15, and 22 every 4 weeks and sunitinib 37.5 mg/day continuously. The primary endpoint was objective response rate, measured every 8 weeks by RECIST version 1.1.ResultsFrom 2015 to 2018, 17 patients were enrolled. The median age was 62.4 years, 47% had a Ki67 >10%, and 70.6% had liver metastasis. Patients received a median of five and four cycles of SUN and EVO, respectively. After a median follow‐up of 15.7 months, 17.6% of patients achieved a complete (n = 1) or partial response (n = 2), and 11 patients had stable disease (64.7%). The median progression‐free survival was 10.4 months (95% confidence interval, 2.6–18.0). Treatment‐related adverse events (grade ≥3) were observed in 64.7% of the patients, the most frequent being neutropenia (35.3%), fatigue (17.6%), and thrombopenia (11.8%). Treatment discontinuation due to toxicity was reported in 88.2% of the patients. No correlation was found between treatment response and DAXX, ATRX, MEN1, SETD2, and PTEN gene mutations.ConclusionSUN plus EVO had a negative toxicity profile that should be taken into account for further clinical research in advanced panNETs. The combination showed moderate activity in terms of treatment response that did not correlate with somatic mutations. (Clinical trial identification number: {"type":"clinical-trial","attrs":{"text":"NCT02402062","term_id":"NCT02402062"}}NCT02402062)Implications for PracticeAddition of hypoxia‐activated prodrugs has been proposed as a potential mechanism to overcome tumor resistance to antiangiogenic agents. Sunitinib and evofosfamide, which were widely proposed as a potential synergistic option, showed modest efficacy in pancreatic neuroendocrine tumors (panNETs), reaching a median objective response rate of 17.6% and median progression‐free survival of 10.4 months. Treatment response does not correlate with the biomarkers analyzed. The high systemic toxicity, with 88.2% of patients discontinuing the treatment, makes this therapeutic approach unfeasible and encourages future research to overcome panNETs'' resistance to antiangiogenic agents with other therapies with a safer profile.     

Impact of Tumor‐Infiltrating Lymphocytes on Overall Survival in Merkel Cell Carcinoma

BackgroundMerkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine carcinoma of the skin. As the clinical course can be variable, prognostic markers are needed to better stratify patients. Prior literature, composed of small series with limited sample size, has demonstrated that tumor‐infiltrating lymphocytes (TILs) are an important prognostic marker in MCC. To validate these findings on a population level, we sought to analyze and report the prognostic value of TILs in a large national data set.Materials and MethodsA retrospective observational cohort study was conducted of patients with nonmetastatic MCC from 2010 to 2015 using the National Cancer Database. Individual variables trending toward significance using a univariable analysis were included in a multivariable Cox proportional hazards model to assess their independent effect on overall survival (OS). TILs were subclassified into none, nonbrisk, and brisk and the survival analysis was performed. Propensity score–weighted multivariable analysis (PS MVA) was performed to adjust for additional confounding.ResultsA total of 2,182 patients met inclusion criteria: 611 (28.0%) were identified as having TILs present, and 1,571 (72.0%) had TILs absent in the tumor. On MVA, subdivision of TIL status into nonbrisk (hazard ratio [HR], 0.750; 95% confidence interval [CI], 0.602–0.933) and brisk (HR, 0.499; 95% CI, 0.338–0.735) was associated with incrementally improved OS compared with no TILs. The association of nonbrisk and brisk TILs with improved OS was retained on PS MVA (Nonbrisk: HR, 0.720; 95% CI, 0.550–0.944; Brisk: HR, 0.483; 95% CI, 0.286–0.814).ConclusionThe presence of nonbrisk and brisk TILs is associated with incrementally improved OS in patients with nonmetastatic MCC in a large national data set. This pathologic feature can aid with risk stratification, estimation of prognosis, and, importantly, decision‐making with respect to treatment intensification in high‐risk patients.Implications for PracticeMerkel cell carcinoma (MCC) is an aggressive neuroendocrine cutaneous malignancy with variable clinical course. Prognostic markers are needed to better risk stratify patients. We present the largest retrospective observational cohort study of patients with nonmetastatic MCC using the National Cancer Database. Our analysis demonstrates an association between increasing degrees of tumor‐infiltrating lymphocytes and incrementally improved survival. These conclusions improve pathologic risk stratification, and decision‐making with respect to treatment intensification. Intensification may include adjuvant radiation therapy to the primary site after wide excision despite small tumor size, to the nodal basin in sentinel lymph node‐negative patients, or offering closer follow‐up.     

Liquid biopsy reveals KLK3 mRNA as a prognostic marker for progression free survival in patients with metastatic castration‐resistant prostate cancer undergoing first‐line abiraterone acetate and prednisone treatment

Circulating RNAs extracted from liquid biopsies represent a promising source of cancer‐ and therapy‐related biomarkers. We screened whole blood from patients with metastatic castration‐resistant prostate cancer (mCRPC) following their first‐line treatment with abiraterone acetate and prednisone (AA‐P) to identify circulating RNAs that may correlate with progression‐free survival (PFS). In a prospective multicenter observational study, 53 patients with mCRPC were included after they started first‐line AA‐P treatment. Blood was drawn at baseline, 1, 3, and 6 months after treatment initiation. The levels of predefined circulating RNAs earlier identified as being upregulated in patients with mCRPC (e.g., microRNAs, long noncoding RNAs, and mRNAs), were analyzed. Uni‐ and multivariable Cox regression and Kaplan–Meier analyses were used to analyze the prognostic value of the various circulating RNAs for PFS along treatment. Detectable levels of kallikrein‐related peptidase 3 (KLK3) mRNA at baseline were demonstrated to be an independent prognostic marker for PFS (201 vs 501 days, P = 0.00054). Three months after AA‐P treatment initiation, KLK3 could not be detected in the blood of responding patients, but was still detectable in 56% of the patients with early progression. Our study confirmed that KLK3 mRNA detection in whole blood is an independent prognostic marker in mCRPC patients receiving AA‐P treatment. Furthermore, the levels of circulating KLK3 mRNA in patients receiving AA‐P treatment might reflect treatment response or early signs of progression.     

Role of aneuploid circulating tumor cells and CD31+ circulating tumor endothelial cells in predicting and monitoring anti‐angiogenic therapy efficacy in advanced NSCLC

Prognosticating the efficacy of anti‐angiogenic therapy through longitudinal monitoring and early detection of treatment resistance in cancer patients remain highly challenging. In this study, co‐detection and comprehensive phenotypic and karyotypic molecular characterization of aneuploid circulating tumor cells (CTCs) and circulating tumor endothelial cells (CTECs) were conducted on non‐small cell lung cancer (NSCLC) patients receiving bevacizumab plus chemotherapy. Prognostic values of the cell‐based significant univariate risk factors identified by Cox regression analyses were progressively investigated. Subjects showing an increase in total post‐therapeutic platelet endothelial cell adhesion molecule‐1 (CD31)^– CTCs and CD31⁺ CTECs exhibited a significantly reduced median progression‐free survival (mPFS) and overall survival. Further stratification analyses indicated that pretherapeutic patients bearing vimentin (Vim)⁺ CTECs (mesenchymal M‐type) at baseline revealed a significantly shortened mPFS compared with patients with Vim^– CTECs. Post‐therapeutic patients harboring epithelial cell adhesion molecule (EpCAM)⁺ CTCs and CTECs (epithelial E‐type), regardless of Vim expression or not, showed a significantly reduced mPFS. Post‐therapeutic patients possessing de novo EpCAM⁺/Vim⁺ (hybrid E/M‐type) CTECs displayed the shortest mPFS. Patients harboring either pre‐ or post‐therapeutic EpCAM^–/Vim^– null CTECs (N‐type) exhibited a better response to therapy compared to patients harboring EpCAM⁺ and/or Vim⁺ CTECs. The presented results support the notion that baseline Vim⁺ CTECs and post‐therapeutic EpCAM⁺ CTCs and CTECs are predictive biomarkers for longitudinal monitoring of response to anti‐angiogenesis combination regimens in NSCLC patients.     

D‐Dimer Enhances Risk‐Targeted Thromboprophylaxis in Ambulatory Patients with Cancer

BackgroundThromboprophylaxis for ambulatory patients with cancer is effective, although uncertainties remain on who should be targeted. Using D‐dimer values from individuals enrolled to the AVERT trial, we sought to identify and validate a more efficient venous thromboembolism (VTE) risk threshold for thromboprophylaxis.Materials and MethodsThe AVERT trial compared thromboprophylaxis with apixaban with placebo among patients with cancer with a Khorana Risk Score ≥2. The D‐dimer measured at randomization was used to calculate an individualized 6‐month VTE risk using the validated CATScore. A modified intention‐to‐treat analysis was used to assess efficacy (VTE) and safety (major and overall bleeding) in the (a) complete cohort and (b) ≥8% and < 8% 6‐month VTE risk thresholds.ResultsFive hundred seventy‐four patients were randomized in the AVERT trial; 466 (81%) with baseline D‐dimer were included in the study. Two hundred thirty‐seven subjects received apixaban; 229 received placebo. In the complete cohort, there were 13 (5.5%) VTE events in the apixaban arm compared with 26 (11.4%) events in the placebo arm (adjusted hazard ratio [aHR] 0.49 [0.25–0.95], p < .05). Number needed to treat (NNT) to prevent one VTE = 17. Eighty‐two (35%) and 72 (31%) patients in the apixaban and placebo arms, respectively, had a 6‐month VTE risk ≥8%. In this subgroup, 7 (8.4%) VTE events occurred with apixaban and 19 (26.3%) events with placebo (aHR 0.33 [0.14‐0.81], p < .05), NNT = 6. Individuals with a VTE risk <8% derived no benefit from apixaban thromboprophylaxis (aHR 0.89 [0.30–2.65), p = .84). Increased rates of overall bleeding were observed with apixaban in both the complete (aHR 2.11 [1.09–4.09], p < .05) and ≥ 8% predicted risk cohorts (aHR 2.87 [0.91–9.13], p = .07).ConclusionA 6‐month VTE risk threshold of ≥8% increases the efficiency of risk‐targeted thromboprophylaxis in ambulatory patients with cancer.Implications for PracticeAmbulatory patients with cancer receiving chemotherapy have an increased risk of venous thromboembolism (VTE). A Khorana Risk Score (KRS) ≥2 is currently the suggested threshold for thromboprophylaxis. Using baseline D‐dimer values from individuals enrolled to the AVERT trial, this retrospective validation study identifies a 6‐month VTE risk of ≥8% as a more efficient threshold for thromboprophylaxis. At this threshold, the number needed to treat to prevent one VTE is 6, compared with 17 when using a KRS ≥2. Conversely, individuals with a predicted risk of <8% derive no clinical benefit from thromboprophylaxis. Future prospective studies should validate this threshold for outpatient thromboprophylaxis.     

Postoperative Adjuvant Therapy Versus Surgery Alone for Stage IIB–III Esophageal Squamous Cell Carcinoma: A Phase III Randomized Controlled Trial

BackgroundRetrospective studies have shown that adjuvant treatment improves survival of patients with stage IIB–III esophageal squamous cell carcinoma, but there is no evidence from prospective trials so far.Materials and MethodsPatients with pathological stage IIB–III esophageal squamous cell carcinoma were randomly assigned to receive surgery alone (SA), postoperative radiotherapy (PORT), or postoperative concurrent chemoradiotherapy (POCRT). PORT patients received 54 Gy in 27 fractions; the POCRT group received 50.4 Gy in 28 fractions, plus concurrent chemotherapy with paclitaxel (135–150 mg/m²) and cisplatin or nedaplatin (50–75 mg/m²) every 28 days. The primary endpoint was disease‐free survival (DFS), and the secondary endpoint was overall survival (OS).ResultsA total of 172 patients were enrolled (SA, n = 54; PORT, n = 54; POCRT, n = 64). The 3‐year DFS was significantly better in PORT/POCRT patients than in SA patients (53.8% vs. 36.7%; p = .020); the 3‐year OS was also better in PORT/POCRT patients (63.9% vs. 48.0%; p = .025). The 3‐year DFS for SA, PORT, and POCRT patients were 36.7%, 50.0%, 57.3%, respectively (p = .048). The 3‐year OS for SA, PORT, and POCRT patients were 48.0%, 60.8%, 66.5%, respectively (p = .048).ConclusionPORT/POCRT (especially POCRT) may significantly improve DFS and OS in stage IIB–III esophageal squamous cell carcinoma.Implications for PracticeThe results of this phase III study indicated that postoperative radiotherapy/postoperative concurrent chemoradiotherapy (PORT/POCRT) could significantly improve disease‐free survival and overall survival in stage IIB–III esophageal squamous cell carcinoma compared with surgery alone with acceptable toxicities. In‐field and out‐of‐field recurrences were comparable between the POCRT and PORT groups, which demonstrates the rationality and safety of the radiation field used in this study. The postoperative regimens in this trial might be accepted as standard treatment options for pathological stage IIB–III esophageal cancer. Larger sample size prospective randomized trials to identify the value are warranted.     

CD24, not CD47, negatively impacts upon response to PD‐1/L1 inhibitors in non–small‐cell lung cancer with PD‐L1 tumor proportion score < 50

CD24, a heavily glycosylated glycosylphosphatidylinositol–anchored surface protein, inhibits phagocytosis as potently as CD47. The relationship between such anti‐phagocytic factors and the immune response with immune–checkpoint inhibitors (ICI) remains unexplored. We evaluated CD24 and CD47 tumor proportion scores (TPS) in 68 of the 106 patients with advanced non–small‐cell lung cancer who participated in a prospective observational study of ICI treatment. We also explored the impact of CD24 TPS and CD47 TPS on ICI efficacy and serum cytokine changes. CD24 positivity (TPS ≥ 1) was negatively associated with progression–free survival (PFS) of ICI when PD‐L1 TPS was < 50 (median PFS; 37 vs 127 d, P = .033), but there was no association when PD‐L1 TPS was ≥ 50 (median PFS; 494 vs 144 d, P = .168). CD24 positivity was also related to significantly higher increase of CCL2 from baseline to 4‐6 wk later, and such increase was notably observed only when PD‐L1 TPS < 50 (P = .0004). CCL2 increase after ICI initiation was negatively predictive for survival after initiation of ICI (median survival time; not reached vs 233 d; P = .028). CD47 TPS high (≥60) significantly suppressed the increase in vascular endothelial growth factor (VEGF)‐A, D and PDGF‐AB/BB after ICI initiation. There was no association, however, between CD47 tumor expression and the efficacy of ICI. In conclusion, CD24, not CD47, is a candidate negative predictive marker of ICI in advanced, non–small‐cell lung cancer with PD‐L1 TPS < 50. Tumor expression of both CD24 and CD47 was associated with changes in factors related to monocytes and angiogenesis after ICI initiation (UMIN000024414).