Apatinib in Combination with S-1 as First-Line Treatment in Patients with Advanced Metastatic Gastric Cancer: Results from an Open,Exploratory, Single-Arm,Phase II Trial

Lessons Learned

• Apatinib combined with S‐1 was not superior to other chemotherapy regimens as first‐line therapy for advanced gastric cancer.
• There was a tendency for patients with lymph node metastasis to have prolonged median progression‐free survival and median overall survival, compared with patients with liver metastasis.

BackgroundThe best choice of first‐line chemotherapy regimen for patients with metastatic gastric cancer is still debated. We combined apatinib and S‐1 as a new first‐line therapy to treat advanced gastric cancer. The efficacy and safety of the combination were assessed, with the goal of determining the most appropriate subgroup of patients who could benefit from this new regimen.MethodsThis study was an open, exploratory single‐arm, phase II trial. Enrolled patients received apatinib plus S‐1 treatment (apatinib, 500 mg, once a day [qd], days 1–21; S‐1, 40 mg/m², bid, days 1–14). The primary endpoints were progression‐free survival (PFS) and safety of this new regimen. Next‐generation sequencing was used to explore potential biomarkers.ResultsA total of 30 patients were enrolled. The median progression‐free survival (mPFS) was 4.21 months (95% confidence interval [CI], 2.29–6.13 months). The median overall survival (mOS) was 7.49 months (95% CI, 4.81–10.17 months). Patients with lymph node metastasis had prolonged mPFS and mOS when compared with those with liver metastasis (mPFS, 4.21 vs. 1.84 months; mOS, 8.21 vs. 6.31 months, p = .08). The most common grade 3 to 4 adverse events were abdominal pain, dizziness, and diarrhea. Gene mutation profiles between the two subgroups were significantly different.ConclusionApatinib combined with S‐1 was not superior to other chemotherapy regimens as first‐line therapy for advanced gastric cancer. Toxicity was consistent with known profiles when given as monotherapy. There was a tendency toward prolonged mPFS and mOS in patients with lymph node metastasis compared with patients with liver metastasis, which could support the need to design a future clinical trial with a better defined patient population.     

Activity of Sorafenib Plus Capecitabine in Previously Treated Metastatic Colorectal Cancer

Lessons Learned

• Treatment for patients with metastatic colorectal cancer (mCRC) typically involves multiple lines of therapy with eventual development of treatment resistance.
• In this single‐arm, phase II study involving heavily pretreated patients, the combination of sorafenib and capecitabine yielded a clinically meaningful progression‐free survival of 6.2 months with an acceptable toxicity profile.
• This oral doublet therapy is worthy of continued investigation for clinical use in patients with mCRC.

BackgroundCapecitabine (Cape) is an oral prodrug of the antimetabolite 5‐fluorouracil. Sorafenib (Sor) inhibits multiple signaling pathways involved in angiogenesis and tumor proliferation. SorCape has been previously studied in metastatic breast cancer.MethodsThis single‐arm, phase II study was designed to evaluate the activity of SorCape in refractory metastatic colorectal cancer (mCRC). Patients received Sor (200 mg p.o. b.i.d. max daily) and Cape (1,000 mg/m² p.o. b.i.d. on days 1–14) on a 21‐day treatment cycle. Primary endpoint was progression‐free survival (PFS) with preplanned comparison with historical controls.ResultsForty‐two patients were treated for a median number of 3.5 cycles (range 1–39). Median PFS was 6.2 (95% confidence interval [CI], 4.3–7.9) months, and overall survival (OS) was 8.8 (95% CI, 4.3–12.2) months. One patient (2.4%) had partial response (PR), and 22 patients (52.4%) had stable disease (SD) for a clinical benefit rate of 54.8% (95% CI, 38.7%–70.2%). Hand‐foot syndrome was the most common adverse event seen in 36 patients (85.7%) and was grade ≥ 3 in 16 patients (38.1%). One patient (2.4%) had a grade 4 sepsis, and one patient (2.4%) died while on treatment.ConclusionSorCape in this heavily pretreated population yielded a reasonable PFS with manageable but notable toxicity. The combination should be investigated further.     

Phase Ib/II Study of Biweekly TAS-102 in Combination with Bevacizumab for Patients with Metastatic Colorectal Cancer Refractory to Standard Therapies (BiTS Study)

Lessons Learned

• A biweekly TAS‐102 plus BEV schedule in patients with heavily pretreated mCRC showed equivalent efficacy with less toxicity compared with the current schedule of TAS‐102 plus BEV combination.
• Biweekly TAS‐102 plus BEV combination could reduce unnecessary dose reduction of TAS‐102, maintain higher doses, and possibly be effective even in cases without chemotherapy‐induced neutropenia (CIN).
• The prespecified subgroup analysis of this study showed an obvious association between CIN within the first two cycles and prognosis of biweekly TAS‐102 plus BEV.

BackgroundTAS‐102 (trifluridine/tipiracil) plus bevacizumab (BEV) combination therapy has shown promising activity in patients with metastatic colorectal cancer (mCRC). However, the previously reported dose and schedule for the TAS‐102 (70 mg/m²/day on days 1–5 and 8–12, every 4 weeks) plus BEV (5 mg/kg on day 1, every 2 weeks) regimen is complicated by severe hematological toxicities and difficult administration schedules. Here, we evaluated the efficacy and safety of a more convenient biweekly TAS‐102 plus BEV combination.MethodsPatients with mCRC who were refractory or intolerant to standard chemotherapies were enrolled. Patients received biweekly TAS‐102 (twice daily on days 1–5, every 2 weeks) with BEV (5mg/kg on day 1, every 2 weeks). The primary endpoint was progression‐free survival rate at 16 weeks (16‐w PFS rate).ResultsFrom October 2017 to January 2018, 46 patients were enrolled. The recommended phase II dose was determined to be TAS‐102 (70 mg/m²/day). Of the 44 eligible patients, the 16‐w PFS rate was 40.9% (95% confidence interval, 26.3%–56.8%), and the null hypothesis was rejected (p < .0001). Median progression‐free survival (PFS) and overall survival were 4.29 months and 10.86 months, respectively. Disease control rate was 59.1%. Common grade 3 or higher adverse events were hypertension (40.9%), neutropenia (15.9%), and leucopenia (15.9%).ConclusionBiweekly TAS‐102 plus BEV showed promising antitumor activity with safety.     

Single-Agent Versus Double-Agent Chemotherapy in Concurrent Chemoradiotherapy for Esophageal Squamous Cell Carcinoma: Prospective,Randomized, Multicenter Phase II Clinical Trial

Lessons Learned

• The efficacy of single‐agent chemotherapy was not significantly different from that of double‐agent chemotherapy in concurrent chemoradiotherapy for inoperable esophageal squamous cell carcinoma.
• Single‐agent concurrent chemoradiotherapy had lower gastrointestinal and hematologic toxicity.
• Overall survival and progression‐free survival were not significantly different between single‐ and double‐agent concurrent chemoradiotherapy.

BackgroundThis multicenter, randomized, phase II trial aimed to compare the efficacy and safety of single‐agent concurrent chemoradiotherapy using the oral fluoropyrimidine S‐1 with those of double‐agent concurrent chemoradiotherapy using S‐1 and cisplatin in patients with inoperable esophageal squamous cell carcinoma.MethodsPatients with inoperable esophageal squamous cell carcinoma (clinical stages I to III) were randomly allocated to the single‐agent group (S‐1) or the double‐agent group (S‐1/cisplatin). The concurrent intensity‐modulated radiation therapy plan was similar for both groups: planning target volume 1.8 Gy/f*30–33f and planning gross target volume of 2 Gy/f*30–33f. The primary outcome measure was the endoscopic complete response rate.ResultsOf the 105 patients randomized, 89 were assessable. The endoscopic complete response rate was 46.9% (23/49) in the single‐agent group and 52.5% (21/40) in double‐agent group. The median progression‐free survival within a median follow‐up of 23 months was 20 and 21 months, respectively. The median overall survival was 26 months and not reached, respectively. Grade 3 hematological toxicities occurred in 4.1% and 27.5% of the patients in the single‐ and the double‐agent group, respectively.ConclusionSingle‐agent chemotherapy in concurrent chemoradiotherapy for inoperable esophageal squamous cell carcinoma has good efficacy and safety, thus warranting a phase III trial.     

A Phase II Study of Apatinib in Patients with Chemotherapy-Refractory Esophageal Squamous Cell Carcinoma (ESO-Shanghai 11)

Lessons Learned

• Apatinib has potential as an effective and safe second‐line or higher treatment for patients with chemotherapy‐refractory esophageal squamous cell carcinoma (ESCC).
• Clinical safety is of potential concern when administering apatinib to patients with uncontrolled esophageal lesions or severe invasion of trachea, bronchi, or major blood vessels.
• To the best of the authors'' knowledge, this is the first prospective phase II study to investigate apatinib for patients with chemotherapy‐refractory ESCC. Apatinib could provide an alternative option for ESCC after first‐line or higher therapy in carefully selected patients.

BackgroundThe aim of this study was to evaluate the efficacy and adverse effects of the oral vascular endothelial growth factor receptor 2 (VEGFR‐2) tyrosine kinase inhibitor apatinib in patients with chemotherapy‐refractory esophageal squamous cell carcinoma (ESCC).MethodsWe enrolled patients with chemotherapy‐refractory ESCC. All patients received continuous apatinib 500 mg once daily.ResultsBetween July 2017 and August 2018, 40 patients were recruited, of whom 5 (12.5%) had uncontrolled primary tumors. Additionally, three patients with partial response (PR) and 23 with stable disease (SD) were observed for overall response rate (ORR) of 7.5% and disease control rate (DCR) of 65.0%. Median progression‐free survival (PFS) was 3.8 months (95% confidence interval [CI], 2.2–5.4); median overall survival (OS) was 5.8 months (95% CI, 3.2–8.4). Common adverse effects were fatigue (15%), hypertension (12.5%), and palmar‐plantar erythrodysesthesia syndrome (10%). Two cases of death from massive bronchopulmonary hemorrhage were observed, and esophageal fistula occurred in another two patients. Notably, both patients with esophageal fistula and one patient with massive fatal bronchopulmonary hemorrhage were individuals with uncontrolled primary tumors (3/5, 60%). Fatal bronchopulmonary hemorrhage in a second patient was associated with major blood vessel invasion.ConclusionApatinib has potential as an effective and safe treatment for patients with chemotherapy‐refractory ESCC whose primary tumors are controlled and without severe invasion of trachea, bronchi, or major blood vessels.     

Safety and Feasibility of Radiotherapy Plus Camrelizumab for Locally Advanced Esophageal Squamous Cell Carcinoma

Lessons Learned

• Radiotherapy plus anti–PD‐1 antibody as first‐line therapy is safe and feasible in locally advanced esophageal squamous cell carcinoma (ESCC).
• Tumor‐infiltrating and peripheral lymphocytes were associated with patient survival.
• Further studies combining chemoradiotherapy with immunotherapy in locally advanced ESCC and exploration of predictive biomarkers are warranted.

BackgroundWe conducted a phase Ib study of radiotherapy plus programmed cell death protein 1 (PD‐1) monoclonal antibody camrelizumab as first‐line treatment for locally advanced esophageal squamous cell carcinoma (ESCC).MethodsWe planned to enroll 20 patients with newly diagnosed locally advanced ESCC. Patients received 60 Gy radiation (2.0 Gy/fraction, 5 fractions/week), with camrelizumab (200 mg every 2 weeks) starting with radiotherapy and continuing for 32 weeks (i.e., for 16 cycles). The primary endpoints were safety and feasibility. Secondary endpoints were rates of radiologic and pathologic response, overall survival (OS), and progression‐free survival (PFS). Study data were collected by the week during radiotherapy (RT), every month during the maintenance camrelizumab treatment, and every 3 months after treatment. Tumor microenvironment and peripheral blood were monitored at baseline and after 40 Gy radiation for association with efficacy.ResultsTwenty patients were enrolled and received treatment. One patient (patient 10) was excluded upon discovery of a second tumor in the bladder during treatment, leaving 19 patients for analysis. Toxicity was deemed tolerable. Fourteen (74%) patients had assessed objective response. At a median follow‐up time of 31.0 months (95% confidence interval [CI], 27.0–35.1), median OS and PFS times were 16.7 months (95% CI, 5.9–27.9) and 11.7 months (95% CI, 0–30.3), respectively. OS and PFS rates at 24 months were 31.6% and 35.5%, respectively. Kaplan‐Meier analysis revealed associations between the following factors and OS/PFS: tumor programmed cell death ligand 1 (PD‐L1) expression, PD‐1⁺CD8⁺, PD‐1⁺CD4⁺ T cells, and PD‐L1⁺CD4⁺ T cells; peripheral blood CD4⁺, CD8⁺, CD4⁺ regulatory T cells, and their subsets.ConclusionRadiotherapy plus camrelizumab had manageable toxicity and antitumor efficacy for locally advanced ESCC. Several biomarkers were associated with clinical benefit and deserve further study.     

A Phase II Clinical Trial on the Combination Therapy of PHY906 Plus Capecitabine in Hepatocellular Carcinoma

Lessons Learned

• A PHY906 and capecitabine combination could be effective as a salvage therapy for patients with hepatocellular carcinoma (HCC) previously treated with multiple systemic therapies.
• This traditional Chinese medicine formulation can work with Western cancer chemotherapeutic agents to improve clinical outcomes or alleviate side effects for patients with advanced HCC.

BackgroundThis study aimed to evaluate efficacy and safety of capecitabine combined with a PHY906 (a pharmaceutical‐grade formulation of four traditional Chinese herbs) in the treatment of advanced hepatocellular carcinoma (HCC) in Asian patients who were positive for hepatitis B virus (HBV).MethodsThis study was an open‐label, phase II safety and efficacy clinical trial of PHY906 and capecitabine in patients with advanced HCC. Patients received 750 mg/m² capecitabine b.i.d. 14 days plus 800 mg of PHY906 b.i.d. on days 1–4 and days 8–11 every 21‐day cycle. The primary endpoint was 6‐month survival rate, and secondary endpoints were progression‐free survival, overall survival, disease control rate, and safety.ResultsThirty‐nine subjects completed the study with a 46.2% stable disease rate. The median progression‐free survival was 1.5 months, and median overall survival (mOS) was 6 months with a 51.3% 6‐month survival rate. The most common adverse events included lower hemoglobin, diarrhea, pain, abdomen (not otherwise specified), fatigue, increased aspartate aminotransferase, and bilirubin. Patients who (a) had not received previous chemotherapies or targeted therapy or (b) had lower starting alpha‐fetoprotein (AFP) levels or (c) had HBV infection showed better clinical outcome.ConclusionOur data showed that PHY906 increases the therapeutic index of capecitabine by enhancing its antitumor activity and reduces its toxicity profile in advanced HCC.     

Neoadjuvant Pyrotinib plus Trastuzumab and Chemotherapy for Stage I–III HER2‐Positive Breast Cancer: A Phase II Clinical Trial

Lessons Learned

• This is the first trial to explore the neoadjuvant therapy of pyrotinib in HER2‐positive operable and locally advanced breast cancer, in combination with epirubicin plus cyclophosphamide followed by docetaxel plus trastuzumab.
• Results primarily showed that pyrotinib in combination with epirubicin plus cyclophosphamide followed by docetaxel plus trastuzumab was effective and safe in HER2‐positive operable and locally advanced breast cancer.
• A subsequent randomized controlled trial is still warranted to confirm these results.

BackgroundThe efficacy and safety of neoadjuvant therapy of pyrotinib, a new irreversible tyrosine kinase inhibitor (TKI), was first estimated in patients with HER2‐positive breast cancer in this phase II study, in combination with trastuzumab and chemotherapy.MethodsBetween February 19, 2019, and November 20, 2019, 20 female Chinese patients with stage I–III HER2‐positive breast cancer were assigned to receive eight cycles of neoadjuvant pyrotinib (P) in combination with four cycles of epirubicin (E) and cyclophosphamide (C) followed by four cycles of docetaxel (T) and trastuzumab (H), once every 3 weeks, referred to as P + EC‐TH.ResultsA total of 19 patients completed the therapy and final surgery. The total pathological complete response (tpCR) rate was 73.7% (95% confidence interval [CI], 48.8–90.9), and no recurrence or metastasis occurred during the short‐term follow‐up period. The objective response rate (ORR) was 100% (95% CI, 82.4–100). The most common adverse events (AEs) were diarrhea and leukopenia in 18 of 20 patients (90%), but no grade 5 AEs were reported.ConclusionThis study showed that in HER2‐positive operable or locally advanced breast cancer, the tpCR rate of P + EC‐TH neoadjuvant therapy was about twice as high as that of EC‐TH neoadjuvant therapy reported in other trials, with tolerable side effects.     

Erlotinib for Non-Small Cell Lung Cancer with Leptomeningeal Metastases: A Phase II Study (LOGIK1101)

Lessons Learned

• This phase II trial evaluated the efficacy of erlotinib for patients with non‐small cell lung cancer with leptomeningeal metastasis.
• The 17 cerebrospinal fluid specimens that were available for epidermal growth factor receptor mutation analysis were all negative for the resistance‐conferring T790M mutation.
• The cytological objective clearance rate was 30.0% (95% confidence interval: 11.9%–54.3%). The median time to progression was 2.2 months.
• The rate of cerebrospinal fluid penetration among these patients was equivalent to those in previous reports regarding leptomeningeal metastasis.

BackgroundLeptomeningeal metastases (LM) occur in approximately 5% of patients with non‐small cell lung cancer (NSCLC) and are associated with a poor prognosis. However, no prospective study has identified an active chemotherapeutic drug in this setting.MethodsPatients were considered eligible to receive erlotinib if they had NSCLC with cytologically confirmed LM. The objective cytological clearance rate, time to LM progression (TTP), overall survival (OS), quality of life outcomes, and pharmacokinetics were analyzed. This study was closed because of slow accrual at 21 of the intended 32 patients (66%).ResultsBetween December 2011 and May 2015, 21 patients (17 with activating epidermal growth factor receptor [EGFR] mutations) were enrolled. The 17 cerebrospinal fluid specimens available were all negative for the T790M mutation, which confers erlotinib resistance. The clearance rate was 30.0% (95% confidence interval [CI]: 11.9%–54.3%), the median TTP was 2.2 months, and the median OS was 3.4 months. Significantly longer TTP and OS times were observed in patients with mutant EGFR (p = .0113 and p < .0054, respectively). The mean cerebrospinal fluid penetration rate was 3.31% ± 0.77%. There was a good correlation between plasma and cerebrospinal fluid (CSF) concentrations, although there was no clear correlation between pharmacokinetic parameters and clinical outcome.ConclusionErlotinib was active for LM and may be a treatment option for patients with EGFR‐mutated NSCLC and LM.     

A Randomized Phase II Study of AGS-16C3F Versus Axitinib in Previously Treated Patients with Metastatic Renal Cell Carcinoma

Lessons Learned

• The primary endpoint of this phase II study that evaluated the efficacy and safety of the investigational compound, AGS‐16C3F, versus axitinib in previously treated patients with metastatic renal cell carcinoma (mRCC) was not met.
• Median progression‐free survival, the primary endpoint, was 2.9 months with AGS‐16C3F and 5.7 months with axitinib (HR, 1.676; 95% CI, 1.107–2.537; p = .015), per investigator assessment
• The safety profile for each study drug was as expected, with the most commonly reported adverse events being fatigue (53%) and nausea (47%) in the AGS‐16C3F arm and fatigue (57%) and diarrhea (48%) in the axitinib arm.
• These results provide a benchmark for axitinib use in heavily pretreated patients with mRCC.

BackgroundAGS‐16C3F is a novel antibody‐drug conjugate that targets cell‐surface ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) and is conjugated to a microtubule disruptive agent. Here we present findings from a phase II study of AGS‐16C3F versus axitinib in metastatic renal cell carcinoma (mRCC).MethodsPatients with mRCC of any histology and disease progression during or after their last treatment regimen were randomized 1:1 to intravenous AGS‐16C3F 1.8 mg/kg every 3 weeks or oral axitinib 5 mg twice daily (starting dose). The primary objective was investigator‐assessed progression‐free survival (PFS) of AGS‐16C3F versus axitinib (RECIST version 1.1).ResultsIn the total population (N = 133), 63% (n = 84) of patients had completed the study at data cutoff (August 21, 2019). Median PFS was 2.9 months with AGS‐16C3F and 5.7 months with axitinib (hazard ratio [HR], 1.676; 95% confidence interval [CI], 1.107–2.537; p = .015). There were no significant differences between arms in secondary efficacy endpoints, including overall survival (13.1 months, AGS‐16C3F and 15.4 months, axitinib; HR, 1.079; 95% CI, 0.681–1.707; p = .747). In the safety population (n = 131), the most commonly reported adverse events were fatigue (53%) and nausea (47%) in the AGS‐16C3F arm and fatigue (57%) and diarrhea (48%) in the axitinib arm. The incidence of diarrhea was lower in the AGS‐16C3F arm than in the axitinib arm (17% vs. 48%), and ocular toxicities were more frequent in the AGS‐16C3F arm than in the axitinib arm (44% vs. 26%).ConclusionThe investigational compound, AGS‐16C3F, did not meet the primary endpoint of this trial. These study results provide a benchmark for axitinib use in heavily pretreated patients with mRCC.     

Salvage Treatment Using Anti–PD-1/CTLA-4 Immunotherapy After Failure of Neoadjuvant Chemotherapy in Microsatellite Instable Gastroesophageal Carcinoma

Perioperative chemotherapy is standard treatment for patients with early high‐risk gastroesophageal adenocarcinoma independent of molecular subtype. Approximately 8% of gastroesophageal cancers have a microsatellite instable phenotype (MSI‐H), and retrospective analyses of neoadjuvant/adjuvant chemotherapy trials suggests no survival benefit in this patient population compared with surgery alone. Patients with advanced MSI‐H malignancies obtain durable responses with immunotherapy using anti–programmed cell death protein 1 (PD‐1) checkpoint blockade. We describe a case of a patient with an early MSI‐H gastroesophageal adenocarcinoma who progressed on neoadjuvant chemotherapy precluding subsequent surgical resection. The patient was subsequently treated with immunotherapy using the anti–PD‐1 antibody nivolumab and the anti–cytotoxic T‐lymphocyte–associated protein 4 (CTLA‐4) antibody ipilimumab leading to a complete remission with biopsies of the residual tumor mass and regional lymph nodes revealing no residual tumor. This case highlights the lack of benefit from neoadjuvant chemotherapy in patients with MSI‐H gastroesophageal cancers and suggests that perioperative anti–PD‐1–based immunotherapy should be further investigated in this patient population.Key Points

• This report describes the successful salvage treatment of a patient with an early high‐risk MSI‐H gastroesophageal carcinoma who progressed through neoadjuvant chemotherapy using combination immunotherapy of the anti–programmed cell death protein 1 (PD‐1) antibody nivolumab and the anti–cytotoxic T‐lymphocyte–associated protein 4 (CTLA‐4) antibody ipilimumab, leading to an ongoing complete remission.
• The case is in keeping with retrospective analyses of perioperative treatment trials demonstrating a lack of chemotherapy benefit in patients with MSI‐H gastroesophageal carcinoma and supports the further investigation of anti–PD‐1–based immunotherapy as a treatment modality in this patient population.
• The case highlights the potential difficulties that may be encountered in the surgical management of patients treated with neoadjuvant immunotherapy with reactive dense fibrotic changes precluding surgical resection.

     

Avelumab,a PD-L1 Inhibitor,in Combination with Hypofractionated Radiotherapy and the Abscopal Effect in Relapsed Refractory Multiple Myeloma

Lessons Learned

• Despite the initial optimism for using immune checkpoint inhibition in the treatment of multiple myeloma, subsequent clinical studies have been disappointing.
• Preclinical studies have suggested that priming the immune system with various modalities in addition to checkpoint inhibition may overcome the relative T‐cell exhaustion or senescence; however, in this small data set, radiotherapy with checkpoint inhibition did not appear to activate the antitumor immune response.

BackgroundExtramedullary disease (EMD) is recognized as an aggressive subentity of multiple myeloma (MM) with a need for novel therapeutic approaches. We therefore designed a proof‐of‐principle pilot study to evaluate the synergy between the combination of the anti–PD‐L1, avelumab, and concomitant hypofractionated radiotherapy.MethodsThis was a single‐arm phase II Simon two‐stage single center study that was prematurely terminated because of the COVID‐19 pandemic after enrolling four patients. Key eligibility included patients with relapsed/refractory multiple myeloma (RRMM) who had exhausted or were not candidates for standard therapy and had at least one lesion amenable to radiotherapy. Patients received avelumab until progression or intolerable toxicity and hypofractionated radiotherapy to a focal lesion in cycle 2. Radiotherapy was delayed until cycle 2 to allow the avelumab to reach a study state, given the important observation from previous studies that concomitant therapy is needed for the abscopal effect.ResultsAt a median potential follow‐up of 10.5 months, there were no objective responses, one minimal response, and two stable disease as best response. The median progression‐free survival (PFS) was 5.3 months (95% confidence interval [CI]: 2.5–7.1 months), and no deaths occurred. There were no grade ≥3 and five grade 1–2 treatment‐related adverse events.ConclusionAvelumab in combination with radiotherapy for patients with RRMM and EMD was associated with very modest systemic clinical benefit; however, patients did benefit as usual from local radiotherapy. Furthermore, the combination was very well tolerated compared with historical RRMM treatment regimens.     

First-in-Class Selective HDAC6 Inhibitor (ACY-1215) Has a Highly Favorable Safety Profile in Patients with Relapsed and Refractory Lymphoma

Lessons Learned

• Oral selective HDAC6 inhibitors could allow for decreased toxicity compared to pan‐class inhibitors, and increased ease of use.
• ACY‐1215 is well tolerated and led to disease stabilization in 50% of patients treated on a twice‐daily dosing schedule.
• Rational drug combinations with ACY‐1215 improve efficacy in patients with lymphoma.
• Biomarkers such as XBP‐1 level or HDAC6‐score may improve patient selection.

BackgroundACY‐1215, ricolinostat, is an oral, first‐in‐class isoform‐selective HDAC6 inhibitor. HDAC6 is a class IIb deacetylase and plays a critical role in protein homeostasis via the unfolded protein response (UPR). Lymphocytes generate a large repertoire of antibodies and depend on an activated UPR to maintain proteostasis. Lymphomas utilize this biology to evade programmed cell death. In preclinical models of lymphoma, ACY‐1215 disrupted proteostasis, triggering apoptosis.MethodsWe translated these findings into a multi‐institution, open‐label, dose‐escalation phase Ib/II study aimed to determine the safety and efficacy in patients with relapsed and refractory lymphoma.ResultsTwenty‐one patients with heavily pretreated lymphoma were accrued. Patients in the phase Ib portion were enrolled on one of two dose cohorts [Arm A: 160 mg daily (n = 3) or Arm B: 160 mg twice daily (n = 10)]. ACY‐1215 was well tolerated. There were no dose limiting toxicities. Most adverse events were grade 1–2, including diarrhea (57%), nausea (57%), and fatigue (43%). Grade 3–4 toxicities were rare and included anemia (9.5%) and hypercalcemia (9.5%). An additional 8 patients were enrolled on the phase II portion, at 160 mg twice daily. Sixteen patients were evaluable for response. ACY‐1215 did not result in any complete or partial responses in patients treated. Eight patients had stable disease (50%) lasting a median duration of 4.5 months, all of whom were treated twice daily. Disease progressed in eight patients (50%) at cycle 2. Five patients were not evaluable due to disease progression prior to cycle 2. The median PFS was 56 days.ConclusionACY‐1215 is an oral selective HDAC6 inhibitor that was safe in patients with relapsed and refractory lymphoid malignancies and led to disease stabilization in half of the evaluable patients.     

Phase Ib Study of Enzalutamide with or Without Sorafenib in Patients with Advanced Hepatocellular Carcinoma

Lessons Learned

• Androgen receptor as assessed by immunohistochemistry is expressed in a high proportion of patients with hepatocellular carcinoma (HCC).
• Enzalutamide at 160 mg orally daily is safe and tolerable in patients with advanced HCC but has no single‐agent antitumor activity.
• Enzalutamide, a CYP3A4 inducer, at a standard dose of 160 mg reduces the exposure of sorafenib, a CYP3A4 substrate.
• Enzalutamide and sorafenib is safe and tolerable in patients with advanced HCC, but the addition of enzalutamide to sorafenib did not enhance the antitumor activity of sorafenib.

BackgroundAndrogen receptor (AR) interference is deleterious to hepatocellular carcinoma (HCC) in preclinical models.MethodsThis is a multicenter, phase Ib study of enzalutamide ± sorafenib in patients with advanced HCC. In part 1, a 3 + 3 dose de‐escalation design with expansion established the recommended phase II dose (RP2D) of enzalutamide in patients in whom sorafenib treatment had failed. In part 2, a 3 + 3 dose escalation with expansion established the safety of enzalutamide with sorafenib in treatment‐naive patients with HCC. Secondary objectives included objective response rate (ORR), progression‐free survival (PFS), overall survival (OS), pharmacokinetics (PK), and determination of AR expression by immunohistochemistry. A 7‐day run‐in with sorafenib alone in part 2 allowed assessment of the impact of enzalutamide on sorafenib pharmacokinetics.ResultsIn part 1, 16 patients received enzalutamide 160 mg daily. No dose‐limiting toxicity (DLT) occurred; 1 patient required dose reduction. Responses were not observed; median PFS and OS were 1.8 (95% confidence interval [CI]: 1.6–3.6) and 7 (95% CI: 3.6 to not reached [NR]) months, respectively. In part 2, patients received sorafenib 400 mg daily (4) or twice a day (8) both with enzalutamide at the recommended phase II dose—no DLTs were observed. ORR was 10% (95% CI: 0.3–44.5), and median PFS and OS were 2.9 (95% CI: 1.6 to NR) and 6.7 (95% CI: 4.6 to NR) months, respectively. Enzalutamide reduced sorafenib exposure by 60%. Tumor AR expression did not associate with outcome.ConclusionEnzalutamide is ineffective in HCC; further development is not supported by this study.     

Does Scalp Cooling Have the Same Efficacy in Black Patients Receiving Chemotherapy for Breast Cancer?

Lessons Learned

• Despite U.S. Food and Drug Administration approval to reduce alopecia, data on efficacy of scalp cooling in Black patients with cancer are limited by lack of minority representation in prior clinical trials.
• Scalp cooling devices may have less efficacy in Black patients; additional studies are required to explore the possible causes for this, including hair texture and cap design.

BackgroundThe Paxman scalp cooling (SC) device is U.S. Food and Drug Administration (FDA)‐approved for prevention of chemotherapy‐induced alopecia. Studies report 50%–80% success rates and high patient satisfaction, yet there have been no studies of SC in Black patients. We conducted a phase II feasibility study of Paxman SC with a planned enrollment of 30 Black patients receiving chemotherapy for stage I–III breast cancer.MethodsBlack patients who planned to receive at least four cycles of chemotherapy with non‐anthracycline (NAC) or anthracycline (AC) regimens were eligible. Alopecia was assessed by trained oncology providers using the modified Dean scale (MDS) prior to each chemotherapy session. Distress related to alopecia was measured by the Chemotherapy Alopecia Distress Scale (CADS).ResultsFifteen patients enrolled in the intervention before the study was closed early because of lack of efficacy. Median MDS and CADS increased after SC, suggesting increased hair loss (p < .001) and alopecia distress (p = .04). Only one participant was successful in preventing significant hair loss; the majority stopped SC before chemotherapy completion because of grade 3 alopecia (>50% hair loss).ConclusionSC may not be efficacious in preventing alopecia in Black women. Differences in hair thickness, hair volume, and limitations of cooling cap design are possible contributing factors.     

Metastatic Low-Grade Sarcoma with CARS-ALK Fusion Dramatically Responded to Multiple ALK Tyrosine Kinase Inhibitors: A Case Report with Comprehensive Genomic Analysis

This article reports a case of advanced metastatic low‐grade sarcoma. The patient was diagnosed with an inoperable large (14 × 12 cm) lesion on his neck in September 2015 and underwent two ineffective chemotherapies in the following 4 months. Interestingly, although several pathologists could not agree on the histopathological diagnosis, the precise molecular pathological diagnosis was obtained using next‐generation sequencing (NGS) and finally brought excellent therapeutic effects. The patient was detected to have CARS‐ALK fusion by NGS and then was successfully treated with crizotinib orally. He received surgical resection of primary and metastatic lesions after tumor shrinkage. The combined treatment brought a durable response for 40 months. Although the tumor recurred in July 2019, the patient has been responding well to the second‐line ALK tyrosine kinase inhibitor alectinib to date. We performed whole genome sequencing on the patient''s primary, metastatic, and recurrent tumors and did comprehensive genomic analysis. Furthermore, our analysis results revealed that a whole genome duplication event might have happened during tumorigenesis of this case.Key Points

• To our best knowledge, this is the first report of a very successful treatment with first‐ and second‐line ALK tyrosine kinase inhibitors for CARS‐ALK fusion–positive metastatic low‐grade sarcoma.
• Molecular pathological result can guide precision treatment for sarcoma, even when the exact histopathology cannot be obtained.
• Multiple samples from this patient were analyzed using whole genome sequencing. Results provided detailed genomic characteristics and showed tumor evolution of this low‐grade sarcoma case.
• A whole genome duplication event might have happened during tumorigenesis of this low‐grade sarcoma case.

     

Clinical Benefit of Tyrosine Kinase Inhibitors in Advanced Lung Cancer with EGFR-G719A and Other Uncommon EGFR Mutations

The optimal management of advanced non‐small cell lung cancer (NSCLC) with noncanonical epidermal growth factor receptor (EGFR) mutations (i.e., exon 19 deletion and exon 21 L858R) is constrained by the heterogeneous behavior of individual uncommon mutations and limited prospective clinical data in this setting. Despite encouraging results with osimertinib from a recently published phase II trial from South Korea, afatinib remains the only currently approved drug for patients with tumors harboring uncommon EGFR mutations (i.e., S768I, L861Q, and/or G719X). When used at the standard dose of 40 mg daily, afatinib is associated with significant rates of treatment‐related adverse events, leading to frequent dose reductions and treatment discontinuations. We report a case of a woman with advanced NSCLC harboring EGFR‐G719A mutation treated with afatinib (at an off‐label pulse dose strategy that merits further evaluation in prospective studies) with sustained partial response for 20 months with manageable expected toxicities. Subsequent disease progression was mediated by off‐target pan‐EGFR inhibitor (including osimertinib)–resistant KRAS mutation and not by acquisition of EGFR‐T790M. We further present the current state of evidence in the literature behind use of first‐, second‐, and third‐generation tyrosine kinase inhibitors and summarize the evolving spectrum of activity ascribed to osimertinib (and newer EGFR inhibitors with a more favorable therapeutic window and intracranial penetration) in this population of patients with advanced NSCLC and uncommon EGFR mutations.Key Points

• Uncommon EGFR mutations characterize a heterogeneous group of patients with advanced non‐small cell lung cancer (NSCLC).
• Afatinib is the only currently U.S. Food and Drug Administration–approved drug for management of advanced NSCLC with uncommon EGFR mutations (S768I, L861Q, and/or G719X).
• Afatinib treatment at 40 mg daily is associated with high rates of adverse events and dose reductions; alternative strategies including pulse intermittent dosing should be evaluated prospectively.
• Osimertinib (with favorable safety profile and intracranial penetration) has shown promising results in this population in a phase II trial from South Korea; additional trials are ongoing.

     

A Phase II Single Arm Pilot Study of the CHK1 Inhibitor Prexasertib (LY2606368) in BRCA Wild-Type,Advanced Triple-Negative Breast Cancer

Lessons Learned

• Monotherapy with prexasertib demonstrated modest activity in BRCA wild‐type, recurrent triple‐negative breast cancer, highlighting the unmet need for combination treatment strategies.
• Neutropenia, anemia, and thrombocytopenia are common with the use of prexasertib but are manageable with supportive care measures. Prophylactic use of granulocyte colony stimulating factor should be considered to avoid dose reductions or treatment delays.
• Pharmacodynamic studies showed prexasertib treatment induced DNA damage in peripheral immune cells.

BackgroundCell cycle checkpoint kinase 1 (CHK1) is a major G2/M cell cycle regulator in tumors with p53 dysfunction, such as triple‐negative breast cancer (TNBC). We hypothesized the second‐generation CHK1 inhibitor, prexasertib, would yield clinical activity in sporadic TNBC.MethodsThis single arm, phase II trial evaluated prexasertib at 105 mg/m² IV every 2 weeks in patients with metastatic/recurrent TNBC. The primary endpoint was overall response rate (ORR).ResultsAll nine patients enrolled were germline BRCA wild‐type (BRCAwt) and had at least one prior treatment. One partial response (PR) was observed (ORR of 11.1%). Four patients experienced stable disease. The median progression‐free survival (PFS) was 86 days (range 17 to 159 days). Grade 3/4 treatment‐related adverse events included afebrile neutropenia (n = 8; 88.9%), anemia (n = 3; 33.3%), and thrombocytopenia (n = 1; 11.1%). Pharmacodynamic studies showed prexasertib treatment induced DNA damage in peripheral immune cells and demonstrated a decrease in activated/reinvigorated CD8 T cells; however, the one patient with a PR showed evidence of T‐cell recovery.ConclusionPrexasertib monotherapy had modest clinical efficacy in BRCAwt TNBC. Further studies of prexasertib in combination with other agents are needed.