Updated efficacy and safety of entrectinib in NTRK fusion-positive non-small cell lung cancer.

OBJECTIVES: NTRK fusions result in constitutively active oncogenic TRK proteins responsible for âˆ¼ 0.2 % of non-small cell lung cancer (NSCLC) cases. Approximately 40 % of patients with advanced NSCLC develop CNS metastases; therefore, treatments with intracranial (IC) efficacy are needed. In an integrated analysis of three phase I/II studies (ALKA-372-001: EudraCT 2012-000148-88; STARTRK-1: NCT02097810; STARTRK-2: NCT02568267), entrectinib, a potent, CNS-active, TRK inhibitor, demonstrated efficacy in patients with NTRK fusion-positive (fp) NSCLC (objective response rate [ORR]: 64.5 %; 2 August 2021 data cut-off). We present updated data for this cohort. MATERIALS AND METHODS: Eligible patients were ≥ 18 years with locally advanced/metastatic, NTRK-fp NSCLC with ≥ 12 months of follow-up. Tumor responses were assessed by blinded independent central review (BICR) per RECIST v1.1 at Week 4 and every eight weeks thereafter. Co-primary endpoints: ORR; duration of response (DoR). Secondary endpoints included progression-free survival (PFS); overall survival (OS); IC efficacy; safety. Enrolment cut-off: 2 July 2021; data cut-off: 2 August 2022. RESULTS: The efficacy-evaluable population included 51 patients with NTRK-fp NSCLC. Median age was 60.0 years (range 22-88); 20 patients (39.2 %) had investigator-assessed baseline CNS metastases. Median survival follow-up was 26.3 months (95 % CI 21.0-34.1). ORR was 62.7 % (95 % CI 48.1-75.9), with six complete and 26 partial responses. Median DoR and PFS were 27.3 months (95 % CI 19.9-30.9) and 28.0 months (95 % CI 15.7-30.4), respectively. Median OS was 41.5 months. In patients with BICR-assessed baseline CNS metastases, IC-ORR was 64.3 % (n = 9/14; 95 % CI 35.1-87.2), including seven complete responders, and IC-DoR was 55.7 months. In the safety-evaluable population (n = 55), most treatment-related adverse events were grade 1/2; no treatment-related deaths were reported. CONCLUSION: Entrectinib has continued to demonstrate deep and durable systemic and IC responses in patients with NTRK-fp NSCLC.

A Phase I, First-in-Human Study of PRL3-zumab in Advanced, Refractory Solid Tumors and Hematological Malignancies.

BACKGROUND: Phosphatase of regenerating liver-3 (PRL-3) is involved in cellular processes driving metastasis, cell proliferation, invasion, motility and survival. It has been shown to be upregulated and overexpressed in cancer tissue, in contrast to low or no expression in most normal tissue. PRL3-zumab is a first-in-class humanized antibody that specifically binds to PRL-3 oncotarget with high affinity and has been shown to reduce tumor growth and increase survival. OBJECTIVE: In the study, we aimed to determine the safety and efficacy of PRL3-zumab in patients with advanced solid tumors and hematological malignancies. METHODS: We conducted a phase I, first-in-human study in advanced solid tumors and hematological malignancies to investigate the safety, tolerability and efficacy of PRL3-zumab. Response rates were evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) for solid tumors. For acute myeloid leukemia (AML) patients, bone marrow response criteria based on the European Leukaemia Network (ELN) 2017 guidelines for AML were used. We also explored the pharmacokinetics and pharmacodynamic relationships of PRL3-zumab in patients. This study was registered with ClinicalTrials.gov: NCT03191682. RESULTS: In the dose-escalation cohort, 11 patients with advanced solid tumors were enrolled into the study. An additional 12 patients with solid tumors and four patients with AML were enrolled in the dose-expansion cohort. Maximum tolerability was not achieved in this study, as there were no dose-limiting toxicities. Potential treatment-emergent adverse events were grade 1 increased stoma output and fatigue and grade 2 vomiting. Best response observed was stable disease in three solid-tumor patients (11.1%). The pharmacokinetics of PRL3-zumab were dose proportional, consistent with an IgG type monoclonal antibody. CONCLUSIONS: PRL3-zumab, a first-in-class humanized antibody, was safe and tolerable in solid tumors and hematological malignancies.

Clinical outcome and prognostic factors for Asian patients in Phase I clinical trials.

BACKGROUND: Patient selection is key in Phase I studies, and prognosis can be difficult to estimate in heavily pre-treated patients. Previous prognostic models like the Royal Marsden Hospital (RMH) score or using the neutrophil-lymphocyte ratio (NLR) have not been validated in current novel therapies nor in the Asian Phase I population. METHODS: We conducted a retrospective review of 414 patients with solid tumours participating in Phase I studies at our centre between October 2013 and December 2020. RESULTS: The RMH model showed poorer prognosis with increasing scores [RMH score 1, HR 1.28 (95% CI: 0.96-1.70); RMH score 2, HR 2.27 (95% CI: 1.62-3.17); RMH score 3, HR 4.14 (95% CI: 2.62-6.53)]. NLR did not improve the AUC of the model. Poorer ECOG status (ECOG 1 vs. 0: HR = 1.59 (95% CI = 1.24-2.04), P < 0.001) and primary tumour site (GI vs. breast cancer: HR = 3.06, 95% CI = 2.16-4.35, P < 0.001) were prognostic. CONCLUSIONS: We developed a NCIS prognostic score with excellent prognostic ability for both short-term and longer-term survival (iAUC: 0.71 [95% CI 0.65-0.76]), and validated the RMH model in the largest Asian study to date.

Upregulation of C/EBPα Inhibits Suppressive Activity of Myeloid Cells and Potentiates Antitumor Response in Mice and Patients with Cancer.

PURPOSE: To evaluate the mechanisms of how therapeutic upregulation of the transcription factor, CCAAT/enhancer-binding protein alpha (C/EBPα), prevents tumor progression in patients with advanced hepatocellular carcinoma (HCC) and in different mouse tumor models. EXPERIMENTAL DESIGN: We conducted a phase I trial in 36 patients with HCC (NCT02716012) who received sorafenib as part of their standard care, and were given therapeutic C/EBPα small activating RNA (saRNA; MTL-CEBPA) as either neoadjuvant or adjuvant treatment. In the preclinical setting, the effects of MTL-CEBPA were assessed in several mouse models, including BNL-1ME liver cancer, Lewis lung carcinoma (LLC), and colon adenocarcinoma (MC38). RESULTS: MTL-CEBPA treatment caused radiologic regression of tumors in 26.7% of HCC patients with an underlying viral etiology with 3 complete responders. MTL-CEBPA treatment in those patients caused a marked decrease in peripheral blood monocytic myeloid-derived suppressor cell (M-MDSC) numbers and an overall reduction in the numbers of protumoral M2 tumor-associated macrophages (TAM). Gene and protein analysis of patient leukocytes following treatment showed CEBPA activation affected regulation of factors involved in immune-suppressive activity. To corroborate this observation, treatment of all the mouse tumor models with MTL-CEBPA led to a reversal in the suppressive activity of M-MDSCs and TAMs, but not polymorphonuclear MDSCs (PMN-MDSC). The antitumor effects of MTL-CEBPA in these tumor models showed dependency on T cells. This was accentuated when MTL-CEBPA was combined with checkpoint inhibitors or with PMN-MDSC-targeted immunotherapy. CONCLUSIONS: This report demonstrates that therapeutic upregulation of the transcription factor C/EBPα causes inactivation of immune-suppressive myeloid cells with potent antitumor responses across different tumor models and in cancer patients. MTL-CEBPA is currently being investigated in combination with pembrolizumab in a phase I/Ib multicenter clinical study (NCT04105335).

Perioperative Chemotherapy for Liver Metastasis of Colorectal Cancer.

The liver is the dominant site of metastasis for patients with colorectal cancer. For those with isolated liver metastases, surgical resection with systemic therapy has led to long-term remission in as high as 80% of patients in well-selected cohorts. This review will focus on how systemic therapy should be integrated with resection of liver metastases; in particular, the use of clinical risk scores based on clinicopathological features that help with patient selection, various approaches to the treatment of micro-metastatic disease (peri-operative versus post-operative chemotherapy), as well as conversion chemotherapy for those with initially upfront unresectable disease will be discussed.

Making sense of adjuvant chemotherapy in colorectal cancer.

Surgical resection is the only curative treatment for locoregional colon cancer. The goal of adjuvant chemotherapy is to eradicate micro-metastatic disease and improve survival. This has been most clearly demonstrated in stage III (node-positive) disease, whereas benefit of adjuvant chemotherapy in stage II disease remains controversial. In stage III colon cancer, 6 months of adjuvant chemotherapy with oxaliplatin-based chemotherapy have been accepted as the standard for the last 15 years. The recent IDEA collaboration has challenged this in 2018; while overall was a negative non-inferiority study, pre-planned subset analyses do support that for patients with low-risk stage III disease, 3 months of XELOX (capecitabine and oxaliplatin combination) is non-inferior to 6 months. In stage II colon cancer, where the potential benefit of adjuvant chemotherapy is small, the emergence of biomarkers has helped in decision-making. Tumors with deficient mismatch repair protein (dMMR) do not benefit from 5-fluorouracil-based chemotherapy. For patients with high clinicopathological risk stage II disease with proficient mismatch repair proteins and good performance status, six months of adjuvant chemotherapy is still recommended. In the management of rectal cancers, where the risk of local recurrence is higher, chemoradiation (CRT) is often included as neoadjuvant or adjuvant therapy in the management of stage II and III rectal cancer. The benefit of adjuvant chemotherapy in rectal cancer has been extrapolated from adjuvant colon cancer studies with updated results from adjuvant rectal cancer studies demonstrating similar benefits. This review summarizes the current landscape of adjuvant therapy for patients with resected stage II and III colorectal cancer.

Current status of gene expression profiling to assist decision making in stage II colon cancer.

The decision regarding adjuvant therapy for patients with stage II colon cancer remains a challenge. In contrast to stage III colon cancer, for which compelling clinical data support the use of adjuvant chemotherapy, the clinical benefit of systemic therapy in unselected patients with stage II disease is modest at best. Risk stratification based on clinicopathologic features and DNA mismatch repair status is commonly used in adjuvant therapy decisions, but these factors do not have a desired level of precision in identifying patients at high risk. Recently, gene expression platforms have been developed to further define risk and to assist in therapeutic decision making for patients with stage II disease. This review describes those platforms that are furthest along in clinical development, in an effort to place their potential clinical application in context.

Predictors of venous thromboembolism recurrence and bleeding among active cancer patients: a population-based cohort study.

Active cancer is the major predictor of venous thromboembolism (VTE) recurrence, but further stratification of recurrence risk is uncertain. In a population-based cohort study of all Olmsted County, Minnesota, residents with active cancer-related incident VTE during the 35-year period from 1966 to 2000 who survived 1 day or longer, we estimated VTE recurrence, bleeding on anticoagulant therapy, and survival and tested cancer and noncancer characteristics and secondary prophylaxis as predictors of VTE recurrence and bleeding, using Cox proportional hazards modeling. Of 477 patients, 139 developed recurrent VTE over the course of 1533 person-years of follow-up. The adjusted 10-year cumulative VTE recurrence rate was 28.6%. The adjusted 90-day cumulative incidence of major bleeding on anticoagulation was 1.9%. Survival was significantly worse for patients with cancer who had recurrent VTE (particularly pulmonary embolism) and with bleeding on anticoagulation. In a multivariable model, brain, lung, and ovarian cancer; myeloproliferative or myelodysplastic disorders; stage IV pancreatic cancer; other stage IV cancer; cancer stage progression; and leg paresis were associated with an increased hazard, and warfarin therapy was associated with a reduced hazard, of recurrent VTE. Recurrence rates were significantly higher for cancer patients with 1 or more vs no predictors of recurrence, suggesting these predictors may be useful for stratifying recurrence risk.

The role of autophagy in cancer: therapeutic implications.

Autophagy is a homeostatic, catabolic degradation process whereby cellular proteins and organelles are engulfed by autophagosomes, digested in lysosomes, and recycled to sustain cellular metabolism. Autophagy has dual roles in cancer, acting as both a tumor suppressor by preventing the accumulation of damaged proteins and organelles and as a mechanism of cell survival that can promote the growth of established tumors. Tumor cells activate autophagy in response to cellular stress and/or increased metabolic demands related to rapid cell proliferation. Autophagy-related stress tolerance can enable cell survival by maintaining energy production that can lead to tumor growth and therapeutic resistance. As shown in preclinical models, inhibition of autophagy restored chemosensitivity and enhanced tumor cell death. These results established autophagy as a therapeutic target and led to multiple early phase clinical trials in humans to evaluate autophagy inhibition using hydroxychloroquine in combination with chemotherapy or targeted agents. Targeting autophagy in cancer will provide new opportunities for drug development, because more potent and specific inhibitors of autophagy are needed. The role of autophagy and its regulation in cancer cells continues to emerge, and studies aim to define optimal strategies to modulate autophagy for therapeutic advantage.

Reduction in plasma cell proliferation after initial therapy in newly diagnosed multiple myeloma measures treatment response and predicts improved survival.

Standard myeloma treatment response criteria are determined principally by changes in the monoclonal protein. Reduction in the size of the proliferative component of malignant plasma cells may be an additional metric of assessing response to therapy. We retrospectively analyzed 176 patients with newly diagnosed myeloma with a measurable plasma cell labeling index (PCLI) at diagnosis and repeat measurement 4 months after initiation of therapy. PCLI response was defined as a ≥ 60% reduction. Baseline PCLI is an independent prognostic factor; therefore, we categorized patients into 3 groups: PCLI ≥ 3% (high), ≥ 1% (intermediate), and < 1% (low). Patients achieving a greater PCLI response had improved median overall survival of 54 months compared with 29 months in nonresponders (P = .02). Improved median overall survival with PCLI response occurred in the high initial PCLI group (28 vs 7 months; P = .003) and intermediate group (64 vs 24 months; P = .002). The application of PCLI response and serum M-spike response together provided further prognostic information. On multivariate analysis, the prognostic value of PCLI response was independent of ß(2)-microglobulin, elevated creatinine, serum M-spike response, and baseline PCLI. We conclude that a significant reduction in plasma cell proliferation in patients with newly diagnosed myeloma is an important predictor of survival.

Autophagy modulation for cancer therapy.

Autophagy is a homeostatic and catabolic process that enables the sequestration and lysosomal degradation of cytoplasmic organelles and proteins that is important for the maintenance of genomic stability and cell survival. Beclin 1 (+/- ) gene knockout mice are tumor prone, indicating a tumor suppressor role for autophagy. Autophagy is also mechanism of stress tolerance that maintains cell viability and can lead to tumor dormancy, progression, and therapeutic resistance. Many anticancer drugs induce cytotoxic stress that can activate pro-survival autophagy. In some contexts, excessive or prolonged autophagy can lead to tumor cell death. Inhibition of cytoprotective autophagy by genetic or pharmacological means has been shown to enhance anticancer drug-induced cell death, suggesting a novel therapeutic strategy. Studies are ongoing to define optimal strategies to modulate autophagy for cancer prevention and therapy, and to exploit it as a target for anticancer drug discovery.

Targeted therapeutic agents for colorectal cancer.

The treatment of colorectal cancer (CRC) has evolved substantially during the past decade with the advent of molecular targeted therapies. Inhibitors to the vascular endothelial growth factor and epidermal growth factor receptor (EGFR) pathways have been shown to enhance the efficacy of cytotoxic chemotherapy in patients with advanced CRC, and anti-EGFR antibodies demonstrate modest activity as monotherapeutic agents. These biologic agents have improved patient outcomes and survival and have been incorporated into routine clinical practice establishing a new standard of care. Molecular markers have recently been adopted into clinical practice with the finding that the KRAS oncogene is a predictive biomarker for anti-EGFR therapy, whereby the therapeutic benefit of anti-EGFR treatment is restricted to tumors with wild-type KRAS. The use of molecular targeted agents has fewer yet more specific toxicities compared with conventional cytotoxic drugs and enables a more personalized approach to cancer therapy. In contrast to the results for advanced CRC, targeted therapies have not shown a benefit in the adjuvant setting for patients with resected colon cancer. The goal of this review is to provide an update on the medical management of CRC, with a focus on the use of targeted therapy.

Pitfalls in the diagnosis of primary amyloidosis.

Primary (AL) amyloidosis is the most prevalent type of systemic amyloidosis, and management of this disease has evolved through the years from supportive care to aggressive treatments that include immunomodulatory agents and high-dose chemotherapy with hematopoietic stem cell transplantation. However, other types of amyloidosis are increasingly recognized, such as familial amyloidosis and senile cardiac amyloidosis, and management of these conditions is different from that of AL amyloidosis. Congo red staining with exhibition of an apple-green birefringence is diagnostic of amyloid. Immunohistochemistry can detect amyloid deposits but has limitations, and newer molecular techniques such as mass spectrometry show promise in determining types of amyloidosis. Physicians need to be aware of clinical scenarios that can mimic AL amyloidosis to avoid misdiagnosis and harm to the patient.

Amyloidosis and POEMS syndrome.

IMPORTANCE OF THE FIELD: Treatment options for amyloidosis and polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome have rapidly increased in the past years, but many patients are diagnosed late in the disease course and do not receive state-of-the art therapy. AREAS COVERED IN THIS REVIEW: Stem-cell transplantation and novel agents have widened the chemotherapy alternatives available in these disorders and combinations of novel agents with high-dose therapy further improve treatment options. This review covers the main areas of debate in the optimal treatment amyloidosis and POEMS patients, focusing on the implications for everyday clinical practice and management strategies published in the past 36 months. WHAT THE READER WILL GAIN: Insights into treatment strategies are provided in the review. Keys to early recognition of the syndromes are reviewed. TAKE-HOME MESSAGE: With early diagnosis most patients are therapy candidates. New agents and new application of stem-cell transplantation have dramatically improved outcomes for these previously uniformly poor prognosis disorders.

Phase 2 trial of pemetrexed disodium and carboplatin in previously untreated extensive-stage small cell lung cancer, N0423.

BACKGROUND: In extensive-stage small cell lung cancer (SCLC), the combination of pemetrexed plus carboplatin has shown activity and appeared to be well-tolerated. We conducted a trial to confirm the efficacy and to assess the tolerability of this chemotherapy combination. METHODS: Patients with untreated extensive-stage SCLC were enrolled in this phase 2 open-labeled study. They receive pemetrexed 500 mg/m(2) and carboplatin (area under the curve of 5) every 21 days for a maximum 6 cycles. The primary endpoint for this trial was the confirmed response rate and the accrual goal was 70 patients. RESULTS: Forty-six eligible patients (29 aged <70 years, 17 aged >or=70 years) were accrued to this study. The efficacy outcomes were similar between the 2 age groups. Overall, the confirmed response rate was 35% (16 of 46; 95% confidence interval [CI], 21%-50%), where all 16 were partial responses. On the basis of these results, we had strong evidence that the study would not meet the preset efficacy criteria and was, therefore, closed before full accrual. The median duration of response was 4.4 months (95% CI, 2.9-5.2). Median overall survival for patients aged <70 years and aged >or=70 years was 9.2 months (95% CI, 5.4-11.6) and 10.8 months (95% CI, 2.2-14.3), respectively. Grade 3 or higher toxicity rates were similar between the younger and older patients. Grade 3/4 and grade 4 hematological toxicities were observed in 46% and 26% of patients, respectively. CONCLUSIONS: Although well-tolerated, the combination of pemetrexed and carboplatin is not as effective as standard therapy in patients with untreated extensive-stage SCLC.

The importance of bone marrow examination in determining complete response to therapy in patients with multiple myeloma.

The current definition of complete response in multiple myeloma includes a requirement for a bone marrow (BM) examination showing less than 5% plasma cells in addition to negative serum and urine immunofixation. There have been suggestions to eliminate the need for BM examinations when defining complete response. We evaluated 92 patients with multiple myeloma who achieved negative immunofixation in the serum and urine after therapy and found that 14% had BM plasma cells more than or equal to 5%. Adding a requirement for normalization of the serum-free light chain ratio to negative immunofixation studies did not negate the need for BM studies; 10% with a normal serum-free light chain ratio had BM plasma cells more than or equal to 5%. We also found that, on achieving immunofixation-negative status, patients with less than 5% plasma cells in the BM had improved overall survival compared with those with 5% or more BM plasma cells (6.2 years vs 2.3 years, respectively; P = .01).

Neither serum ferritin nor the number of red blood cell transfusions affect overall survival in refractory anemia with ringed sideroblasts.

In a retrospective study of 126 adult patients with French-American-British-defined refractory anemia with ringed sideroblasts (RARS), staging by the International Prognostic Scoring System was highly predictive of survival outcome (P < 0.0001). In addition, red blood cell (RBC) transfusion requirement at diagnosis (P = 0.001), but not the number of RBC units transfused during the disease course (P = 0.17), was independently associated with inferior survival. There were no correlations between survival and serum ferritin level, measured either at diagnosis (median 567 ng/mL, range 16-3,475; P = 0.24) or during follow-up (median 1,108 ng/mL; range 238-43,500; P = 0.72). Similarly, there was no difference in survival when patients were stratified by serum ferritin levels of < or > or =1,000 ng/mL at diagnosis or peak serum ferritin levels of <1,000, 1,000-5,000, or >5,000 ng/mL during follow-up. The current study does not support the contention that transfusional hemosiderosis is an adverse prognostic factor in "good risk" myelodysplastic syndrome.