Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies in patients with advanced or metastatic solid tumors, including patients ...with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring
, or
gene fusions, naïve to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the recommended phase II dose. Entrectinib was well tolerated, with predominantly Grades 1/2 adverse events that were reversible with dose modification. Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with
-rearranged lung cancer.
Gene fusions of
, and
(encoding TRKA/B/C, ROS1, and ALK, respectively) lead to constitutive activation of oncogenic pathways. Entrectinib was shown to be well tolerated and active against those gene fusions in solid tumors, including in patients with primary or secondary CNS disease.
.
fusions are oncogenic drivers of various tumors, including non-small cell lung cancers (NSCLC). The safety and antitumor activity of the multikinase RET inhibitor RXDX-105 were explored in a phase ...I/Ib trial. A recommended phase II dose of 275 mg fed daily was identified. The most common treatment-related adverse events were fatigue (25%), diarrhea (24%), hypophosphatemia (18%), maculopapular rash (18%), and nonmaculopapular rash (17%). In the phase Ib cohort of RET inhibitor-naïve patients with
fusion-positive NSCLCs, the objective response rate (ORR) was 19% (95% CI, 8%-38%,
= 6/31). Interestingly, the ORR varied significantly by the gene fusion partner (
< 0.001, Fisher exact test): 0% (95% CI, 0%-17%,
= 0/20) with
(the most common upstream partner for
fusion-positive NSCLC), and 67% (95% CI, 30%-93%,
= 6/9) with non-
partners. The median duration of response in all
fusion-positive NSCLCs was not reached (range, 5 to 18+ months). SIGNIFICANCE: Although
is the most common
fusion in NSCLCs, RET inhibition with RXDX-105 resulted in responses only in non-
-containing cancers. Novel approaches to targeting
-containing tumors are needed, along with a deeper understanding of the biology that underlies the differential responses observed.
.
Chromosomal rearrangements involving neurotrophic tyrosine kinase 1 (NTRK1) occur in a subset of non-small cell lung cancers (NSCLCs) and other solid tumor malignancies, leading to expression of an ...oncogenic TrkA fusion protein. Entrectinib (RXDX-101) is an orally available tyrosine kinase inhibitor, including TrkA. We sought to determine the frequency of NTRK1 rearrangements in NSCLC and to assess the clinical activity of entrectinib.
We screened 1378 cases of NSCLC using anchored multiplex polymerase chain reaction (AMP). A patient with an NTRK1 gene rearrangement was enrolled onto a Phase 1 dose escalation study of entrectinib in adult patients with locally advanced or metastatic tumors (NCT02097810). We assessed safety and response to treatment.
We identified NTRK1 gene rearrangements at a frequency of 0.1% in this cohort. A patient with stage IV lung adenocrcinoma with an SQSTM1-NTRK1 fusion transcript expression was treated with entrectinib. Entrectinib was well tolerated, with no grade 3–4 adverse events. Within three weeks of starting on treatment, the patient reported resolution of prior dyspnea and pain. Restaging CT scans demonstrated a RECIST partial response (PR) and complete resolution of all brain metastases. This patient has continued on treatment for over 6 months with an ongoing PR.
Entrectinib demonstrated significant anti-tumor activity in a patient with NSCLC harboring an SQSTM1-NTRK1 gene rearrangement, indicating that entrectinib may be an effective therapy for tumors with NTRK gene rearrangements, including those with central nervous system metastases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Increased glucocorticoid receptor (GR) signaling is a proposed compensatory mechanism of resistance to androgen receptor (AR) inhibition in metastatic castration-resistant prostate cancer (mCRPC). ...ORIC-101 is a potent and selective orally-bioavailable GR antagonist.
Safety, pharmacokinetic/pharmacodynamic, and antitumor activity of ORIC-101 in combination with enzalutamide were studied in patients with mCRPC progressing on enzalutamide. ORIC-101 doses ranging from 80 to 240 mg once daily were tested in combination with enzalutamide 160 mg once daily. Pharmacokinetics/pharmacodynamics was assessed after a single dose and at steady state. Disease control rate (DCR) at 12 weeks was evaluated at the recommended phase 2 dose (RP2D).
A total of 41 patients were enrolled. There were no dose-limiting toxicities and the RP2D was selected as 240 mg of ORIC-101 and 160 mg of enzalutamide daily. At the RP2D, the most common treatment-related adverse events were fatigue (38.7%), nausea (29.0%), decreased appetite (19.4%), and constipation (12.9%). Pharmacokinetic/pharmacodynamic data confirmed ORIC-101 achieved exposures necessary for GR target engagement. Overall, for 31 patients treated at the RP2D, there was insufficient clinical benefit based on DCR (25.8%; 80% confidence interval: 15.65-38.52) which did not meet the prespecified target rate, leading to termination of the study. Exploratory subgroup analyses based on baseline GR expression, presence of AR resistance variants, and molecular features of aggressive variant prostate cancer suggested possible benefit in patients with high GR expression and no other resistance markers, although this would require confirmation.
Although the combination of ORIC-101 and enzalutamide demonstrated an acceptable tolerability profile, GR target inhibition with ORIC-101 did not produce clinical benefit in men with metastatic prostate cancer resistant to enzalutamide.
Rituximab is commonly used as a single agent or in combination therapy for non-Hodgkin's lymphoma (NHL). Ibritumomab tiuxetan radioimmunotherapy targets the same antigen as rituximab and has ...demonstrated efficacy in rituximab-naïve NHL. This study evaluated ibritumomab tiuxetan in the treatment of rituximab-refractory follicular NHL.
Eligible patients were refractory to rituximab; this was defined as no objective response to rituximab (375 mg/m(2) weekly for 4 weeks) or time to progression (TTP) of < or = 6 months. The ibritumomab tiuxetan treatment regimen consisted of pretreatment with rituximab (250 mg/m(2) intravenously on days 1 and 8) to deplete peripheral blood B cells, then yttrium-90 ibritumomab tiuxetan (0.4 mCi/kg; maximum, 32 mCi) intravenously on day 8, administered on an outpatient basis. An imaging/dosimetry dose of indium-111 ibritumomab tiuxetan (5 mCi) was injected after rituximab (day 1) in 28 patients.
Fifty-seven patients were treated. The median age was 54 years, 74% had tumors > or = 5 cm, and all were extensively pretreated (median, four prior therapies; range, one to nine). The estimated radiation-absorbed doses to healthy organs were below the study-defined limit in all patients studied with dosimetry. The overall response rate for the 54 patients with follicular NHL was 74% (15% complete responses and 59% partial responses). The Kaplan-Meier-estimated TTP was 6.8 months (range, 1.1 to > or = 25.9 months) for all patients and 8.7 months for responders. Adverse events were primarily hematologic; the incidence of grade 4 neutropenia, thrombocytopenia, and anemia was 35%, 9%, and 4%, respectively.
Ibritumomab tiuxetan radioimmunotherapy is effective in rituximab-refractory patients. The only significant toxicity is hematologic.
Radioimmunotherapy (RIT) with yttrium-90 ((90)Y)-labeled anti-CD20 antibody ((90)Y ibritumomab tiuxetan; Zevalin, IDEC Pharmaceuticals Corporation, San Diego, CA) has a high rate of tumor response in ...patients with relapsed or refractory, low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL). This study presents the safety data from 349 patients in five studies of outpatient treatment with (90)Y ibritumomab tiuxetan.
Patients received rituximab 250 mg/m(2) on days 1 and 8, and either 0.4 mCi/kg (15 MBq/kg) or 0.3 mCi/kg (11 MBq/kg) of (90)Y ibritumomab tiuxetan on day 8 (maximum dose, 32 mCi). Patients were observed for up to 4 years after therapy or until progressive disease.
Infusion-related toxicities were typically grade 1 or 2 and were associated with rituximab. No significant organ toxicity was noted. Toxicity was primarily hematologic, with nadir counts occurring at 7 to 9 weeks and lasting approximately 1 to 4 weeks depending on the method of calculation. After the 0.4-mCi/kg dose, grade 4 neutropenia, thrombocytopenia, and anemia occurred in 30%, 10%, and 3% of patients, respectively, and after the 0.3-mCi/kg dose, these grade 4 toxicities occurred in 35%, 14%, and 8% of patients, respectively. The risk of hematologic toxicity increased with degree of baseline bone marrow involvement with NHL. Seven percent of patients were hospitalized with infection (3% with neutropenia) and 2% had grade 3 or 4 bleeding events. Myelodysplasia or acute myelogenous leukemia was reported in five patients (1%) 8 to 34 months after treatment.
Single-dose (90)Y ibritumomab tiuxetan RIT has an acceptable safety profile in relapsed NHL patients with less than 25% lymphoma marrow involvement, adequate marrow reserve, platelets greater than 100,000 cells/ micro L, and neutrophils greater than 1,500 cells/ micro L.
Mildly thrombocytopenic patients with relapsed or refractory low-grade non-Hodgkin lymphoma (NHL) have an increased risk of chemotherapy-induced myelosuppression following treatment. The safety and ...efficacy of radioimmunotherapy with a reduced dose of90Y ibritumomab tiuxetan (0.3 mCi/kg 11 MBq/kg; maximum 32 mCi 1.2 GBq) was evaluated in 30 patients with mild thrombocytopenia (100-149 × 109 platelets/L) who had advanced, relapsed or refractory, low-grade, follicular, or transformed B-cell NHL. The ibritumomab tiuxetan regimen included an infusion of rituximab (250 mg/m2) and injection of 111In ibritumomab tiuxetan (5 mCi 185 MBq) for dosimetry evaluation, followed 1 week later with rituximab (250 mg/m2) and90Y ibritumomab tiuxetan (0.3 mCi/kg 11 MBq/kg). Patients (median age, 61 years; 90% stage III/IV at study entry; 83% follicular lymphoma; and 67% with bone marrow involvement) had a median of 2 prior therapy regimens (range, 1-9). Estimated radiation-absorbed doses were well below the study-defined maximum allowable for all 30 patients. With the use of the International Workshop criteria for NHL response assessment, the overall response rate was 83% (37% complete response, 6.7% complete response unconfirmed, and 40% partial response). Kaplan-Meier estimated median time to progression (TTP) was 9.4 months (range, 1.7-24.6). In responders, Kaplan-Meier estimated median TTP was 12.6 months (range, 4.9-24.6), with 35% of data censored. Toxicity was primarily hematologic, transient, and reversible. The incidence of grade 4 neutropenia, thrombocytopenia, and anemia was 33%, 13%, and 3%, respectively. Reduced-dose ibritumomab tiuxetan is safe and well tolerated and has significant clinical activity in this patient population.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
9.
Neutropenia in Patients Treated with Rituximab Voog, Eric; Morschhauser, Franck; Solal-Céligny, Philippe
The New England journal of medicine,
06/2003, Volume:
348, Issue:
26
Journal Article
Peer reviewed
To the Editor:
Rituximab is effective in B-cell lymphomas either as a single agent or combined with chemotherapy. Its toxic effects are generally mild and transient.
1
,
2
We report eight cases of ...acute and severe neutropenia that occurred 8 to 23 weeks after the administration of rituximab for non-Hodgkin's lymphoma or chronic lymphocytic leukemia. All patients had a normal polymorphonuclear-cell count before rituximab treatment (Table 1). None of the known causes of neutropenia were found. Previous treatment with rituximab two to four months before the development of neutropenia was a common factor in these eight patients, which suggests that rituximab . . .
To the Editor:
Rituximab targets CD20+ B cells. It is used increasingly for the treatment of B-cell non-Hodgkin's lymphoma, alone or in combination with cytotoxic agents.
1
,
2
We report two patients ...with non-Hodgkin's lymphoma in whom interstitial pneumonitis developed after rituximab therapy.
Patient 1 was an 82-year-old woman who presented with bruising. Her blood count showed a hemoglobin concentration of 8.6 g per deciliter, a white-cell count of 57,100 per cubic millimeter, a lymphocyte count of 44,900 per cubic millimeter, and a platelet count of 32,000 per cubic millimeter. A bone marrow biopsy showed diffuse infiltration with small BCL1+ and . . .
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