Tyrosine-kinase inhibitor

Tyrosine kinase inhibitor prolongs postprogression survival in NSCLC patients

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Tyrosine kinase inhibitor (TKI) was found to prolong postprogression survival (PPS) in non-small cell lung cancer patients (NSCLC) patients, according to a research presented at the recent IASLC Asia Pacific Lung Cancer Conference (APLCC) 2016 in Chiang Mai, Thailand.

TKI continuation was significantly associated with longer PPS in patients with exon 19 deletion, compared to discontinuation (p=0.02). Of the 144 patients 63 patients with a single lesion had a significantly longer PPS compared to those with 2 to 3 and ≥4 lesions (p=0.015). TKI continuation was also associated with a stable disease compared to the previous scan (p=0.017). [APLCC 2016, abstract ABS 081]

Multivariate analysis of age, gender, smoking history, change compared to prior scan, site progression extracranial lesions, brain metastasis, and chemotherapy showed longer PPS in NSCLC patients with exon 19 deletion, but not those with L858R mutation (p=0.03).

Currently, the role of continuing first generation TKI in NSCLC patients after progression remains unknown, said the researchers. This study aimed to explore factors that may show benefit for TKI continuation, including longer PPS.

NSCLC patients with exon 19 deletions may benefit most from TKI continuation, said the researchers. However, larger prospective studies are required to strengthen these findings, they added.

Study participants included 144 NSCLC patients treated with epidermal growth factor receptor (EGFR)-TKI from June 2009 to October 2014, in West China Hospital, Sichuan University. Patient records were retrospectively retrieved, and the number of progressive lesions upon first progression was recorded.

A Phase 2 Trial of Ponatinib in Philadelphia Chromosome–Positive Leukemias.

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BACKGROUND

Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor–refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph-positive ALL).

METHODS

We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months.

RESULTS

Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event.

CONCLUSIONS

Ponatinib had significant antileukemic activity across categories of disease stage and mutation status.

 

Source: NEJM

 

FDA Approves New Drug to Treat Chronic Myelogenous Leukemia.

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The Food and Drug Administration has approved bosutinib (Bosulif) to treat chronic myelogenous leukemia (CML), a blood and bone marrow disease that usually affects older adults. Bosutinib is intended for patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive CML who are resistant to or who cannot tolerate other therapies, including imatinib (Gleevec).

Most people with CML have a chromosomal aberration called the Philadelphia chromosome, which causes the bone marrow to make an abnormal tyrosine kinase enzyme called Bcr-Abl. This enzyme promotes the proliferation of abnormal and unhealthy infection-fighting white blood cells called granulocytes. Bosutinib is a tyrosine kinase inhibitor (TKI) that works by blocking Bcr-Abl signaling.

Bosutinib’s safety and effectiveness were evaluated in a clinical trial involving 546 adults with chronic, accelerated, or blast phase CML. All of the patients had been previously treated with at least one TKI, either imatinib or imatinib followed by dasatinib (Sprycel) and/or nilotinib (Tasigna).

Among patients with chronic phase CML, 34 percent of patients who had been treated previously with imatinib and 27 percent of those who received more than one prior TKI achieved a major cytogenetic response within 24 weeks.

Among patients with accelerated phase CML who had received at least one prior TKI, 30 percent had their blood counts return to the normal range (a complete hematologic response) by week 48, and 55 percent achieved a complete hematologic response, no evidence of leukemia, or return to chronic phase (an overall hematologic response) by week 48. Among patients with blast phase CML who had received at least one prior TKI, 15 percent had a complete hematologic response and 28 percent an overall hematologic response by week 48.

The most common side effects observed in those receiving bosutinib were diarrhea, nausea, a low level of platelets in the blood, vomiting, abdominal pain, rash, anemia, fever, and fatigue.

Source: NCI