榴莲视频

A majority of patients with advanced EGFR/HER2-mutant non-small cell lung cancer (NSCLC) benefited from treatment with the tyrosine kinase inhibitor (TKI) poziotinib, according to a preliminary clinical trial.

An efficacy cohort of 79 patients who received investigational poziotinib 16 mg as initial therapy had an objective response rate (ORR) of 28% and disease control rate (DCR) of 86%. Overall, 72 of 79 (91%) patients had tumor reduction averaging 25.5%. Initial data from an ongoing dosing evaluation involving previously treated and untreated patients showed objective responses in seven of 30 patients and stable disease in 11 treated with 16 mg, resulting in a DCR of 60%.

Tolerability remains a challenge, as a majority of patients in the dosing study required treatment interruptions and dose reductions, and about a third of patients treated with 16 mg had grade ≥3 adverse events, reported Adrian Sacher, MD, of Princess Margaret Cancer Center in Toronto, during the (ESMO TAT) virtual meeting.

"[The efficacy] is not entirely surprising, given that we know poziotinib is an active drug," said Sacher. "I think the challenge with poziotinib is often maintaining the dose at a level that retains efficacy, given the potential for side effects."

The data came from the ongoing phase II international multicohort involving patients with advanced NSCLC associated with EGFR or HER2 mutations, particularly exon 20 insertions. The primary endpoint is ORR, and secondary endpoints include DCR, duration of response, safety, and tolerability. Sacher reported data for an efficacy cohort of patients with EGFR 20 insertions treated in first line with poziotinib 16 mg QD and for a dosing cohort of treated and untreated patients with EGFR or HER2 exon 20 insertions, treated with doses ranging from 6 to 16 mg (including 8 mg BID).

PIK3CA-Mutant Cancers

A fourth of patients with previously treated advanced PIK3CA-mutant cancers responded to a PI3K-alpha selective inhibitor in an .

Overall, five of 33 patients with tumors harboring PIK3CA mutations obtained objective responses with CYH33, including one complete response (CR) in a patient with ovarian clear cell carcinoma. Four of the five responses, including the one CR, occurred in 17 patients with tumors that had confirmed mutations, resulting in an overall response rate of 23.5% in the target population. Another 11 patients, all with PIK3CA-mutant tumors, had stable disease.

Partial responses were observed in colorectal cancer (unknown mutation status), breast cancer, ovarian cancer, and gastric cardia cancer, reported Xiao-Li Wei, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China.

"At the [recommended phase II] 40-mg dose level, the objective response rate was 25% and 33% at the 40-mg dose level in patients with PIK3CA mutations," she said. "The safety profile was manageable, and we observed no grade 4 or higher treatment-related adverse events [TRAEs]. The main grade 3 treatment-related adverse events are all on-target toxicities, which are observed in other PI3K inhibitors. After dose interruption or management, the toxicities can recover to grade 1 or baseline."

The analysis included 39 patients treated with CHY33 doses of 1 to 60 mg. The cohort included 21 (53.8%) patients with confirmed PIK3CA mutations. The most common tumor types represented in the study were colorectal, breast, cervical, and nasopharyngeal cancers. Almost half of the patients had received three or more prior lines of therapy and 28 (72%) had least two prior lines. The most common TRAE was hyperglycemia, which occurred in 33 of 39 (84.6%) of patients and reached grade 3 severity in 20 (51.3%) patients, accounting for all but three grade 3 TRAEs (one case each of decreased appetite, nausea, and diarrhea).

TTK Inhibitor in Breast Cancer

An investigational mitosis inhibitor demonstrated preliminary activity and manageable toxicity in combination with paclitaxel for previously treated HER2-negative breast cancer.

Objective responses occurred in three of 29 patients who received paclitaxel and CFI-402257, and eight other patients had stable disease for more than 16 weeks. Three-fourths of the patients had already received a CDK4/6 inhibitor for advanced disease, and 21% had received three or more prior lines of therapy.

"CFI and weekly paclitaxel has a manageable toxicity profile. Dose-dependent neutropenia was the main toxicity, and increased age was associated with a higher likelihood of grade 4 neutropenia," said Mihaela Mates, MD, of the Cancer Center of Southeastern Ontario in Kingston.

CFI-402257 is a selective inhibitor of monopolar spindle 1 (Mps 1 or TTK), a key regulator of the mitotic spindle assembly checkpoint. Increased TTK expression is associated with poor prognosis in breast cancer, and its inhibition induces lethal chromosomal errors in genomically unstable tumors, said Mates.

Following evidence of efficacy in preclinical models, the combination of CFI-402257 and paclitaxel was evaluated in a involving patients with advanced HER2-negative breast cancer, treated with at least one prior regimen. The primary objective was safety/tolerability, and the key secondary endpoint was clinical benefit rate (response plus stable disease).

Across the range of doses from 84 to 252 mg, more than 90% of the patients developed neutropenia, lymphopenia, low white blood cell count, and anemia. More than 60% of patients had dose-dependent grade ≥3 neutropenia and low white blood cells. Grade ≥3 lymphopenia occurred in 45% of the patients and anemia in 14%. The most common nonhematologic toxicities were fatigue, alopecia, nausea, back pain, diarrhea, peripheral sensory neuropathy, extremity pain, dyspnea, and constipation. Two patients had grade ≥3 extremity pain and one each had fatigue and back pain.