A longer duration of chemotherapy exposure was possible in patients with metastatic triple-negative breast cancer who received trilaciclib, an investigational CDK4/6 inhibitor, in addition to gemcitabine and carboplatin (GC) compared with GC alone.
Joyce A. O’Shaughnessy, MD
A longer duration of chemotherapy exposure was possible in patients with metastatic triple-negative breast cancer (mTNBC) who received trilaciclib, an investigational CDK4/6 inhibitor, in addition to gemcitabine and carboplatin (GC) compared with GC alone. Despite the longer duration of GC, the incidence of major adverse hematologic events (MAHE) was significantly lower in trilaciclib recipients compared with those who received chemotherapy without trilaciclib, according to results of a randomized phase II study.
In addition, tumor response rates were higher and there was a trend toward longer progression-free survival (PFS) in patients receiving 1 or 2 doses of trilaciclib per cycle in addition to GC compared with chemotherapy alone.
Preliminary data from the phase II trial showed that a median of 20.0 weeks of GC could be given when trilaciclib was dosed once per cycle and a median of 19.0 weeks of GC was possible when dosed twice per cycle, compared with a median of 14.4 weeks with chemotherapy alone,1 reported Joyce O’Shaughnessy, MD, and colleagues at the 2018 San Antonio Breast Cancer Symposium.
“Adjusting for the duration of chemotherapy, trilaciclib demonstrated multi-lineage myelopreservation benefits,” the study authors stated in their poster presentation.
“Trilaciclib prevented or delayed clinically significant MAHE,” said O’Shaughnessy, chair of Breast Cancer Research, Baylor-Sammons Cancer Center, Dallas. “It was these MAHE, prolonged neutropenia, dose reductions, platelet transfusions, red blood cell (RBC) transfusions, that seem to be impacted.”
The incidence of MAHE was a prespecified exploratory composite measure of the effect of trilaciclib, and included all-cause hospitalizations, dose reductions, febrile neutropenia, prolonged severe neutropenia, and red blood cell and platelet transfusion. Patients who received chemotherapy alone had a higher rate of MAHE (19%) relative to patients who received trilaciclib (13% with 1 dose per cycle and 9% with 2 doses per cycle), with the difference between the trliaciclib groups and the GC group significant (P = .0181). There were significant decreases in all-cause hospitalizations (P = .0099), prolonged severe neutropenia (P =.0406), and RBC transfusions on/after 5 weeks (P = .0197) in the trilaciclib groups versus GC alone.
The median cumulative dose of gemcitabine increased from 7,306.2 mg/m2 in the chemotherapy alone to 9,643.7 mg/m2 and 10,959.6 mg/m2 in the groups receiving 1 and 2 doses of trilaciclib per cycle, respectively. A similar increase in the median total carboplatin dose was observed—15 AUC with chemotherapy alone versus 20 AUC in both trilaciclib groups.
Among response evaluable patients, those randomized to the triplet had an objective response rate (ORR) of 36.7% to 43.3%, depending on the trilaciclib dosing schedule, compared with 29.2% with GC alone. All responses in all groups were partial responses. Median PFS among the intent-to-treat (ITT) population was 7.9 months in the 2 trilaciclib arms combined compared with 5.4 months in the patients randomized to GC alone (P = .0189). The probability of remaining progression-free at 6 months was higher for patients receiving trilaciclib versus GC alone (69% vs. 43%; P = .0169).
Trilaciclib is being developed to reduce the myelosuppressive effects of chemotherapy and preserve immune system function rather than directly target tumor proliferation,” the investigators said. Patents with mTNBC were chosen for the study because it is predominantly a functionally CDK4/6-independent disease and because cytotoxic chemotherapy is the backbone of treatment for mTNBC and is often limited by myelotoxicities.
The trial included a total of 98 patients with mTNBC in the US and European Union who had received 0 to 2 prior systemic cytotoxic therapies in the locally recurrent or metastatic setting and who had no symptomatic brain metastases.
Patients were randomized 1:1:1 to: GC alone (G: 1000 mg/m2; C: AUC 2) using a standard schedule (days 1 and 8 every 21 days), trilaciclib (240 mg/m2) administered on the same days as standard GC above, an alternate schedule that dosed trilaciclib on days 1, 2, 8, and 9 and GC on days 2 and 9 every 21 days.
On the days when both tilaciclib and GC were scheduled, tilaciclib was administered intravenously prior to GC infusion. Prophylactic growth factors were not allowed in cycle 1; otherwise supportive care was allowed as needed.
The median age of the 102 patients enrolled (4 withdrew consent and were not treated) was 57 years, all had an ECOG performance status of 0 (53%) or 1 (47%), 62.7% had received no systemic therapy in the recurrent/metastatic setting and 37.3% received 1 or 2 prior lines. Six (5.9%) had brain metastases and 25.5% had liver metastases at baseline. Tumor subtyping showed basal-like in 52.2%.
Data cutoff was July 30, 2018 for multi-lineage myelosuppression endpoints and November 1, 2018 for tumor efficacy endpoints. Twenty-nine percent of patients had died at the time of the tumor efficacy data cut, all but 3 due to disease progression.
In addition to increasing the duration of GC exposure and the cumulative dose of GC, adding trilaciclib to GC decreased the rate of dose modifications (defined as dose reductions, cycle delays, and day 8 and 9 doses not given) to as low as 43% compared with a rate of 49% of GC dose modifications per cycle with chemotherapy alone.
The percentage of patients experiencing myelosuppression events was not significantly different between the arms, but doesn’t take into account the increase in drug exposure in patients who received trilaciclib, the authors explained. The proportion of patients receiving red blood cell transfusions on or after 5 weeks was similar across arms, but the mean units/patient was lower in patients randomized to trilaciclib (2 units per arm) compared with GC alone (3 units). Likewise, the percentage that received platelet transfusions was similar between the groups, but the mean units/patient was lower in patients that received trilaciclib (4 units and 3 units) compared with GC alone (8 units).
The number of grade 3-4 treatment-emergent adverse events (TEAEs) was comparable between arms. The most frequent TEAEs overall were those attributable to cytotoxic chemotherapy.
The rates of grade 3-4 neutropenia were 78.8% in patients who received 1 dose of trilaciclib versus 54.3% in the patients who received 2 doses of trilaciclib and 60% in the chemotherapy alone-treated patients. The grade 3-4 rates of thrombocytopenia (24.2% with one dose per cycle and 40.0% with 2 doses) and anemia (18.2% with 1 dose per cycle and 31.4% with 2 doses) were lower with trilaciclib compared with GC alone (43.3% and 40.0%, respectively).
Commenting on the data, Foluso O. (Bisi) Ademuyiwa, MD, MPH, associate professor at Washington University, St. Louis said, “we currently don’t have any strategies to prevent hematopoietic stem and progenitor cell exhaustion other than limiting chemotherapy doses.”
She added, “I think that the myelopreservation data is promising, however, more data from ongoing studies is needed to understand the impact of neutropenia, particularly as there seems to be differential effects on neutropenia depending on the cohort tested, and neutropenia is an established side effect of the CDK4/6 inhibitors.”
O’Shaughnessy J, Wright GS, Thummala AR, et al Trilaciclib (T), a CDK4/6 inhibitor, dosed with gemcitabine (G), carboplatin (C) in metastatic triple negative breast cancer (mTNBC) patients: Preliminary phase 2 results. Presented at 2018 San Antonio Breast Cancer Symposium; December 5-7, 2018; San Antonio, Tx. Abstract PD1-01.