ESMO Breast Cancer：New Results from Phase 2 Trial Confirm Benefit of Trilaciclib in Reducing Adverse Events Related to an Antibody Drug Conjugate (ADC)

Simcere Zaiming, an innovative oncology-focused biopharmaceutical company and a subsidiary of Simcere Pharmaceutical Group, today annouces that, the  preliminary results from 30 patients enrolled in its ongoing Phase 2, single arm study of trilaciclib administered prior to the antibody-drug conjugate (ADC), sacituzumab govitecan-hziy in patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) has been presented at the European Society for Medical Oncology (ESMO) Breast Cancer 2023 Annual Congress(Poster #201P) .

These data highlight the potential for trilaciclib to meaningfully reduce adverse events related to use of sacituzumab. As expected, patients with PD-L1(+) tumors appear to respond earlier than patients with PD-L1(-) tumors. The Company expects to reach the overall survival (OS) endpoints in the first quarter of 2024.

Data generated across multiple preclinical and clinical studies to date show that the mechanism of action of trilaciclib has the greatest effect on longer term endpoints including OS rather than earlier efficacy measures such as ORR and progression free survival (PFS), consistent with that of other immunotherapies like checkpoint inhibitors. Data suggest that this is likely due to trilaciclib’s mechanism of action that protects the immune system from the initial damage from ADC therapy and enhances long term immune surveillance by increased generation of certain memory T cells. This dual benefit may be important for patients who receive additional therapies subsequent to their ADC therapy.

“These preliminary results continue to show the consistent myeloprotection benefit of trilaciclib when administered prior to sacituzumab, relative to the previously published single agent safety profile of this ADC, including clinically meaningful reductions in myelosuppressive events like neutropenia and anemia, and greater than 50 percent reduced incidence of diarrhea,” said Raj Malik, M.D., Chief Medical Officer at G1 Therapeutics. “It is too early to determine the efficacy of trilaciclib prior to sacituzumab in this patient population. However, early indications suggest a higher response rate in patients with PD-L1 positive tumors, which commonly have an immune inflamed tumor microenvironment and are thus more likely to respond early to immunotherapies. Given that this trial includes a heavily pretreated patient population, we are enthusiastic about these data to date; we will continue to monitor efficacy to assess the potential of trilaciclib to improve overall survival - by protecting the immune system and stimulating long term immune surveillance - when combined with additional regimens beyond gemcitabine/carboplatin and expect the overall survival data in the first quarter of 2024.”

These results are being presented at the European Society for Medical Oncology (ESMO) Breast Cancer 2023 Annual Congress.

Patient Demographics

As of the data cut date of April 3, 2023, all patients (N = 30) had received at least one dose of any study drug and 93.3% of patients had metastatic disease. Patients received a median (range) of 5.5 (1-20) cycles of treatment, and median follow-up was 5.5 months. Eleven (11) patients remain on study treatment and 22 patients remain in the study. In addition, a majority (73.3%; 22/30) of enrolled patients had received prior PD-(L)1 immunotherapy and 63.3% of patients had PD-L1(+) tumors.

Safety Data (n=30): Trilaciclib was well tolerated when administered prior to sacituzumab. Safety results showed a clinically meaningful on-target effect of trilaciclib to reduce (>50%) the rates of multiple adverse events compared to the previously published sacituzumab govitecan-hziy single agent safety profile from the ASCENT trial, including myelosuppression (neutropenia, anemia) and diarrhea due to the presence of CDK4/6-expressing cells in the intestinal crypt.

¹Adapted from Bardia A, et al. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med 2021;384:1529-41. DOI: 10.1056/NEJMoa2028485. Table 3

Treatment-related adverse events (TRAE) of any grade related to any study drug were reported in 76.7% of patients, the most common of which were fatigue, alopecia, nausea, and diarrhea. Adverse events (AEs) leading to treatment discontinuation of study drug occurred in one patient.

Initial Efficacy Results

With a median follow-up of 5.5 months, it is too early to determine the efficacy of trilaciclib prior to sacituzumab in this patient population. Initial results to date show that ORR is higher in patients with PD-L1(+) mTNBC (confirmed ORR=35.3%) relative to the overall study population (confirmed ORR=25.0%). To date, one additional patient has experienced an unconfirmed response. The median Progression Free Survival (mPFS) with trilaciclib plus sacituzumab was 4.1 months. The Company expects to reach the OS endpoints in the first quarter of 2023.

This study includes a highly pretreated patient population, with 73.3% of patients having received prior PD-(L)1 treatment. Prior data from the ASCENT trial have shown that patients pretreated with PD-(L)1 therapy show lower initial responses to sacituzumab (28.4% in pretreated patients vs. 37.5% in untreated patients), and a lower mPFS vs the overall population (4.2 months pretreated patients vs.5.6 months in untreated patients) (Bardia A, et al. Figures S5 and 2).

To date, one patient in G1’s trial achieved a partial response (59% reduction in the sum of longest diameters; SLD) after initial progressive disease (21% increase in SLD) with continuation of therapy after progression at the investigator’s discretion, as the patient seemed to be deriving clinical benefit with trilaciclib and sacituzumab. This patient was not included in the confirmed response calculation. This type of improvement after continued therapy post-progressive disease has been observed with immunotherapies like checkpoint inhibitors but is not usually associated with cytotoxic therapies alone, further suggesting the potential immunotherapeutic benefit of trilaciclib. 

About Triple Negative Breast Cancer (TNBC)

According to the American Cancer Society, nearly 300,000 new cases of invasive breast cancer are diagnosed annually in the U.S. Triple-negative breast cancer makes up approximately 15-20% of such diagnosed breast cancers. TNBC is cancer that tests negative for estrogen receptors, progesterone receptors, and excess HER2 protein. Because mTNBC cells lack key growth-signaling receptors, patients do not respond well to medications that block estrogen, progesterone, or HER2 receptors. Instead, treating mTNBC typically involves chemotherapy, radiation, and surgery. TNBC is considered to be more aggressive and have a poorer prognosis than other types of breast cancer. In general, survival rates tend to be lower with mTNBC compared to other forms of breast cancer, and mTNBC is also more likely than some other types of breast cancer to return after it has been treated, especially in the first few years after treatment. It also tends to be higher grade than other types of breast cancer.