Therapeutics: trilaciclib as an anticancer agent

Myelosuppression can be a significant problem in patients undergoing cancer chemotherapy treatment; the non-targeted agents kill both cancer cells and healthy cells, including stem cells in the bone marrow that produce blood cells

As a result, patients are often dogged by anaemia, fatigue and an increased risk of infection; they frequently require rescue interventions such as transfusions of blood or platelets, or treatment with growth factors.

G1 Therapeutics is investigating the potential of trilaciclib, an intravenous CDK4/6 inhibitor, as a myelopreserving agent.

Haematopoietic stem and progenitor cells are dependent on CDK4/6 for proliferation and preclinical data suggest that treatment with trilaciclib renders the cells resistant to chemotherapy induced cytotoxicity.

It is now being investigated in patients with various forms of cancer who are undergoing chemotherapy to prevent the cell damage happening in the first place, with the hope of reducing the need for additional drug treatment to counteract myelosuppressive side-effects.

In a blinded, placebo-controlled Phase II study, 91 patients with previously treated extensive-stage small cell lung cancer (ES-SCLC) were given 240 mg/m2 of trilaciclib plus either 0.75 or 1.5 mg/m2 of topotecan or a placebo plus the higher dose of topotecan, intravenously, on the first five days of 21-day cycles.1

In the higher topotecan dose group given trilaciclib, 40.6% of subjects developed severe neutropenia, compared with 75.6% of the placebo group; the duration in the first cycle was two days compared with eight. The efficacy of the chemotherapy was comparable both with and without trilaciclib.

The results of three randomised, double blind, placebo-controlled Phase II trials in patients with ES-SCLC were pooled to determine the effects of trilaciclib on myelosuppression endpoints.2

Across the three trials, 242 patients were given standard chemotherapy regimens of etoposide plus carboplatin, this combination plus atezolizumab, or topotecan plus either trilaciclib or a placebo.

Median overall survival and progression-free survival were comparable between trilaciclib and placebo, whereas 44% of the trilaciclib group had grade 3/4 haematologic events, compared with 77% of the placebo group.

Among those patients who continued past the first cycle of chemotherapy, 9% had at least one chemotherapy dose reduction compared with 31% of those given the placebo.

It has also been investigated in a randomised, open label Phase II study in 142 patients with metastatic triple-negative breast cancer, in combination with gemcitabine and carboplatin chemotherapy.3 In all, 102 patients were given the chemotherapy, either with or without trilaciclib.

Although no significant differences were seen in myelosuppression endpoints, the regimen was generally well tolerated and the overall survival results were encouraging. Trials continue, with a study in colorectal cancer also planned.

References

  1. L.L. Hart, et al., J. Clin. Oncol., 37(Suppl.), Abst. 8505 (2019).
  2. J. Weiss, et al., J. Clin. Oncol. 38(Suppl.), Abst. 12096 (2020).
  3. A.R. Tan, et al., Lancet Oncol. 20, 1587 (2019).

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