Registrational Trials for the FDA Approval of Trilaciclib
An expert in the management of small cell lung cancer gives an in-depth review of the study design, safety, and efficacy of the clinical trials that led to the FDA approval of trilaciclib for chemotherapy-induced myelosuppression.
Ralph Boccia, MD: We know that trilaciclib is a CDK 4/6 inhibitor. It is rationally designed and used in clinical trials—I’m going to present those data to you in just a second. It protects the hematopoietic stem cell from the cytotoxic effects of the chemotherapy. It inhibits the cell cycle in hematopoietic stem cells in G1, which is the resting phase. We know that most hematopoietic stem cells are actually in the rest phase, but when they begin to cycle through the cell cycle, unfortunately they become exposed to the elements at that point, and any outside anoxic event such as chemotherapy can affect them. That’s what results in myelosuppression. The drug was studied in patients with extensive small-cell lung cancer, knowing that the cytostatic chemotherapy used, the platinum drugs and etoposide, are powerfully myelosuppressive. There is an unmet need in bringing drugs to market that can protect the cell rather than using agents such as cytokines to try to salvage the cell once it’s already been suppressed.
I’d like to mention 3 trials and focus on the randomized phase 2 trial. We have the randomized phase 2 trial, which I believe is the more important of the trials because it’s looking at the standard of care and thinking about what the NCCN [National Comprehensive Cancer Network]Guidelines are for frontline therapy for extensive small-cell lung cancer. The preferred regimens are really using EC [etoposide, carboplatin]—etoposide and platinum, and that could be carboplatin or cisplatin, with or without an I/O [immuno-oncology] agent. Atezolizumab is 1 preferred regimen for frontline therapy. Another I/O drug that also can be used with EC [etoposide, carboplatin] therapy is durvalumab. Then you can use EC [etoposide, carboplatin] alone without I/O therapy. Those would be the 3 preferred regimens.
Now I’m going to talk a little about the second trial, which looked at that doublet rather than the triplet, so the EC [etoposide, carboplatin]. That was a phase 1b/2 study. There was a dose-finding component to it before getting to the phase 2 trial. Then the third trial was for patients with relapsed/refractory disease. The first 2 trials, as I mentioned, were frontline. The third trial is in relapsed disease, where we know the preferred agent is topotecan. That study was also a dose-finding phase 1b/2 trial as well. The randomized phase 2 trial looked at adding trilaciclib to EC [etoposide, carboplatin], vs placebo plus EC [etoposide, carboplatin]. Patients were randomized ahead of time and treated with the trilaciclib at 240 or 200 mg/m2 given before each of the cytotoxic days: 1, 2 and 3. The EC [etoposide, carboplatin] is the same in all. It was an AUC [area under the curve] of 5 mg/mL/min for carboplatin, and the etoposide was 100 mg/m2 on days 1, 2, and 3. The trilaciclib was given on days 1, 2, and 3 before the chemotherapy was given.
Patients were then looked at for primary and secondary outcomes. The primary end point of this study was the percentage of patients who developed severe neutropenia, meaning less than 500 cells, and the duration of severe neutropenia. Secondary end points included use of ESAs [erythropoiesis-stimulating agents], use of GCSF, the percentage of patients who required a packed red cell transfusion after week 5, and overall safety in general. The results of this study showed us that we could, in fact, protect these hematopoietic progenitor cells in all 3 lines. There was a significant reduction in the primary end point of severe neutropenia from 49% to 2%. There was improvement in duration of severe neutropenia. In the placebo arm it was 4 days, and it was 0 days, basically, in the treatment arm with trilaciclib. There was a reduction in the febrile neutropenia from 6% in the placebo arm to 2% in the treatment arm. There were reductions in the percentages of patients getting GCSF, getting the ESAs, and requiring transfusions.
The second study I mentioned was a proof-of-concept study looking at the use of trilaciclib in patients given EC [etoposide, carboplatin] alone: the doublet, as I mentioned at the beginning. The primary end point of that was safety and tolerability because it’s a proof-of-concept study. The secondary end points were the efficacy studies as well. What we know about this drug is that it can cause some fatigue. It can cause some hyperkalemia, hypocalcemia, and hyponatremia. Honestly, if you look at the comparator arm, the percentage that are numerically slightly better—by 3% or 4%, with 20% to 25% of patients getting all-grade fatigue, but it’s in the order of 3% to 4% they get grade 3 or 4 fatigue. Same thing for the hyponatremia, hypocalcemia, and hypokalemia above the transaminases—in the 10%-to-20% range with only a couple of percentage points of patients getting a grade 3 or 4 toxicity. The proof of concept was that it was safe and tolerable.
The secondary end points were the overall responses, and they were quite similar to the phase 2 trial, the randomized trial that I just presented to you. It was 42% of the patients who were on the placebo arm that had severe neutropenia compared with just a couple of percentage points—I think it was 6% in the patients who were on the treatment arm with trilaciclib. It was a similar improvement in duration of severe neutropenia, 6% or 8% of the patients actually developed neutropenic fever on the placebo arm compared with 2% or 3% on the treatment arm. Same reduction in the incidence of need for GCSF, the need for ESAs, and a similar marked reduction of about half the need for packed red cell transfusions. Clearly it was a multilineage protection of these cells. The final and third 1 was in the second line, where the preferred agent is single-agent topotecan, and the phase 1b component—the doses of the trilaciclib—were increased as well as the doses of the topotecan.
In the phase 2b component, there were 3 doses of trilaciclib tested: 200 mg/m2, which was originally thought to be the perfect dose; 240 mg/m2; and 280 mg/m2. It was found that at 200 mg/m2, the area under the curve was too low, and the protection was too brief. At 280 mg/m2, the higher dose, the cell cycle arrest in G1 was too long, and the incidence of adverse events was higher because the cells were then released. The chemotherapy had affected them because they were in G1 too long. The 240 mg/m2 dose was selected as the ideal dose, and that is the dose that we use in clinical practice after the FDA approval. The incidence of severe neutropenia dropped, the duration of severe neutropenia dropped, the need for GCSF or ESAs dropped, the transfusion needs dropped. All these about halved. Clearly, we saw multilineage protection from trilaciclib, which could arrest the hematopoietic stem cells in the G1 phase.
Jim Schwartz, RPh: Dr Boccia has already gone over the results of the HART study, telling us the results and why this is an important drug in treating small-cell lung cancer. The regimens that it’s being compared against or being used with are important because that’s the standard therapy. Topotecan single agent is the drug of choice in second- and third-line treatment of small-cell lung cancer. Very myelosuppressive, so it’s important that these data were done by using the actual treatment given in these patients. The small-cell lung cancer tumor cells replicate independently of the CDK4/6, so they’re not affected at all by the drug. These patients are older with many multiple comorbid conditions, so it’s important that a drug like this is available to help prevent some myelosuppression that would happen ordinarily.
Transcript Edited for Clarity
