Jared Weiss, MD, of UNC Lineberger Comprehensive Cancer Center, highlights clinical trial data that led to the approval of trilaciclib in patients receiving a chemotherapy-containing regimen for extensive-stage small cell lung cancer.
Jared Weiss, MD: Trilaciclib was approved based on the results of 3 randomized phase 2 studies. The first, the O2 study evaluated carboplatin and etoposide, then standard frontline chemotherapy either alone or with the addition of trilaciclib. Part 1 of the study was phase 1. It found DLT [dose-limiting toxicity] recommended phase 2 dose, safety, and tolerability, and part 2 was efficacy based aimed at myelo-preservation safety, tolerability, PK [pharmacokinetics] and antitumor efficacy.
While the O2 study was being conducted, the standard of care shifted. We know now that we have a survival advantage from the addition of PD-L1 to carboplatin and etoposide chemotherapy. And as a result, the O5 study was conducted. This was carboplatin, etoposide, and atezolizumab alone or with the addition of trilaciclib, 107 patients randomized. It was a placebo-controlled, double-blind study. The primary end points were myelo-preservation, safety, tolerability, PK, and antitumor efficacy.
To evaluate the effect of trilaciclib on an already-beaten-up bone marrow, the O3 study was conducted, which was topotecan plus or minus. It was a 2-part study. The first part, DLT, is recommended phase 2 dose, safety, and tolerability; the second part, efficacy. The outcomes of these studies were remarkably similar. The primary end point of mean duration of grade 4 severe neutropenia and patients with grade 4 neutropenia, severe neutropenia was improved. The most impactful was probably carboplatin-etoposide-atezolizumab. With or without mean duration of grade 4 severe neutropenia, patients went from 4% to 0%. Patients with grade 4 severe neutropenia went from 49% to 2%.
From there, in all the studies we had strong trends toward improvements in the other end points. They were what common sense would expect. Proportion of patients with febrile neutropenia events decreased numerically. Patients with G-CSF [granulocyte colony stimulating factor] administration decreased numerically. Same for grade 3/4 anemia, red blood transfusion, ESA [erythropoiesis-stimulating agents] use, and grade 3/4 thrombocytopenia. It was done to increase the sensitivity of the analysis. Because all the data looked rather similar, they combined all the data from these 3 studies. And the outcomes were the same, except instead of saying trend we now get significance for most of these outcomes. That’s meaningful because we have a clean transition from mechanism of action to numeric count preservation to a reduction in defined adverse events.
The patient-reported outcomes are the most important outcomes of these 3 studies. Before seeing the patient-reported outcomes we had a clean progression from mechanism of action to numeric count preservation to reduction in adverse events. But as a rather critical clinician consumer of data, I would have said who cares in the absence of quality-of-life data. Otherwise, they’re just numbers. Those data was, in fact, shown. There was improvement in physical well-being, functional well-being, fatigue, anemia trial outcome index, and fact anemia total. The fatigue numbers are the most impactful to me as a clinician.
Fatigue is the physical quality-of-life harm that my patients complain about the most. Simultaneously it’s the 1 that until now I was least equipped to do much about. There are guidelines about management of fatigue. There are certainly things that I do in practice to try to improve fatigue for my patients, but I’ll admit, we don’t do that well as clinicians improving fatigue. Here we finally have a drug that will prevent some of the fatigue of small cell chemotherapy. That’s the biggest deal of all these data.
Transcript edited for clarity.