Trilaciclib Reduces Risk of Neutropenia, Improves QoL in Adult Patients with ES-SCLC

In an interview with Targeted Oncology following the FDA approval announcement for trilaciclib, Jared Weiss, MD, an assistant professor of medicine at the University of North Carolina Chapel Hill, discusses the use of trilaciclib in clinical practice and how it can improve patient quality-of-life by reducing the rate of neutropenia.

For patients with extensive-stage small cell lung cancer (ES-SCLC) who are at risk for developing chemotherapy-induced bone marrow suppression, trilaciclib (Cosela) is now an FDA approved drug. The agent was shown to help significantly improve the quality of life (QoL) for adult patients receiving chemotherapy for ES-SCLC.

Approval of the agent was based on 3 randomized, double-blind, placebo-controlled trials in patients with ES-SCKC. In total, 245 patients were evaluated. The studies were G1T28-02 (NCT02499770), G1T28-05 (NCT03041311), and G1T28-03 (NCT02514447).

Pooled data from all 3 studies found that patients who took trilaciclib had fewer and less frequent hospitalizations that were required for chemotherapy-induced myelosuppression or sepsis versus the placebo. Patients taking the agent also had few incidents of severe neutropenia or grade ¾ anemia compared with the placebo. Over all three studies, 11.4% of patients in the trilaciclib arm and 52.9% in the placebo arm had severe neutropenia.

Adverse event (AEs) were observed with trilaciclib. The most common AEs observed were fatigue, reduced levels of calcium, potassium, and phosphate, increased levels of aspartate aminotransferase, headache, and pneumonia. The study investigators noted that interstitial lung disease, acute drug hypersensitivity, and injection site reactions are possible with trilaciclib.

In an interview with Targeted Oncology following the FDA approval announcement for trilaciclib, Jared Weiss, MD, an assistant professor of medicine at the University of North Carolina Chapel Hill, discusses the use of trilaciclib in clinical practice and how it can improve patient quality-of-life by reducing the rate of neutropenia.

TARGETED ONCOLOGY: Before trilaciclib was approved, what was the unmet medical need in the field?

WEISS: Cytotoxic chemotherapy has been the mainstay of cancer therapy for decades. One of the most important toxicities of cytotoxic chemotherapy is myelosuppression. There are 3 major blood cell lines that we think about clinically the white cells, the red cells, and the platelets. When white blood cell count goes down, particularly neutrophils, the patient is at risk of infection. When red blood cells as measured by hemoglobin go down, patients become fatigued and short of breath. In lung cancer, shortness of breath is a particularly problematic symptom patients face compared to other cancers because of the pulmonary source. Fatigue is the most common AE both in cancer and chemotherapy, and we have essentially no clinical tools to effectively combat it.

The body comes with a lot more platelets than you need. So bleeding is not a major problem. But as with the other blood counts, when the platelets are too low, it can lead to dose reductions in chemotherapy or delays in chemotherapy, which are psychologically distressing to patients and can affect the efficacy of treatment.

The problem is that we've come to accept myelosuppression and its downstream sequelae because there wasn't a whole lot that we can do about it. With regards to neutrophils, either as primary prophylaxis or secondary prophylaxis, we have Neulasta, which can be given after chemotherapy. The problems with Neulasta are that it causes its own toxicities, most notably bone pain, and that it's reactive instead of being proactive. You're giving it after you have the problem. So, you're not actually protecting the myeloid precursors, you're just getting the numbers back up after. It only addresses 1 line, it's only the neutrophils that you're helping.

In particular, physicians have become somewhat blasé about anemia. Over time transfusion thresholds have fallen. This has occurred because of safety data about blood transfusion, safety data about the ESA's, and shortages of blood supply. In the context of the lowering of the hemoglobin threshold for transfusion, we've come to accept that lower hemoglobin levels are okay. Most people in general have a hemoglobin of 15 or 16., but we're now routinely allowing patients to go down to 8 before we consider a transfusion. There's historic data from showing that even at much higher hemoglobin levels patients are fatigued. So, as you go from 15, or 16, down to 12, or 10 to 8, the patient suffers from very real fatigue as a consequence. And so, there is a massive unmet need there, although not one that doctors recognize. When doctors talk about blood counts, we mostly talk about neutropenia, because it's what most affects us as clinicians. But, it's probably anemia, that patients feel the worst. We have not only a large unmet need, but I believe a lack of cultural recognition of the patient need that is there.

TARGETED ONCOLOGY: What is your key takeaway on the clinical trial results seen with this agent that led to this FDA approval?

WEISS: This is a quality-of-life drug. It was studied in 3 randomized phase 2 studies that were all the standard-of-care plus or minus trilaciclib. The first study was etoposide and carboplatin plus or minus trilaciclib in frontline ES-SCLC. As that study was being done, PD-L1 inhibition became standard-of-care to be added. So, the second trial was etoposide, carboplatin, atezolizumab (Tecentriq) plus or minus trilaciclib. The third study was the standard second-line drug, topotecan plus or minus trilaciclib.

What all 3 studies showed was a reduction in severe grade 4 neutropenia, their primary endpoint, but also protection of the other cell lines, most notably, reductions in anemia. What's interesting about the data set from these 3 randomized phase 2 studies, as well as the pooled data, is the remarkable consistency in the story.

The mechanism of action here is a short acting IVCD 4 CDK4/6 inhibitors. The idea is to keep the bone marrow progenitors out of cycle while the chemotherapy is washing by. We know that cytotoxic chemotherapy poisons cells while they're dividing, and so, the idea is to provide this short-term protection for the bone marrow progenitors. Notably, SCLC cells are obligate RB Null, which means that they're not going to be affected by the drug for better or for worse. So, there's no hypothesis about improving or harming disease-related outcomes. It's purely a quality-of-life drug.

Moving from that mechanism of action, you then see reductions in all of the cell lines in the cytopenias. Those translate to reductions in adverse events. I don't think I would care about any of this if it didn't translate either to an improvement in survival or an improvement in quality-of-life. Robust patient reported outcomes were gathered on this study, and there was an improvement in quality-of--life, which was most remarkably, in fatigue and patient-reported fatigue. This is what I hear the most from my patients and what I feel the most unable to help with as a clinician.

TARGETED ONCOLOGY: How would you advise physicians on managing the toxicities of this agent and their patients?

WEISS: When we think about adding another drug to standard-of-care, the usual question is, well, how much does this increase toxicity? And is it worth it? In this case, adding trilaciclib decreases total toxicity, it does not increase it. And as you might expect, most of those decreases come from myelosuppression and its downstream sequelae. The question here is not how much does this increase toxicity. It decreases it improving the patient experience. The most common thing that I've seen in my experience with this agent is local irritation. In community practice patients are often treated through report anyway, the patient has already been treated to report this as a non-issue. If treated to a peripheral IV line, then conservative management, including site rotation and slowing of infusions work, honestly, it's not been a big deal in actual practice. But the bigger picture here is that this is not an agent increasing toxicity, but rather decreasing.

One interesting thing that emerged from this study was a substantial reduction in alopecia. We weren't looking for alopecia n these 3 studies. It wasn't the goal here the goal, the goal was myeloprotection. But it makes common sense given the mechanism of action of CDK4/6 inhibition. It adds to the evidence that the drug is working and the way that it's supposed to and some patients care quite a bit about alopecia and it's a nice extra benefit for those patients.

TARGETED ONCOLOGY: In your opinion, how could this impact the field?

WEISS: In my practice, trilaciclib is now the standard of care to be added. Prior to carboplatin, etoposide, carboplatin, etoposide and atezolizumab or prior to topotecan. What I don't know is how the field is going to feel about this. And over time, as I mentioned earlier, I think that there's a lack of recognition of the extent of the problem. In terms of neutropenia, doctors already have a solution, pegfilgrastim (Neulasta), but it's a problematic solution. But from the perspective of neutropenia, I think there can be a lack of enthusiasm from the oncologic community, and as I've expressed, I think doctors don't recognize just how much our patients are impacted by fatigue. I'm hoping that perhaps there will be more attention to fatigue in general, as a consequence of being able to do something about it. But it really depends on whether doctors take a look at this agent and recognize a solution to a real problem. If you believe that pegfilgrastim is okay, and you don't recognize fatigue as a problem, or I'll go even further, as a clinician, if you don't focus intently on quality-of-life, you might miss the importance of being able to address all of these problems. It is my hope that though various educational efforts, we can draw attention not just to trilaciclib per se, but also to the importance of managing fatigue and maximizing quality-of-life in general.

References:
1.FDA Approves Drug to Reduce Bone Marrow Suppression Caused by Chemotherapy. FDA. February 12, 2021. Accessed February 12, 2021. https://bit.ly/2NqMuaU
2.Ferrarotto R, Anderson I, Medgyasszay B, et al. Trilaciclib reduces the need for growth factors and red blood cell transfusions to manage chemotherapy-induced myelosuppression. J Thorac Oncol. 2021;16(suppl 4):OA03.08. doi:10.1016/j.jtho.2020.10.026