 Trilaciclib has been included in the NCCN [National Comprehensive Cancer Network] Guidelines for management of myelosuppression, especially in patients who are receiving chemoimmunotherapy for extensive-stage small cell lung cancer or chemotherapy for extensive-stage small cell lung cancer. And I find that this may be a nice approach for patients who are older than the age of 65 and patients where I need to come in with a prophylactic approach and want to boost the immune microenvironment. One of the largest unmet needs is that growth factor support and ESA [erythropoiesis-stimulating agent] support often will support only a couple of lines; it doesn’t support trilineage hematopoiesis. Often, we come in with these agents after “the damage” has been done. The biggest advantage of using something like trilaciclib is that we’re coming in before cytotoxic chemotherapy, and the overall goal is to support the immune microenvironment. It does offer advantages from that standpoint. The older patients, who are more likely to experience overall myelosuppression, would be favored candidates for this approach.

 With trilaciclib we have a drug that reduces the myelosuppressive effects of small cell chemotherapy and improves patient-reported quality of life. It also makes treatment easier for the doctor and nurse. It’s a lot of work managing neutropenia, anemia, and to an extent thrombocytopenia. In my opinion, the data are sufficient that in my practice I use it for every patient getting carboplatin-etoposide, carboplatin-etoposide-atezolizumab—the most frequent use—and topotecan. There has been recent cost analysis that suggests that trilaciclib may be cost effective. In my mind, there isn’t a reason to not use it in any patient. I use it in every patient.

In thinking about adverse events from trilaciclib, we need to turn the paradigm on its head a little. What I mean is that normally, when we introduce a new drug, the question is how much improvement in PFS [progression-free survival] and OS [overall survival] is it worth to accept the additional adverse effects that the drug provides. In this case it’s the exact opposite. Trilaciclib globally reduces the adverse effects of small cell chemotherapy, and the safety question was, “Does it harm efficacy in terms of PFS and OS?” The answer was no. What I’ve observed the most in clinical practice are localized irritative effects at the infusion sites. In terms of what’s most helpful, if in your practice you use a port, the issue goes away for you. When a port is used for chemotherapy, there’s no issue. I don’t always use ports in my practice. What I’ll do if patients are experiencing this is I’ll ask the nurse to slow the infusion. We rotate sites, and ice packs have also been helpful.

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Advantages associated with the administration of trilaciclib in appropriate patients receiving a chemotherapy-containing regimen for extensive-stage small cell lung cancer.

Trilaciclib: Treatment Considerations

 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 

 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.

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.

ES-SCLC: Trilaciclib for Chemo-Induced Myelosuppression

 Chemotherapy in combination with immunotherapy is the standard of care for management of patients with extensive-stage small cell lung cancer. We now have not 1 but 2 immunotherapy agents, including atezolizumab and durvalumab, that are approved and administered with a platinum-based etoposide combination doublet. The chemotherapy portion of it works by unfortunately indiscriminately killing proliferative cells, which may include immune cells. Therefore, the hypothesis is that the full benefit of the combination chemotherapy-immunotherapy combination may not be realized because of the resulting myelosuppression.

The idea that an intervention that prevents chemotherapy-induced myelosuppression and thereby maintaining immune system function could therefore reduce the adverse events, or adverse consequences of chemotherapy, and potentially augment the antitumor efficacy of these chemoimmunotherapy agents by maintaining the immune milieu and maintaining the myeloid progenitor cells and protecting the proliferating cells.

Trilaciclib is a first-in-class myelo-preserving therapy that is being evaluated or has been evaluated in several trials to prevent chemotherapy-induced myelosuppression, especially in adult patients with extensive-stage small cell lung cancer. The way that it works is by transiently arresting the CDK4/6-dependent cells in the G1 phase. It can prevent them from proliferating in the presence of cytotoxic chemotherapy, and therefore it can provide resistance to chemotherapy-induced damage and maybe even favorably alter the tumor-immune microenvironment through this transient T-cell inhibition and have some differential effect on T-cell subsets. There have been a few studies in which trilaciclib has been administered before chemotherapy, resulting in preservation of the cell lines with no significant impact on the chemoimmunotherapy. This offers a promising approach in the future.

 Normal healthy cells in the body, including those in the bone marrow, are dependent on CDK4/6 to move from G1 to S phase of the cell cycle. That’s a normal healthy cell function. In contrast, some cancers such as small cell are Rb null and, therefore, not dependent on CDK4/6 to progress. A drug like trilaciclib is an IV [intravenous] short-acting CDK4/6 inhibitor, and it holds the bone marrow progenitors and theoretically potentially other cells out of the cell cycle while the chemotherapy is washing by it. Chemotherapy of course is a poison, but it’s a selective poison in that it poisons cells while they’re dividing. The idea is that you stop the bone marrow progenitors from progressing into the cell cycle; they’re protected against chemotherapy. Small cell was the first cancer in which this was studied because you would not hypothesize or expect any effect for better or for worse on the cancer itself. Any effect seen would be purely on myelo-protection, and there wouldn’t be potential clinical benefit or harm from action of the CDK4/6 inhibitor on tumor cells.

The rationale for using CDK4/6 inhibitors to prevent myelosuppression in patients receiving chemotherapy-containing regimens for extensive-stage small cell lung cancer.

Myelopreservation With CDK4/6 Inhibitors 

: What are the recommendations from the NCCN [National Cancer Comprehensive Network] with regard to management of chemotherapy-induced myelosuppression? We look at neutropenia, and I did discuss with you briefly earlier that we think in terms of what the risk is of febrile neutropenia in a patient who’s receiving chemotherapy. And we think about the chemotherapy regimens as either high risk for febrile neutropenia, intermediate risk, or low risk. For my high-risk regimens, I often will come in with prophylactic growth factor support, which may be short-acting growth factor support, but it’s not feasible because it has to be dosed daily subcutaneously. Or I would use a long-acting growth factor support like pegfilgrastim that could either be administered as an on-site body injector, so patients don’t have to come in the next day to receive it, or they come in the next day, depending on insurance approvals, etc.

Usually for anemia, if hemoglobin is less than 11 [g/dL], I would observe. If it’s less than 8 [g/dL], I usually proceed with a blood transfusion. I don’t use erythropoietin stimulating agents [ESAs], and the reason for that is because there is a black box warning, at least in the curative intent setting, that ESAshave been shown to accelerate oncogenesis. And since there is this black box warning in the adjuvant setting, I tend to stay away from it even in the metastatic setting. For platelets I will hold if they’re less than 100,000 [per μL], and I look for any additional underlying causes that may be causing thrombocytopenia.

Most recently, we also saw that trilaciclib, which is a CDK4/6 inhibitor, can support bone marrow and reduce myelosuppression, especially in patients who receive chemotherapy or chemoimmunotherapy for extensive-stage small cell lung cancer. It is included in the NCCN guidelines, but as a category 2B recommendation. It does involve a few extra steps in terms of its use, so I haven’t adopted it into my practice, but it certainly offers a new intriguing way to manage myelosuppression.

: The NCCN provides us guidance on how to manage and prevent myelosuppressive events. Of note, there’s the baseline guidance and then modified guidance during COVID-19. The baseline guidance is that for patients with at least a 20% risk of febrile neutropenia to give primary prophylactic filgrastim or pegfilgrastim. For patients at intermediate risk, which they define as a 10% to 20% risk of febrile neutropenia, they say that you can consider this prophylaxis based on patient-specific risk factors, such as prior chemotherapy or radiotherapy, persistent neutropenia, known bone marrow involvement with the cancer, recent surgery, liver or renal dysfunction or age of over 55 years. And for patients with low febrile neutropenia risk, defined as less than 10%, we shouldn’t do it. NCCN says that for secondary prophylaxis, if pegfilgrastim or filgrastim were not used as primary prophylaxis in a prior cycle, you can add them. If they were used, you should then consider dose reduction or a change in treatment. Interestingly, for treatment of febrile neutropenia, NCCN is mostly negative on this. First, if prophylactic pegfilgrastim or filgrastim had been used, they say there’s no purpose in doing anything further. And if there hadn’t been, you're only supposed to do it if the patient is at high risk for an infection-related complication.

Now in the COVID-19 era, the NCCN has liberalized guidance and they’ve expanded the primary prophylactic use of G-CSF [granulocyte colony-stimulating factor]. They’ve changed the threshold that for the intermediate-risk patients, they're now recommending the use of G-CSF. For chemotherapy-induced anemia, interestingly NCCN largely defers to the American Association of Blood Banks. And they want you to consider how symptomatic the patient is as well as their hemoglobin threshold. In the era of COVID-19, NCCN recommends reducing that threshold to only transfuse for hemoglobin less than 7 [g/dL]. For thrombocytopenia, again, the threshold has been lowered in the COVID-19 era for patients who are either bleeding, or you can even go far lower, they went all the way down to 10, and said you could consider thrombopoietin here to prevent the need for platelet transfusions. For anemia, I would call these guidelines controversial. Patients with cancer will start feeling more fatigued if hemoglobin’s below normal, and at least in the old ESA literature, feel better when you get their hemoglobin up. Of course, we all know the ESA story. They were overused, they led to adverse events, and they now have a black box warning. But those historic data do show us that if you get a patient down to a hemoglobin of 7 [g/dL], they’re going to feel quite lousy. And I will publicly confess that in my practice, I transfuse more liberally than that for reasons of quality of life of our patients.

Guidance for managing chemotherapy-induced myelosuppressive events in patients with extensive-stage small cell lung cancer based on risk stratification criteria, available therapies, and prophylaxis options.

Charu Aggarwal, MD, MPH, University of Pennsylvania Hospital

Articles

Trilaciclib: Treatment Considerations

ES-SCLC: Trilaciclib for Chemo-Induced Myelosuppression

Myelopreservation With CDK4/6 Inhibitors

Guidelines for Managing Chemo-Induced Myelosuppression in ES-SCLC