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Hetty Carraway, MD, highlights the importance of early diagnosis across all patients with MDS.

Importance of Early Diagnosis of MDS for Lower and Higher-risk Patients

Ralph Boccia, MD, FACP, and Hetty Carraway, MD, review Myelodysplastic Syndromes [MDS] risk stratification criteria used in their practices.

Risk Stratification of Myelodysplastic Syndromes [MDS]

We’re all pleased with the FDA approval and the NCCN [National Comprehensive Cancer Network] recommendations to use trilaciclib in the population of patients with extensive small-cell lung cancer, given these very myelosuppressive drugs. It’s clearly been an unmet need because all patients have experienced neutropenic fever, hospital admissions, drug reductions, severe quality-of-life-imposing situations. It will be nice to finally have available, in an FDA-approved context, a drug that has multilineage potential to be myelo-protected. With the NCCN recommendation and the data, we can easily justify treating all our patients who are getting EC [etoposide, carboplatin] with or without I/O [immuno-oncology] or topotecan to get this drug.

There’s no drug that isn’t going to be a cost to patients. We always worry about the pharmacoeconomics, but if you think about all the cytokines that we use in the population of patients with extensive small-cell lung cancer given EC [etoposide, carboplatin], there probably is going to be something similar in price or perhaps even a cost savings. It’s easy to justify on a cost basis. The other thing is that it’s important to improve the patient’s quality of life, as we said. If we can spare the patient from needing to go to the hospital, if we can spare the patient from being admitted to the hospital, if we can stay on therapy for the full 4 cycles that these patients require, then the outcomes may be better in a general standpoint.

We’ve gone through all the information on trilaciclib and the effect it has in use in patients with small cell lung cancer. In terms of access, it’s available at all the major wholesalers. Getting it should not be a problem. The question is getting it approved and paid for. In terms of reimbursement, it’s a new drug, so it will be billed through Medicare with a miscellaneous code, NOC [not otherwise classified], usually J3490. For 6 months it’s going to be billed at WAC [wholesale acquisition cost] times 6. After that, it will have an ASP [average sales price]. The important thing is it should take away or greatly diminish the use of growth factors. The WAC price of one 300-mg dose of trilaciclib is about $1400. More patients than not will get 2 doses, so that’s about $2,800 WAC price. The WAC price of the pegfilgrastim is over $5000, even for the cheapest biosimilar. So if just 1 dose of trilaciclib can take out the cost of that 1 pegfilgrastim, it is really going to be a big benefit.

In terms of problems with reimbursement, any new drug always has problems when it first comes out if it’s got a miscellaneous code. The manufacturer will go to the payers and explain the incident and what effect this will have, not only on the patient’s outcome—to be able to stay on the drug longer at the correct dose—but also on cutting out a certain percentage of the use of growth factors, which will be a drug savings and doesn’t happen too often. Usually, drugs come out and they’re almost as expensive as the previous therapy. In this case, it should cut other expenses, and that’s a gain for everybody. The patient gets better treatment, with fewer adverse effects, and at a lower cost. The NCCN update that includes use of trilaciclib indicates that it’s for curative, adjuvant, or palliative settings or as secondary prophylaxis in small-cell lung cancer. It also has a specific indication to decrease the use of GCSF, which is what it’s intended to do, along with making the chemotherapy be used longer. Once the payers, Medicare, and Medicaid understand the value of this drug, it should not be a problem. As I said, all new drugs get access pretty slowly, but this drug should be taken up quickly because it’s cheaper, it’s very effective, and it’s going to be good for the patients in treating their small-cell lung cancer.

We finally have something that can improve outcomes, potentially by reducing the pancytopenia from the myelotoxicity in patients given EC [etoposide, carboplatin] or topotecan with extensive small-cell lung cancer. We’ve already seen that this reduces the need for these agents, exposure to the hospital, and has the potential to improve quality of life. There have been some looks at patient-reported outcomes, and we expect that to be published at some point in the future, so stay tuned. Meanwhile, the FDA has approved the drug, which means that we can give the drug and get authorized for payment. The NCCN has given us a recommendation that effective use and should be considered. So we plan to continue using it. We were part of the clinical trial. We plan to use it on all our patients getting EC [etoposide, carboplatin] and topotecan for that reason.

Ralph Boccia, MD, and Jim Schwartz, RPh, discuss the overall impact the approval for trilaciclib will have on patients’ treatment outcomes, health care expenses, and quality of life.

Impact of Trilaciclib on the Treatment Landscape

The most common adverse events that were seen with trilaciclib were fatigue, hypocalcemia, and hypokalemia. If you look at the 2 arms of the study, numerically each was in the 25% range, compared with roughly the 20% range. There’s no huge difference between the placebo arm and the treatment arm. The grade 3s and 4s were on the order of about 5%. Serious adverse events occurred in about 30% of patients. Remember, this is a patient group with extensive small-cell lung cancer, so there’s a lot of pulmonary involvement. We saw a respiratory failure, and we saw a hemorrhage with sharp thrombosis. If you look at the adverse events themselves, we see those same adverse events in the population in general, but 30% of the patients develop them on the clinical trials. Of some 240 patients who were looked at, 9% had to discontinue therapy because of an adverse event. That’s less than 10% of patients who were intolerant of the drug on the clinical trial.

The other thing to look at is the skin effects. It’s 1 of the more common things—about 20% of patients had some cutaneous adverse event. That could be pain, injection site, erythema, or phlebitis. So it’s a drug that can cause some injection site reactions, which is something to be looked out for. Sometimes there could be pain during the infusion itself, and you may have to dilute it more, you may have to stop and flush things through. For about 20% of patients’ injection sites, there is pain on infusions or afterward some phlebitis that can occur because of the irritant nature potentially.

We’ve learned about the adverse effects that we need to watch for. An important 1 is the incidence of injection site reactions. There’s a 21% incidence of these reactions: phlebitis and thrombophlebitis. If it occurs, it usually has an average of 1 day, but it does make this drug an irritant. As I said, it’s important to dilute this drug and to run it in slowly at first. To pay very close attention, especially if it’s being run through a peripheral line, to make sure that there’s not inflammation or redness. What needs to be done is to stop the infusion and run normal saline through the arm to get the drug out of the vein. Start again if it does resolve. If it’s a peripheral IV [intravenous] being given, rotate the arms each time so you don’t wear out the vein in either arm. And watch very carefully, especially with peripheral IVs, to make sure that that doesn’t develop and to stop it right away.

In the clinical trial, there was 1 patient who developed interstitial lung disease. There’s always this theoretical question that’s asked. However, there aren’t any scientific data to support that when you have 1 patient that developed interstitial lung disease. If you look at the atezolizumab data alone, if you look at the nivolumab data, if you look at the durvalumab data, we see that pneumonitis can occur. You would have to do a biopsy to find out if it was chemical pneumonitis or autoimmune pneumonitis. But the mere fact that only 1 patient of 240 developed interstitial lung disease, of 1 form or another, speaks volumes to the potential pulmonary safety of the drug.

Ralph Boccia, MD, and Jim Schwartz, RPh, build a discussion on the potential adverse effects of trilaciclib, including fatigue, hypocalcemia, hypokalemia, injection site reactions, pneumonitis, and interstitial lung disease.

Potential Adverse Effects of Trilaciclib

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.

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.

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.

Registrational Trials for the FDA Approval of Trilaciclib

I want to start with the role of CDK4/6 in normal bone marrow function. CDK4/6 is cyclin-derived kinase. There are a number of them in the body, 1 through 9. These are specifically CDK4 and CDK6, and they form complexes in the hematopoietic cells. They drive cell proliferation. It’s important for the cell cycle for these 2 kinases to be present. In the G1 phase, they bind to the D-cyclin protein. As that builds up, as more of those conjugates form, it triggers a positive feedback loop that commits cells so they pass from the restriction point, from the G1 portion of the cell cycle to the S transition, where DNA synthesis starts. Both kinases are already active and present in the hematopoietic cells. At that point in the G1 cycle, they begin combining with the D-cyclin. They build up. That causes at a certain point for it to move on to the S phase. That’s the reason why these 2 are important substances in the maturation of these cells.

Now that we know the role of the CDK4 and CDK6 kinases, we want to talk about a new agent that’s out now to inhibit their action, and that’s trilaciclib. It’s a small-cell molecular inhibitor of these 2 kinases, and it protects the hematopoietic cells from chemotherapy-induced exhaustion. When they’re introduced into the body, they enter the hematopoietic cells, and they bind to the CD4 and CDK kinases. Because they’re tying up those 2 kinases, they cannot bind to the D-cyclin. All those are tied up, so the cell does not reach the point where they have enough CDK4/6 and D-cyclin conjugates to enter the S phase. They are stuck in the G1 phase, and they cannot move on to S or the DNA synthesis or the G2, where they have further growth, and certainly not to mitosis. As long as these drugs are inhibited by this new drug trilaciclib, the cell is stuck in the G1 portion of the cell cycle, and that protects it from anything that might occur. Chemotherapy acts in many places: the S, the G2, and the M phase. Because it never enters those, they’re protected from being damaged or even destroyed by the chemotherapy. This cell cycle rest by trilaciclib is transient, reversible, and dose related. As you know, there are a number of oral CDK4/6s available. Why are they not working in this way? The primary answer is that it’s dose related. Because they do this, it protects the cell and provides lasting protection against short- and long-term toxicity that could be caused by these hematopoietic cells.

We have the mechanism of action of trilaciclib. How does this benefit a patient undergoing chemotherapy for small-cell lung cancer? The regimens being given—etoposide and carboplatin with or without an immunotherapy, as well as topotecan in the second or third line—are very myelosuppressive. By preventing the cells from being injured during the administration of the chemotherapy, it allows the patient to stay on the prescribed dose of the chemotherapy longer. When they develop neutropenia or anemia or any of these things, there have to be dose stoppages. They may have to reduce the dose. It avoids treatment delays and the expensive treatment of myelosuppressive adverse effects that occur, such as neutropenia, infection, and thrombocytopenia. These things can lead to the risk of infection, fatigue, and bleeding. Overall, it allows the patient to stay on the recommended dose longer, avoid delays, and avoid the treatment of adverse effects. Ultimately, the purpose of cytotoxic chemotherapy is to get as much drug to the patient as you can without too many adverse effects. The addition of trilaciclib cuts out most of the hematopoietic damage and allows the patient to get more of the drug and stay on it longer, resulting in better outcomes.

How is this drug given? The dosing is 240 mg/m2. It’s given within 4 hours of chemotherapy. It’s an irritating drug. But it has effect within 4 hours, so it has to be given within 4 hours of the chemotherapy administration. It reaches its maximum effect at 12 hours and has a half-life of 36 hours, so it acts a long time but goes away quickly. It should be administered in normal saline. It needs to be at a concentration of 0.3 to 3 mg/mL. The drug is irritating, so it needs to be diluted. In general, 250 mL should take care of most doses since it’s in 300-mg vials and the dose is 240 mg/m2. Most patients are going to need more than 300 mg/m2. It will probably be between 300 and 400 or 500 mg/m2. If you put it in 250 mg/m2, that will get it within the range of 0.3 to 3 mg/mL. It should have an inline filter, 0.2- or 0.22-micron filter inline. It can be given over 30 minutes, and it would be good for the first dose to start out slowly. It’s an irritant, and it can cause injection site reactions. This is seen more with a peripheral IV [intravenous] administration. It should not be as much of a problem given through a central line. But when it’s given through a peripheral IV, then it needs to be watched carefully, and the arm that it’s given in should be rotated each time so 1 vein is not worn out from getting this drug.

Jim Schwartz, RPh, provides key insights into the recent approval of trilaciclib and discusses how CDK4/6 inhibition potentially improves response to cytotoxic chemotherapy by protecting patients from myelosuppression.

Trilaciclib in SCLC: Mechanism of Action and Dosage

Extensive small-cell lung cancer is still treated with combination chemotherapy with and without immuno-oncology drugs. That means that, unfortunately, we still face significant difficulty with myelosuppression.

Myelosuppression is still a problem in the sense that it sometimes affects our ability to give effective drugs, treat the cancers and provide symptomatic relief from those cancers. That said, with the development of neutropenia, patients can end up getting infections and in the hospital. Sometimes they end up in the hospital and then going to skilled nursing facilities, which puts them off schedule. Sometimes they never get back on schedule, and the effect of the treatment was abrogated by the neutropenic febrile event that occurred.

In addition to neutropenia, we face anemia. Although we’ve effectively had the erythrocyte-stimulating proteins for many years, they are not completely effective. The development of anemia has become a problem. The use of these drugs has become problematic, has resulted in a black-box warning, and could potentially affect the outcomes of treatments in patients with cancer. The use of ESAs [erythropoiesis-stimulating agents] has not been a perfect solution in any way, shape, or form. The same goes with thrombocytopenia in the sense that it can also affect your ability to give full doses, to stay on schedule or on time, and it may at some point require the use of transfusions. This means that—at the least—patients end up at infusion centers and have to spend the time and the money and endure the toxicity that these can provide. Overall quality of life can be affected. The efficacy of the therapy can be affected, and the ability to administer the drugs on schedule and on time is often affected.

Ralph Boccia, MD, discusses myelosuppression with chemotherapy and highlights its impact on treatment outcomes and patient quality of life.

Ralph Boccia, MD, Johns Hopkins Medicine

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