Lowell L. Hart, MD, FACP

Despite recent advancements in the treatment landscape for extensive-stage small cell lung cancer (ES-SCLC), physicians are still challenged by complications associated with chemotherapy. Chemotherapy-induced myelosuppression (CIM) is one of these complications and can result in serious clinical consequences, such as anemia, neutropenia, and thrombocytopenia. Dose delays or dosage reductions are sometimes used to manage CIM, but they can affect the efficacy of a treatment regimen and impact patient outcomes.

Precision Medicine Perspectives in Small Cell Lung Cancer

series, experts in the management of ES-SCLC consider some challenges and unmet needs associated with current standard-of-care approaches. In the second and last interview of the series, Lowell L. Hart, MD, scientific director of clinical research at Florida Cancer Specialists & Research Institute, Fort Myers, Florida, reflects on the effect that CIM can have on optimal disease management and discusses the role of agents like trilaciclib.

™: How do you usually treat CIM in patients with SCLC? Does your approach differ when addressing multilineage issues, such as anemia, neutropenia, and thrombocytopenia?

The best way to address CIM is to try to prevent it from happening. One of the things we’re finding is that severe hematologic toxicity in the treatment of patients with SCLC is much more common than most practitioners realize, and I can put myself in that same category when we started looking at it more concretely. SCLC is one of those cancers for which chemotherapy is still the mainstay of treatment. As everyone knows now, immunotherapy is coming into the fore, and other new agents are, as well. But still, for frontline treatment and for second-line treatment, we’re using a lot of chemotherapy, which is significantly myelosuppressive. It leads to a lot of hematologic difficulties that require dose delays, transfusions, and that sort of thing. For many years, we’ve used growth factor support with agents (eg, filgrastim, pegfilgrastim, and all the newer versions of these things) to support the neutrophil lineage.

Many years ago, Jeffrey Crawford, MD, from the Duke Cancer Center, was the first person to publish on the use of filgrastim in avoiding severe neutropenia in patients with SCLC. Filgrastim only addresses the white blood cells, so the other parts of the hematologic profile (eg, the possibilities of anemia and thrombocytopenia) are not addressed, and they can become problems, too. That’s really the issue from a quality-of-life standpoint, from a cost-control standpoint, and from the standpoint of being able to get an efficacious amount of chemotherapy. These are all problems that need to be addressed.

™: When do you begin using therapeutics to address multilineage hematologic toxicity? Are there certain agents or treatment settings for which this approach may be beneficial?

When you’re treating a patient in the first-line setting, it’s important to try to get the treatment in and keep the doses maintained to keep the patients on schedule as much as possible. Our patients are doing much better now with the advent of combined therapy that we’re using now, so it is very important to try to get their disease under control as quickly as possible. Generally speaking, we’ve used growth factors for those patients. I usually have used pegfilgrastim either with the on-body injection or the next-day injection for patients in the first-line setting.

The other time that we really run into issues is in the second- or third-line settings when a drug like topotecan is used. In a study for which I was the principal investigator, we used topotecan in full doses either with or without the use of trilaciclib, the new intravenous (IV) CDK inhibitor. Once you’re getting to second- or third-line treatment, it’s a more palliative setting. What I have generally done over the years before the advent of these new ways of looking at this would be to cut the doses down significantly, because I found pretty much no one could take a full dose of topotecan. We would sacrifice some of the efficacy in this setting to try to keep the patients out of trouble from hematologic suppression. Obviously, that’s not the best way to do it from the standpoint of trying to get the maximum benefit from palliative chemotherapy, but it’s something that we’ve done for a long time.

The picture is changing, in that we now have this new agent—trilaciclib—available. We can keep these drugs that are more efficacious and use full doses much more than we used to be able to without the number of delays that would lead to decreased efficacy and potential for severe problems like neutropenic fever, the need for transfusions, and those sorts of things.

™: How has the approval of trilaciclib affected the treatment landscape for patients with SCLC?

It has definitely changed the picture, especially in the first-line setting in extensive-stage disease. Many patients with SCLC—since it’s one of the most aggressive human tumors—will present with extensive-stage disease just beyond the thorax. Those are the patients who we’re treating now with first-line carboplatin/etoposide and a checkpoint inhibitor. With those patients, as I mentioned before, it’s important to try to get the full doses of chemotherapy in so they can get their benefit. In using trilaciclib with those patients, I am finding several advantages. One is that you may be able to avoid the use of other growth factors, which have their own adverse effects (eg, bone aches and pain) and are common in patients receiving pegfilgrastim.

Trilaciclib is given on the same day as chemotherapy, so you save the patient from having to come back to the clinic or office an extra day. Many practices, including both my academic practice and my private practice, are trying to use biosimilar forms of pegfilgrastim, which do not come with on-body formulations; the patient would have to return to the clinic the following day, which results in some additional expense and time.

You also have the potential to support the platelet lineage, avoid anemia, and possibly prevent the need for transfusions. Regarding possible delays, expense, and exposure to blood clots, I think there are a lot of potential advantages to using something that’s going to give you trilineage support rather than just simply thinking about giving someone an injection to try to support their neutrophils.

Trilaciclib doesn’t affect the efficacy of chemotherapy. The idea with trilaciclib is to slow down the bone marrow turnover transiently so that it will be less sensitive to the effects of chemotherapy. I explain it to patients by saying that you’re transiently anesthetizing the bone marrow when the chemotherapy’s hitting. It’s given IV just before the treatment, and, because of this, we’re potentially able to switch and give patients a treatment that’s going to preserve and maintain their quality of life. We did quality of life testing in a lot of the randomized trials, and we found that it was superior in patients who received trilaciclib versus patients who did not. I see this as a supportive care treatment that will give patients less need for transfusions or less chance of having neutropenic complications and that will preserve their quality of life.

I recently had a patient with extensive-stage SCLC. Unfortunately, we were not able to get the trilaciclib approved for his first cycle, so I gave him pegfilgrastim. Subsequently, it was approved by his insurance carrier, so I switched and gave him trilaciclib for his second cycle. His quality of life was better on the second cycle of chemotherapy than on the first, with the exact same doses of chemotherapy given both times. He didn't have to come back a fourth day to get treated, and he didn't have bone aches and pains, which he had a little bit with the first cycle. It was overall easier for him, and he did very well with it. We're continuing with his third and fourth cycles with trilaciclib. He was unintentionally his own control in using the drug versus not using the drug.

™: What effect do you anticipate the availability of an agent like trilaciclib will have when it comes to the tolerability of the chemotherapy?

What doctors have always done, if the chemotherapy's not tolerable, is to reduce the dose until it is tolerable. However, we all know that the reason chemotherapy agents are approved and studied at certain doses is because those are the doses that are most effective in treating the cancer based on several factors (eg, patient's body surface area or creatinine level). If you start to deviate from that and give a much lower dose, then it's common sense that you're going to get less efficacy of the treatment.

Trilaciclib is not going to change the long-term disease control rate with the cancer, but it's potentially going to make it easier to get full doses of treatment, which gives you at least a theoretical advantage in controlling the cancer. It's going to improve the patient's quality of life, and we found very few adverse effects from giving IV trilaciclib. Once in a while, somebody could have a slight local reaction at the site of the infusion, but that is fairly minimal.

It does not affect things like nausea or vomiting, either, for the good or the bad, but it does affect hematologic tolerability. For the treatment of SCLC, that's the number 1 thing that we deal with, especially when you're talking about second- and third-line treatment with topotecan. It is not a difficult drug to give, but it does have a very significant marrow toxicity. My standard has always been to give cut doses of the drug or give it just once a week rather than 5 days continuously. The cut doses haven’t worked that well in the past, but we can now get back to the full potential of that drug.

™: Looking to the future, what do you see as the long-term role becoming of agents like trilaciclib? Do you foresee any additional advancements on the horizon in this space?

There's nothing else that's been FDA-approved as a trilineage myeloprotective agent. There are 1 or 2 that are still in experimental trials, but there's nothing that's close to being developed; trilaciclib is the only one that's recently come to market.

We've gotten away from using erythropoietin stimulating agents (ESAs) in most settings now because of concerns about whether they would lead to increased adverse effects for the patient. They might even have a stimulating effect on tumor growth, so, for the past 10 years, there have been questions about the use of ESAs in patients with cancer. We don't use them at all now in patients when there is a curative potential; even in the palliative setting, there have been questions raised. There's much less use of those agents than there was 10 or 15 years ago. There will be other agents coming along eventually. There are a few other ESAs that are coming around, but, again, they're not close to being FDA approved.

One thing that I see on the horizon is other potential uses for trilaciclib. At Florida Cancer Specialists & Research Institute, we're participating in a study using it along with treatment for advanced colorectal cancer. There have been other studies—Joyce O'Shaughnessy, MD, was one of the lead investigators in a study in triple-negative breast cancer. They had some very interesting data, perhaps showing a survival benefit in the patients who were in the trilaciclib arm.

A lot of things about how the CDK4/6 inhibitors interact with the immune microenvironment have not been entirely worked out yet, and the companies involved in the development of these drugs are interested in the possible beneficial effect that they could have on the immune microenvironment. That's a very hot topic in medical oncology in various settings now that we're using so many of these checkpoint inhibitors and other immune-stimulating agents. The things that affect the immune microenvironment and might affect the response of other agents are very highly investigated now; there will be more to come.

Trilaciclib is a very interesting drug, in that it's a quick-acting IV CDK4/6 inhibitor versus the agents that we've used for the last few years in the breast cancer field, which are low-dose oral agents that are used for a longer period of time. It's a very interesting and novel concept, and there may be more of these types of therapies to support other tumor types.

In many other tumor types for which chemotherapy is still used extensively, we see myelosuppression as being a big problem. We've done some surveys, and we're doing some further research on how frequent severe myelotoxicity is reported in patients in our practice in Florida. We're trying to look at this in a systematic way in patients with SCLC, and it's much more frequent than many physicians, including myself, would have estimated. If you just asked us off the top of our heads how often we see severe myelosuppression problems in these patients, a lot of doctors would think it's not common. But it’s much more common and much more severe than we usually believe. When this survey data comes out, it's going to be very interesting and surprising for a lot of people.

Videos

In this companion article, Dr. Lowell L. Hart shares key insights into how trilaciclib has begun to impact the management of chemotherapy-induced myelosuppression in patients with SCLC.

EP. 4B: Considering Chemotherapy-Induced Myelosuppression and the Impact of Trilaciclib on Its Management



One of the things we're finding is that severe hematologic toxicity in the treatment of [patients with] small cell [lung cancer] is much more common than most practitioners realize, and I can put myself in that same category when we started looking at it more concretely. Small cell [lung] cancer is [certainly] one of those cancers where chemotherapy is still the mainstay of treatment. As everyone knows now, immunotherapy is coming into the fore, and other new agents are [as well], but still for frontline treatment and for second-line treatment, we're using a lot of chemotherapy, which is significantly myelosuppressive. It leads to a lot of hematologic difficulties [that require] dose delays, transfusions, [and] that sort of thing. For many years, we've used growth factor support with agents such as filgrastim, pegfilgrastim, and all the newer versions of these things to support the neutrophil lineage.

Many patients with small cell lung cancer—since it's one of the most aggressive human tumors—will present with extensive stage disease beyond just the thorax. Those are the patients who we're treating now with first-line carboplatin/etoposide and the checkpoint inhibitor. With those patients, as I mentioned before, it's important to try and get the full doses of chemotherapy in so they can get their benefit. I have now started using trilaciclib with those patients, and I find there are several advantages to doing that. One, you may be able to avoid the use of other growth factors, which have their own [adverse] effects, such as bone aches and pain, which are common in patients receiving pegfilgrastim.

You also save the patient from having to come back to the clinic or office on an extra day. Obviously, this is a three-day treatment anyway. Many practices, including both my academic practice and my private practice, are trying to go to more biosimilar forms of pegfilgrastim, which do not come with on-body formulations, so the patient would have to return to the clinic with some expense and time taken coming back for an extra day in that. You avoid needing to do that.

You also have the potential [to] support the platelet lineage, avoid anemia, and possibly [prevent] the need for transfusions with all of that. [Regarding] possible delays, expense, and exposure to blood clots, I think there [are] a lot of potential advantages to using something that's going to give you trilineage support rather than simply thinking about giving someone an injection to try and support their neutrophils.

It's not going to change the long-term disease control rate with the cancer, but it's [potentially] going to make it easier to get full doses of treatment, which gives you at least a theoretical advantage in controlling the cancer. It's going to improve the patient's quality of life, and we found very, very few [adverse] effects from giving [intravenous] trilaciclib. Once in a while, somebody could have a slight local reaction at the site of the infusion, but [that is] fairly minimal.


In the second interview of the series, Dr. Lowell L. Hart of Florida Cancer Specialists & Research Institute considers the impact of chemotherapy-induced myelosuppression in small cell lung cancer and examines how trilaciclib fits into the current treatment landscape.

EP. 4A: The Role of Trilaciclib in the Management of Chemotherapy-Induced Myelosuppression in SCLC

Lowell L. Hart, MD, FACP, scientific director of clinical research, Florida Cancer Specialists, and associate professor of medicine, Wake Forest University School of Medicine, discusses the effect of CDK4/6 inhibitor, trilaciclib (G1T28) on myelosuppression in patients with previously treated extensive-stage small cell lung cancer receiving topotecan. Hart presented the phase II results from the blinded, multicenter study during the 2019 ASCO Annual Meeting.

CDK4/6 inhibition prevents sensitive cells from going through the cell cycle, says Hart. Patients with small cell lung cancer lose the ability to utilize retinoblastoma, a protein that suppresses tumors. Since bone marrow cells are sensitive, the idea behind the study was to pause bone marrow cell growth with CDK4/6 inhibition to make the cells dormant until chemotherapy was administered.

For years, the standard of care for patients with small cell lung cancer was topotecan-based chemotherapy. However, because of extreme cell growth in these patients, oncologists struggled to find the right dosage that could keep blood counts normal. These patients then developed myelosuppression.

Lowell L. Hart, MD, FACP, scientific director of clinical research, Florida Cancer Specialists, and associate professor of medicine, Wake Forest University School of Medicine, discusses the effect of CDK4/6 inhibitor, trilaciclib on myelosuppression in patients with previously treated extensive-stage small cell lung cancer receiving topotecan. Hart presented the phase II results from the blinded, multicenter study during the 2019 ASCO Annual Meeting.<br />
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Lowell L. Hart, MD, FACP | Authors

Articles

EP. 4B: Considering Chemotherapy-Induced Myelosuppression and the Impact of Trilaciclib on Its Management

EP. 4A: The Role of Trilaciclib in the Management of Chemotherapy-Induced Myelosuppression in SCLC

Discussing the Benefits of Trilaciclib Plus Topotecan for Treatment of Extensive-stage SCLC