CIN in Solid Tumors


General considerations surrounding the risk of chemotherapy-induced neutropenia in solid tumors.

Joyce O’Shaughnessy, MD: Hello, and thank you for joining this Targeted Oncology™ presentation titled “Selective Immunomodulatory Microtubule Binding Agents (SIMBA): A Novel Approach to Chemotherapy-Induced Neutropenia.” Chemotherapy-induced neutropenia, or CIN, is 1 of the main dose-limiting adverse effects for our patients treated with chemotherapy regimens. Aside from its potential to limit the duration of an effective therapy regimen, CIN is associated with febrile neutropenia, increased morbidity and medical costs, and even potential early mortality. Our discussion today will focus on a novel class of therapy, selective immunomodulatory microtubule binding agents—so novel that there’s only 1 so far—that may help play a role in preventing the development of CIN in high-risk patients with solid tumors. We’ll also discuss some relevant data recently presented at ASCO [American Society of Clinical Oncology Annual Meeting]. I’m Joyce O’Shaughnessy, the celebrating women chair in breast cancer research at Baylor University Medical Center and the chair of breast cancer research within Texas Oncology and the US Oncology Clinical Trials Network. I’m joined by Dr Andrew Seidman, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York and an old friend. Very happy to be here with you, Andy, to discuss this fascinating new agent plinabulin and its mechanism of action.

Let’s start by talking about chemotherapy-induced neutropenia. It’s been awhile since we focused on that because we thought we had the answers. Let’s dust off what we know about the risk of chemotherapy-induced neutropenia.

Andrew D. Seidman, MD: Joyce, it’s great to be talking with you about this subject today. I was just thinking back to 3 decades ago when I was finishing my oncology training. Filgrastim had just emerged on the scene, and I was running around doing bone marrows on patients getting MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride, cisplatin] chemotherapy for bladder cancer. We were trying to dose escalate MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride, cisplatin] with GCSF measuring myeloid precursors, etc. Fast-forward 30 years, and we’ve gone from filgrastim, to pegfilgrastim, to different mechanics of giving the injection, but we really haven’t pushed the bar much further. Many of us have accepted that despite myeloid growth factor support, there’s still going to be some small proportion of patients who will get into trouble. Who will have febrile neutropenia, which is neutropenia that causes dose reductions and dose delays? We’ll have fun talking about whether we should be accepting that as the way things will always be.

Joyce O’Shaughnessy, MD: It’s true. The new data that have emerged on this drug plinabulin, this first-in-class SIMBA, are really quite thought-provoking. It’s so different, and it has brought me back to remember, think about, and focus on the limitations of our available therapies. I’ve got patients who are in the midst of demonstrating the limitations and particularly this rapid development of grade 4 neutropenia that comes so quickly. Then we have to wait for the pegfilgrastim to kick in. That’s the limitation—once it kicks in it’s fantastic, but it doesn’t work for a day or 2. When we get people myelosuppressive regimens and they’re going to get neutropenic, they go down so quickly. That’s the danger, as we know. The faster it falls, the more dangerous it is. But let’s step back just a little for a second, Andy. Do all chemotherapy agents cause the chemotherapy-induced neutropenia? Are there certain agents? How common is it? What guidance do we have?

Andrew D. Seidman, MD: Most chemotherapeutic agents cause some bone marrow suppression; variable in terms of, of course, myeloid vs erythroid vs platelet toxicity. Clearly those effects are also dependent upon dose, schedule, and the use of some of these agents in combinations. Anthracyclines, platinum agents, antimicrotubule agents such as taxanes and vincas, and antimetabolites can all cause myelosuppression. [These are] DNA-damaging agents. It’s dose and schedule dependent and dependent on their use in combinations. But from an impact point of view, when you think about the epidemiology of cancer—breast, lung, colon, prostate—these are diseases with solid tumors where we frequently use myelosuppressive agents such as those that I’ve mentioned.

Joyce O’Shaughnessy, MD: I was reviewing the NCCN [National Comprehensive Cancer Network] Guidelines around this because for the guidelines to support the prophylactic use of hematopoietic growth factor—filgrastim, pegfilgrastim—the risk for febrile neutropenia needs to be above 20%. I’m thinking back to docetaxel at 100 mg/mL2, for example, or docetaxel, doxorubicin hydrochloride, cyclophosphamide, or TAC regimen. Initially it was pretty stringent. You had to be more than 20%. That’s a pretty high number. Of course, it was very effective, and that led to FDA approval of the agents. But more recently, with the availability and the focus on the fact that 20% is a little high—and of course, the concern around COVID-19—what’s happened? Have you expanded the use beyond those regimens that are the highest in terms of CIN?

Andrew D. Seidman, MD: I always thought 20% seemed high, and I don’t know how much of that threshold was driven by cost-benefit analysis. The cost of a hospitalization isn’t trivial, of course, so in the context of COVID-19 pre-vaccination, we were being quite careful and maybe using growth factors more liberally. In the postvaccination setting, perhaps less so. Certainly, in the world of breast cancer, our default position for many patients is dose-dense chemotherapy with growth factor support. But even in the metastatic setting, I had to think very carefully about using drugs like eribulin or sacituzumab govitecan, where I know I’m going to be putting my patients at risk. These aren’t drugs that we necessarily use myeloid growth factors for from the get-go.

Joyce O’Shaughnessy, MD: Exactly. We’ll come to that. We’ll talk about some of the practical realities of trying to figure out how to syncopate the introduction of some filgrastim in these regimens, as you said, in the metastatic setting where you’re not sure how much patients are going to need.

Transcript edited for clarity.

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