: One of the biggest aspects of this ASCO [American Society of Clinical Oncology] meeting was patient-reported outcomes and quality of life-related issues. I think those were studied in this trial. We’ve seen that]patients are more content avoiding hospitalizations and avoiding time spent in our treatment areas for supportive care and transfusions. Those are important factors that we should consider. It’s a 30-minute infusion prior to each day of therapy, so we are looking at this from a whole experience perspective—not only from numerical markers, but also from subjective, graspable patient-reported outcomes that are seemingly improving the patient’s journey. That is very difficult with extensive-stage small-cell lung cancer. The chemotherapy is very effective in the first-line setting but is very harsh. It’s interesting to see that we’re not only affecting numerical toxicities, but objective experience for patients as well.

: Correct. You mentioned quality of life, Martin. When you see the toxicity profile or adverse reactions from trilaciclib, the therapy is very well tolerated. Perhaps the most common effect that you see with trilaciclib is irritation where we give the infusion. Usually, it is a discomfort or pain where the medication is passing through, perhaps with some erythema or redness. When that happens, we start the infusion and flush the catheter with either normal saline or dextrose 5 normal saline. That should take care of the problem. Interstitial tissue has been reported with this disease. Thoracic oncology is very important, especially when the patient is going to be exposed to immunotherapy—such as atezolizumab or durvalumab—which is another standard of care worldwide, or here in the United States. This issue of ILD [interstitial lung disease] is important to us. The report has been only 1 case, but we need also to mention that it’s very well tolerated. The most common adverse effects we have seen with trilaciclib are that more than 10% of the patient population has been fatigued, had hypocalcemia, hypoglycemia, or some elevation of the aspartate transaminase. Those are the things we see with trilaciclib.

: I don’t think it’s a new side effect. We’ve seen the CDK4/6 [cyclin-dependent kinase 4/6] inhibitor showing low levels of ILD, but I think, overall, they are very manageable. In the bigger context of immunotherapy, it’s a problem that we’re monitoring for very closely in the clinic.

: What patients are you choosing for trilaciclib? For which patients would you say this is appropriate? Are there any patients for whom you say it is not appropriate?

: At this moment, the indication that we have for trilaciclib is for extensive-disease small cell lung cancer, first-line or second-line therapy. I treat all my patients with trilaciclib as a myeloprotectant. As you know, we give trilaciclib within 4 hours prior to the infusion of chemotherapy. You do that, the classic regimen for small cell lung cancer, on day 1, day 2, and day 3. Similarly, for topotecan, there is an infusion every day. The issue here is that when trilaciclib, that myeloprotectant, is given, within a window of 1 to 4 hours before you start infusion of chemotherapy. I made my decision a long time ago to use this myeloprotectant and be proactive more than reactive.

: I can second that. I think we have looked at this from many angles. We have discussed the treatment outcomes and the patient experience, but we also evaluated the internal cost of care delivery. The question that may come up is about adding another drug. Is this going to increase the budget of the cost of care delivery? As it turns out, it actually saves money. Hospitalization is expensive. We all know the cost of emergency room visits. Transfusions are exorbitantly high. We not only provide a smoother journey for the patient, but we also save money by being proactive in the protection of this bone marrow situation.

: I completely agree with you, Martin. You mentioned the issue of what happened with COVID-19. With the system so overwhelmed, we need to be prepared for the future. Perhaps, hopefully, it’s the last pandemic, but you never know what could happen. When you have something like trilaciclib that can avoid those hospitalizations—because of neutropenia—to avoid a transfusion and those kinds of things will significantly help the health care system. We need to be prepared for that. As I said, as long as the patient can stay at home with their family and their loved ones, that is a plus. That's exactly what we want to see regarding quality of life in the health care system.

: Absolutely. I would definitely second that.

Videos

Focusing the discussion on the clinical trials that led to the FDA approval of trilaciclib, experts in ES-SCLC share key insights into the drug’s safety and its effect on patient quality of life.

An Overview of Trilaciclib Safety and Patient QOL Outcomes 

: What are the remaining unmet needs in myeloprotection? Especially in small cell lung cancer, but maybe even a bigger context.

: Martin, as I said before, I would like to see this myeloprotectant agent move forward in other indications, not only small cell lung cancer. As you mentioned, there are so many regimens that we need to investigate. There are some clinical trials using trilaciclib in the space of metastatic colorectal cancer, which we use. For example, a combination of FOLFOX [folinic acid, fluorouracil, oxaliplatin]plus bevacizumab is used. In fact, I just started a patient on this regimen last week in my clinic. There are studies using trilaciclib in this specific scenario because we know that FOLFOXI plus bevacizumab will cause myelosuppression in the patient. Remember, this therapy is every 2 weeks. We need to keep those progenitor cells as intact as we can. There are some other studies done on breast cancer, triple-negative breast cancer, in which, unfortunately, the female patient with triple-negative breast cancer must go to systemic chemotherapy. Chemotherapy is sometimes myelosuppressive, especially when we use a regimen that cannot cause neutropenia but can cause thrombocytopenia. As I mentioned before, trilaciclib, this myeloprotectant, covers all lineage. It’s not only the progenitor for the white blood cells and the neutrophils, but also in the red blood cell lineage and the megakaryocyte for the platelets.

: We’re seeing the timing of platelet and white blood cell destruction and lack of recovery much earlier than in red blood cells. They can both be equally dangerous in their own right. You mentioned triple-negative breast cancer. Are you seeing any other strategies that are on the horizon? Are there any disease spaces where you think this would be an interesting area?

: I would say that there are many myelosuppressive regimens, but the sarcoma ones are what I’m really interested in because these regimens are very myelotoxic. I think that we need to investigate those areas. This is also in the GU [genitourinary] space, the same thing. We have some chemotherapy regimens that involve 2, 3, or 4 drugs. I think that we need to investigate that as well.

: I think we’re seeing the concern. Whether or not we are experiencing the same outcomes, we don’t necessarily have retinoblastoma pathway impairments that may protect from CDK6 [cyclin-dependent kinase 6] impact. I think this may be an opportunity for a genomic guidance situation where we can do this tumor by tumor, as we’re sequencing more of the tumors. Again, small cell lung cancer is one of the few biogenic defined tumor types with 

: Thank you, Dr Santos, for a wonderful discussion. Thank you to you for your insightful comments and thank you to our audience for listening to us today.

: Dr Dietrich, it’s always a pleasure to share this forum with you. I’m looking forward to seeing you another time. It’s important what we are doing. We are providing our cancer patients with new hope so they know there is something more to deliver than just therapy. We are also watching them, to protect them from side effects of therapy. I think it is very important what we are doing. Thank you once again for having us.

Martin Dietrich, MD, PhD, and Edgardo Santos, MD, FACP, offer closing remarks on unmet needs and future directions in the management of CIM including other disease states where trilaciclib may offer myeloprotective benefit.

Unmet Needs and Future Directions in the Management of CIM

 Dr Dietrich, can you explain the use of CDK4/6 inhibitor trilaciclib [Cosela] in providing prophylaxis for chemotherapy-induced myelosuppression in the setting of small cell lung cancer?

 That has a very interesting mechanism. The cyclin-dependent kinases are involved in cell cycle progression. We’ve seen this in clinical trials. For breast cancer treatment, CDK4/6 inhibitors are common because they’re among the most common, predictable effects is myelosuppression. This is typically a cyclin-dependent kinase 6–mediated effect. As 1 of the resistance mechanisms, this is where the idea was born to use CDK4/6 inhibitors in breast cancer. When using CDK6 in breast cancer treatment, RB, the retinoblastoma protein—which that has a major guardian function in conjunction with TP53—is lost. In small cell lung cancer, 

 dual mutations are essentially a genotypic definition of small cell lung cancer.

You already have a histology that informs that about the genotype. We know that these patients have impairments in the retinoblastoma protein through mutations, therefore making it very interesting for patients with small-cell lung cancer. You can stop the cell cycle progression in the bone marrow by inhibiting CDK4 and CDK6¾particularly with trilaciclib [Cosela]—but you’re not affecting possible cell cycle progression. One concern is that if we arrest cell cycle, do we have static with a cytotoxic drug in conjunction? As it turns out, based on the molecular differentiator of RB presence, the bone marrow acts very differently and can be protected through cell cycle arrest, while the small cell tumor cells continue to proliferate uninhibitedly by CDK4/6 inhibition. There’s no impact on small cell lung cancer, making it a very refined approach to protect the bone marrow. It doesn’t affect the treatment of small cell lung cancer, allowing organ-specific supportive care.

 Exactly. The beauty of arresting, as you mentioned, those stem cells in the G1 [growth 1] phase of the mitosis cycle, is avoiding those hematopoietic stem cells from moving forward; meanwhile, the patient receives chemotherapy. That’s the beautiful thing going on with supporting our patient with cancer¾trying to avoid this myelosuppression and a lot of problems, for not only the patient but also the caregivers, family, and others.

 Another aspect, biologically, is protecting the wide cell lineage. We’re using, in almost all patients, combination immunotherapy up front and preserving the white blood cell population. There’s a biological rationale that we may positively affect the impact of immunotherapy. It’s not what we’re protecting against, but it’s certainly 1 we hope we can promote by maintaining an improved white blood cell count.

 Correct. We’re talking about white blood cell count, but by arresting the hematopoietic stem cells, we also impact the red blood cells, the platelets, and the megakaryocyte lineage. We’ll discuss this more in clinical stories, but basically, we’re impacting not only neutropenia but also anemia and thrombocytopenia.

Edgardo Santos, MD, FACP, and Martin Dietrich, MD, PhD, share insights into the mechanism of action of CDK4/6 inhibitors for the prevention of myelosuppression in ES-SCLC.

Myeloprotective Benefit of CDK4/6 Inhibition in ES-SCLC

 Dr Santos, could you walk us through the different settings where trilaciclib [Cosela] has been tested in both the first and second-line setting of small cell lung cancer [SCLC]? Could you give us a bit of an overview as to what the impact was and what the clinical trial populations looked like?

 Trilaciclib [Cosela], which is an intravenous CDK4/6 inhibitor with a short half-life, has been studied extensively for use in small cell lung cancer as a first-line and second-line therapy. There are 3 studies. One was done on patients with extensive-disease small-cell lung cancer who were exposed to chemotherapy. You mentioned before carboplatin [Paraplatin] plus etoposide [Toposar] as a standard of care worldwide. There was a primary end point and a secondary end point looking for severe neutropenia and the duration of severe neutropenia. There were other secondary end points needed for secondary prophylaxis. The amount of transfusion, if needed, is a secondary analysis.

There was a second study done on the same population, but this time on patients who also received immunotherapy¾in this case, atezolizumab [Tecentriq]. As we know, chemotherapy-immunotherapy is the standard of care today for first-line extensive disease in small cell lung cancer and with similar primary and secondary end points. The first study was on the second line for patients who progress after a platinum-based doublet. They went on to receive topotecan, which is another agent we use in the second line. Those regimens, carboplatin-etoposide and carboplatin-etoposide plus immunotherapy—in this case, atezolizumab [Tagrisso] and topotecan—carry a high risk of myelosuppression.

In this study, and in those 3 phase 2 studies, the patient received the therapy, trilaciclib [Cosela], and another group received the placebo. We found that severe neutropenia and the duration of the severe neutropenia was significantly in favor of those who received trilaciclib vs patients who received the placebo. Similarly, in a descriptive manner on the secondary end point, the amount of transfusion¾of red blood cells or platelets, as well as the amount of anemia¾seen on those patients was also less in patients who received trilaciclib [Cosela] vs the group that received the placebo.

Because of these data, the pool analysis of these 3 clinical trials that I just presented, the FDA approved trilaciclib [Cosela] for the indication to avoid chemotherapy-induced myelosuppression. Today trilaciclib [Cosela] is the only myeloprotection we have to treat patients with cancer. We’d like to move this compound, this CDK4/6 inhibitor, to other clinical therapies, not only for small cell lung cancer. How can we protect these hematopoietic stem cells?

 Edgardo, could you comment on the outcomes, and the efficacy differences we’re seeing between the patients receiving placebo vs patients treated with trilaciclib [Cosela]? Were there any signals seen?

 For patients who responded to trilaciclib [Cosela], 1 advantage is avoiding a problem with myelosuppression, avoiding use of this growth factor support, or avoiding the worst-case scenario: the patient ending up in the hospital. There are some scenarios in which a patient who responded to trilaciclib [Cosela] also has some T-cell clonal expansion, because you’re protecting the hematopoietic stem cells. Some studies have also reported that we’re helping the immunologic effect against the cancer. I consider that very important. By doing that, we also kill the intensity of the regimen, so we don’t have to do dose reduction.

 I’ve seen fewer dose delays and less dose-reduction efficacy. This speaks to the differentiating impact of this regimen on cancer cells vs bone marrow cells.

 Dr Santos, you spoke about the first-line setting use of trilaciclib [Cosela] prior to platinum-etoposide treatment in the first-line setting. How do you see the role of topotecan [Hycamtin] in second- or later-line settings? What’s your approach there?

 The problem we have in extensive-disease small-cell lung cancer is that the disease grows so fast. Then in the second line¾and sometimes third line on patients who can receive third line¾patients are more compromised and the therapies are more myelosuppressive than in the first line, unfortunately. We have a rate of neutropenia of 70% or 80% when we move to second-line therapy for small cell lung cancer. Something like trilaciclib [Cosela], which we can provide the patient ahead of time, can protect hematopoietic progenitor cells. That’s the beauty. We’re living in an era where if we have something that can help us, we can be proactive and not reactive because once the patient gets neutropenia, a lot of things could happen.

We’re going to give growth factor support. Similarly, if the patient gets chemotherapy anemia, the same thing happens—either growth factor support or sometimes transfusion—so we can keep up with the pace of the therapy. There’s no question in my mind that with a high incidence of neutropenia in second- or third-line therapy for small cell lung cancer, trilaciclib [Cosela] needs to be on board as a myeloprotectant to avoid this issue.

 I’m hearing you say that the need may be even bigger in a later-line setting.

 We do the same in our practice. We’re trying to preempt, especially in neutropenic complications, but we shouldn’t underestimate the impact on quality of life from anemia and other myelosuppressive impacts that we see.

Renowned leaders in thoracic oncology discuss efficacy data from key clinical trials that led to the FDA approval of the CDK4/6 inhibitor trilaciclib for CIM prophylaxis in ES-SCLC, including the drug’s role in later treatment lines.

Trilaciclib Efficacy in the Prevention of CIM in ES-SCLC

 Hello. I’m Dr Martin Dietrich from Florida Cancer Specialists in Orlando Florida.

 My name is Dr Edgardo Santos from Florida Precision Oncology and GenesisCare in Aventura Florida. I’m a medical oncologist. Martin, it’s nice to see you.

Thank you. We’re here during ASCO [American Society of Clinical Oncology Annual Meeting] with so many data in oncology. Let me ask you this question about chemotherapy-induced myelosuppression: how frequent is this problem in extensive-disease small cell lung cancer?

 Myelosuppression is 1 of the biggest problems and biggest needs for supportive care in small cell lung cancer. We’re seeing neutropenia in the rates of 70% or 80%. Both of us practice in Florida, in a geriatric population, so it’s almost a ubiquitous problem affecting both white and red cell lineages.

 Martin, are there any risk factors that predispose the patient to developing chemotherapy-induced myelosuppression? What do you think about those important risk factors while seeing a patient in your clinic?

 Several risk factors are present. Obviously, 1 is age. We’re seeing predisposition there. Bone marrow infiltration, if present, will probably be less frequent in small cell lung cancer. We can think about pretreatment. There are other bone marrow conditions that may be preexistent in an older-patient population: kidney dysfunction, EPO [erythropoietin] deficiency, and others. There are many predisposing factors in a real-world population that would enhance the concern of myelosuppression.

 In oncology, we have several treatments for patients with cancer. We’re going to discuss more about the treatments for extensive-stage small-cell lung cancer. What kind of therapy comes to mind when you know that you need to be more proactive because you already foresee the possibility of chemotherapy in myelosuppression? What therapy regimens come to mind right away?

 Typically, the doublets are at the top of our minds when we treat extensive-stage small cell lung cancer. Any of the regimens are aggressive and extensive, typically given over several days. Carboplatin [Paraplatin] or cisplatin [Platinol-AQ] have slightly different involvements with the bone marrow, but we typically see significant myelosuppression regardless. Etoposide [Toposar] and topotecan [Hycamtin] are very suppressive regimens that require growth factor supports, frequently and are oftentimes prophylactic, with an anticipated risk far above 20%¾more in the range of 80%. We’re seeing these parts. They have mostly predisposed patients to a concern of infection, hospitalization, possible sepsis, and worse outcomes. On the other hand, they’ve also affected quality of life with a significant amount of anemia, need for transfusions, low energy, shortness of breath, and the presence of preexisting conditions¾which are already prevalent in the small cell population¾ that will be aggravated by additional suppression of the bone marrow and anemia.

Dr Santos, in your patient population, what impact do you see of myelosuppression on your patients? How does it affect your treatments? How does it affect your patients in general?

 When the patient is exposed to a myelosuppressive regimen, and they develop neutropenia, there’s a serious consideration. You can develop neutropenia grade 1 or 2, no problem, but when the patient starts to get grade 3 with some symptoms or grade 4, especially with a fever, that’s an emergency situation. The patient needs to be admitted to the hospital. If the patient doesn’t have an infection, the patient can easily get back to the regimen. The patient could develop a serious infection that could become fatal, an outcome that we don’t want, or the infection will certainly cause a delay on therapy. If there’s no way to prevent that, then we have to reduce the dose sometimes. As you know, Martin, when we do dose reduction in therapy, we lose efficacy¾ several clinical trials have shown that. Dose reduction is something we prefer to avoid unless it’s extremely necessary. Certainly, the issue of neutropenia will bring a serious issue for the patient in several aspects.

 One of the most frequent emergencies that we see in medical oncology is the patient that comes into the hospital with neutropenic fever, with all the downstream effects happening.

Two leaders in the management of ES-SCLC provide an overview of chemotherapy-induced myelosuppression including key risk factors and its effect on patient outcomes.

An Overview of Chemotherapy-Induced Myelosuppression in ES-SCLC

 Dr Santos, could you give us an overview of the NCCN [National Comprehensive Cancer Network] recommendations regarding the management of myelosuppression?

 From the NCCN, we have a stratification based on the regimen therapies for SCLC. Certain regimens carry a higher risk to developing this problem of suppression. As you mentioned, Martin, there’s the issue of not only neutropenia but also severe anemia and thrombocytopenia. There are different regimens. The NCCN recommends the use of prophylaxis on regimens that have a high risk of developing myelosuppression, which is more than 20%. There’s another category of regimen if the risk of developing myelosuppression is 10% to 20%, plus another clinical risk factors: age, bone marrow infiltration, prior radiation therapy, prior chemotherapy, and comorbidities such as diabetes, chronic obstructive pulmonary disease, and liver disease all play an important role in deciding what patient population deserves prophylactic management to avoid this myelosuppression.

 Has that changed for you in the pandemic?

 That changed significantly during the pandemic. With all the issues we’ve had in the last 2 years to avoid exposure with the patient, for obvious reason, we sometimes have had to modify not only the regimen but also our approach to being more proactive with the prophylaxis. We don’t want to send the patient¾in the middle of pandemic¾to the hospital when the health care system was completely overwhelmed with so many cases of COVID-19.

 In your clinic, if you have an extensive-stage small cell lung cancer patient, do you favor a prophylactic approach of treatment? How do you manage those patients?

 You and I are thoracic oncology. We see a lot of patients with extensive-disease small-cell lung cancer. That regimen for extensive-disease small cell lung cancer is very myelosuppressive, so we always use prophylactic treatment. In my clinic, I always use prophylactic to avoid that kind of problem. Usually, it’s neutropenia, but sometimes patients that develop pancytopenia, in which red blood cell, platelet, and white blood cell counts are depleting.

 It’s very difficult to predict what a patient is going to have.

 It’s very difficult. Some patients respond very well to prophylaxis, and some of them do not, but we’ve made progress in this field.

 Are there any unmet needs that you see for patients?

 In terms of prophylaxis, an unmet need is to continue making progress in what we have right now. We have a medication that can protect stem cells. We’re using it now, specifically in small cell lung cancer. I’d like to see an expansion in these prophylaxes¾which are proactive, not reactive¾in order to create a regimen other than 1 for a small cell lung cancer. There’s an unmet need in oncology on how to take advantage of this kind of prophylaxis and put it in another clinical setting.

Expert panelists review considerations in the prophylactic treatment of chemotherapy-induced myelosuppression with special attention paid to unmet needs related to the use of G-CSF and ESAs.

Edgardo Santos, MD, FACP

Articles

An Overview of Trilaciclib Safety and Patient QOL Outcomes

Unmet Needs and Future Directions in the Management of CIM

Myeloprotective Benefit of CDK4/6 Inhibition in ES-SCLC

Trilaciclib Efficacy in the Prevention of CIM in ES-SCLC

An Overview of Chemotherapy-Induced Myelosuppression in ES-SCLC

Prophylactic Approaches to the Management of CIM in ES-SCLC