Luis E. Raez, MD

Addressing Myelotoxicity as a Consequence of Treatment for Extensive-Stage Small Cell Lung Cancer

, experts consider key factors in the optimal management of patients with extensive-stage small cell lung cancer (ES-SCLC). Chemotherapy-induced myelosuppression (CIM) can impact the bone marrow resulting in decreased activity and reduced red/white blood cells in addition to platelets. Patients with extensive stage-small cell lung cancer (ES-SCLC) receiving chemotherapy can develop these conditions, resulting in poorer health outcomes. Luis E Raez, MD, Chief Scientific Officer, and Medical Director of the Memorial Cancer Institute, discusses chemotherapy induced myelosuppression (CIM) and its impact on blood cells. Dr. Raez highlights past and present obstacles faced by oncologists when treating CIM in patients with ES-SCLC. Lastly, Dr. Raez discusses the emergence of trilaciclib in patients who develop CIM for ES-SCLC and its clinical implications from recently published data.

Targeted Oncology™: Briefly define chemotherapy induced myelosuppression (CIM). How does it affect red blood cells, white blood cells and platelet production?

: Chemotherapy in small cell lung cancer is hard for the patients. We still use a very old regimen: carboplatin and etoposide. These agents were developed in the 1980s, more than 40 years ago. For that reason, it is no surprise that these drugs are very toxic for the bone marrow. There is a 50% chance or higher that patients will experience Grade 4 myelosuppression through either anemia, thrombocytopenia, or neutropenia. For this reason, we make myelosuppression into consideration each time that we treat patients with chemotherapy. According to current NCCN guidelines, the chance of myelosuppression in patients, specifically neutropenia, is more than 20%. Additionally, with the use of growth factor support, the risk of myelosuppression in patients on chemotherapy is between 10-20%. We must check the patient’s comorbidities to assess whether use of growth factor support is appropriate. Overall, these regimens will impact the patient’s bone marrow as a result.

Targeted Oncology™: HL is a 68-year-old woman who was recently diagnosed with extensive stage small lung cancer, and recently update with carboplatin and etoposide. After two cycles of treatment, she developed thrombocytopenia. How would you manage this patient’s thrombocytopenia and how do patients on chemotherapy typically develop thrombocytopenia?

: Managing thrombocytopenia in this specific case is a very common scenario seen in clinical practice. It is estimated that one-third of our patients with this treatment regimen will experience severe thrombocytopenia. Typically, we don't have a product that can protect patients from thrombocytopenia. In the last 20 years, we have made considerable attempts with several different growth factor drugs for managing thrombocytopenia. Prior to the recent approval of Trilaciclib, we didn't have a product that could be commonly used. The problem with thrombocytopenia is that it causes dose delays. Following chemotherapy, the patient comes for another cycle of treatment and if their platelet count is >100,000, there's going to be a dose delay. Typically, we don't transfuse platelets in patients until severe thrombocytopenia is present and as a result, platelets are not an option. If the patient, for example, has 70,000 platelets, they don’t need a transfusion, but we must delay chemotherapy and postpone treatment to allow for recovery. Another problem we face is inadequate management of thrombocytopenia. Due to mismanagement, we must begin dose reductions since we didn't effectively protect the patients. We don't want the patients to risk having severe thrombocytopenia and then worry that it could happen again. If we are unable to reduce the patient’s risk from thrombocytopenia, we will have to dose reduce chemotherapy. As a result, the intensity of chemotherapy decreases and ultimately may result in poorer outcomes. 

Targeted Oncology™: What advice do you have for community oncologists who treat thrombocytopenia in patients receiving chemotherapy?

: Clinically, it has been very intriguing for us to learn about Trilaciclib with the recent publications. Interestingly, recent publications have shown that Grade 3/4 thrombocytopenia can be reduced in patients to nearly half [50%]. I think this product [Trilaciclib] is very valuable. The reduction in the number of platelet transfusions does not occur due to its uncommon use in patient. Overall, the best endpoint to measure is the reduction in severity of thrombocytopenia. Hopefully, this will allow us to timely administer chemotherapy in patients for their following cycles.

Targeted Oncology™: Please review the secondary myelosuppressive endpoints assessed in the pooled analysis of the impact of trilaciclib on CIM from the randomized trials in patients with extensive stage small cell lung cancer. How are they defined and what were the results of these endpoints?

: In a recent publication, a pooled analysis of three clinical trials were conducted with Trilaciclib. Of those trials, two investigated frontline therapy with carboplatin and etoposide while the other trial assessed second line therapy and beyond with topotecan. In this pooled analysis, the primary endpoint assessed was the duration of severe neutropenia. The duration and occurrence of severe neutropenia in Cycle 1 is the standard that was used in these studies to assess the utility of these drugs. Specifically, in the case of Trilaciclib, we see that the pooled analysis shows that the severity of neutropenia can be reduced from nearly 50% to about eleven or 12%, with tremendous statistical significance. Overall, the severity of neutropenia was the most significant endpoint. The secondary endpoint assessed related to white blood cells, red blood cells, and platelets. For white blood cells, the most important secondary endpoint was febrile neutropenia. Febrile neutropenia, in this study, decreased from 9-3% with very close statistical significance. However, the use of growth factor support in patients decreased from 55% to 28%. Since the use Trilaciclib in prophylactic treatment, the use of growth factor support has nearly halved which was statistically significant. Grade 3/4 anemia was also shown to decrease by 50%, from 30-20% which has lowered the rate of transfusions as well. Additionally, the administration of ESAs also decreased. Specifically for thrombocytopenia, 1/3 of patients experienced severe thrombocytopenia (Grade 3 and 4), with <75,000 platelets. Following the use of Trilaciclib, severe thrombocytopenia was shown to decrease by half, from around 36% to 19%. Platelet transfusions were no different in these studies, but as mentioned previously, it's not an endpoint that we look for. Typically, we only transfuse platelets in patients when their platelet count is <15,000. In the area of platelet transfusions, we do not expect much change. However, while most patients are in the platelet range of 70,000, this is still not good as it doesn't allow for the use of chemotherapy.

Targeted Oncology™: What were some adverse events seen in the publication of the pooled results of trilaciclib in CIM? What was the impact of trilaciclib on hospitalization rates and how are injection site reactions managed in patients?

: Regarding adverse events that we see with Trilaciclib, it’s difficult to evaluate while using chemotherapy concurrently. There are adverse events for both chemotherapy and Trilaciclib. It is challenging to differentiate the source of the adverse event. Certainly, you can see, for example, that the number of hospitalizations went down from 13% to four percent since using Trilaciclib. Averse events, like fatigue, are difficult to differentiate between Trilaciclib and chemotherapy. There are specific adverse events ones that originate from Trilaciclib. For example, injection site reactions were more commonly seen with Trilaciclib (13%) compared to placebo (2.5%). The chance of phlebitis was nine percent with 0.8 [percent]. Most of these adverse events were low grade, including hypersensitivity reactions (4% versus 3%). Even with placebo, it’s amazing that you can have reported hypersensitivity reactions. That's mainly the way that we saw specific adverse events and they usually do not prevent the use of the agent in the next cycle.

Targeted Oncology™: How does the safety and tolerability profile of trilaciclib factor into your decision when you initiate treatment? What other factors might you consider?

: Given all the data available, the deciding whether to use Trilaciclib is not a difficult choice, personally. I understand that these are small studies in only one tumor type, lung cancer, small cell lung cancer, but the current standard of care is very low realistically. Currently, we do not have a lot of standard of care options for patients. The only standard of care option that we have is to use growth factor support for patients that have >50% chance risk of severe neutropenia. That will only protect our white blood cell line and does not protect a patient’s platelets or anemia. I think that if physicians want to, based on the data, consider using Trilaciclib to protect not only the white blood cells, but also protect patients from the risk of anemia and thrombocytopenia. Given the data, it's very interesting that we see decreased occurrences of severe neutropenia and decreased usage of growth factor support to rescue patients. Ultimately, there are a lot of endpoints that I think very valuable.

Targeted Oncology™: What has been your experience with using trilaciclib in patients receiving chemotherapy? Do you foresee trilaciclib having a role in other tumor types?

: We have had the opportunity to use Trilaciclib and I think it's very interesting. With more than 20 years practicing with carboplatin/etoposide, there’s has never been a good agent to protect patients from anemia and thrombocytopenia. Presently, we have the option now. As I said before, we previously had options to protect patients from neutropenia, but now we have an option that can cover three blood cell lines for myelosuppression which is very interesting. While the drug’s approval is limited to small cell lung cancer, it is of my hope that further evidence is accumulated so that it [Trilaciclib] can be used in other tumor types. When we approved the use of growth factor support more than 20 years ago, we didn't test for every single tumor type to get approval. So, that is why we're looking forward for more data so our colleagues can benefit from this knowledge and these results. So far, I’ve seen many thoracic oncologists not only excited but interested in this agent as consideration for use in daily practice.

Articles

In this companion article, Dr Luis Raez provides insights into effective management patients with extensive-stage small cell lung cancer who develop chemotherapy-induced myelosuppression.  

EP 12B: Management of Chemotherapy Induced Myelosuppression (CIM) in ES-SCLC 

Immediate Past President, Florida Society of Clinical Oncology

Luis E. Raez, MD, FACP, FCCP, is the medical director and chief scientific officer of Memorial Cancer Institute, as well as

director of the thoracic oncology program for Memorial Health Care System. He is aslo a clinical professor of medicine at Florida International University (FIU), Research Professor of Medicine at Florida Atlantic University (FAU), and visiting professor of medicine at Cayetano Heredia University in Peru. Currently, Dr Raez designs phase 1-3 clinical trials with new chemotherapeutic agents and combinations. Dr Raez does translational research in the areas of cancer vaccines and has been funded by National Cancer Institute and the pharmaceutical industry.

This year alone, more than 1.9 million Americans will face a new cancer diagnosis, including more than 236,000 people who will be diagnosed with lung cancer.

As a medical oncologist, it is my duty to provide treatment and take care of people who have cancer. Throughout my career, I have been fortunate to witness a significant improvement in how we understand cancer; however, common misconceptions about how we treat this disease still exist. While Lung Cancer Awareness Month may have just ended, it is crucial to continue spreading education and awareness about the disease, our recent advances in diagnosis and treatment, as well as the enduring health disparities that exist across the cancer continuum.

As a critical tool at the forefront of personalized medicine, biomarker testing is fundamentally transforming and enhancing the way in which we diagnose and treat cancer. It is crucial to continue spreading awareness about the importance of comprehensive biomarker testing to improve patient outcomes.

Our understanding of cancer has evolved. Within broad cancer types, such as lung cancer, we now know that there are many subtypes, some of which are driven by specific genomic alterations. One goal of a cancer treatment plan is to determine whether one of these specific genomic alterations is the cause of a patient’s cancer diagnosis.

Biomarker testing, also known as genomic testing, looks for alterations in cancer’s genes and can help identify the underlying drivers of a tumor. Results of biomarker testing can show which treatment is likely to work best for the patient. This critical step in a cancer patient’s treatment journey is what allows clinicians to prescribe targeted, precision therapies and, just as importantly, avoid treatments that may not work as well.

Though truly capitalizing on the promise of biomarker testing requires ensuring equitable access to high-quality diagnostic testing. Despite biomarker testing’s potential to improve progression-free survival and overall survival, access barriers may be impacting health outcomes for racial and ethnic minorities and other medically underserved populations.

In many cases, targeted therapies are available to treat genetic aberrations that can effectively stop the spread of and ultimately inhibit tumor growth.

Compared with traditional treatments like chemotherapy that kill both healthy cells and cancer cells, targeted therapies are less toxic to healthy cells. Patients who are treated with targeted therapies tend to have fewer adverse events, better disease outcomes, and improved quality of life.

Without comprehensive biomarker testing, doctors and patients have limited knowledge of whether a specific alteration is driving the way cancer behaves and if a targeted treatment can be recommended. This knowledge empowers doctors to determine eligibility for targeted treatment options or clinical trials and can avoid potentially less effective treatment choices.

Furthering the adoption of biomarker testing depends upon addressing the system-wide barriers that stand in the way of greater utilization. Reimbursement challenges and logistical concerns are commonly cited by providers, which could be an acute concern for those working with predominantly underserved communities.

On November 11 and 12, the Florida Society of Clinical Oncology (FLASCO) brought together oncologists with the shared mission of closing health equity gaps to discuss new research, advocacy, and policy around cancer disparities. The event touched on numerous key issues driving health inequities, including how disparities in molecular profiling are responsible for several of the inferior cancer treatment outcomes in minority patients, particularly due to the lack of adequate knowledge of cancer they are facing and the lack of proper treatment.

If you want more robust information about the totality of the health of your patients, we encourage you to learn more about biomarker testing and why it is important.

1. Cancer facts & figures. American Cancer Society. Accessed November 14, 2022. https://bit.ly/3uN2O8B

2. Bruno DS, Hess LM, Li X, Su EW, Yajun EZ, Patel M. Racial disparities in biomarker testing and clinical trial enrollment in non-small cell lung cancer (NSCLC). 

 2021;39(15_suppl): 9005. doi:10.1200/JCO.2021.39.15_suppl.9005

3. Biomarker testing is changing the face of lung cancer. Lung Cancer Initiative of North Carolina. Accessed November 14, 2022. https://bit.ly/3uKvtuX

4. Kaminski A, Szamreta EA, Shah R, et al. Barriers to next-generation sequencing despite increased utilization: U.S. physician survey results.

2021;39(15_suppl):e18754. doi:10.1200/JCO.2021.39.15_suppl.e18754

5. What is comprehensive biomarker testing? Bridging the biomarker gaps. FLASCO. Accessed December 15, 2022. https://bit.ly/3FtxpNp

Luis E. Raez, MD, FACP, FCCP, immediate past president of Florida Society of Clinical Oncology, evaluates the role of biomarker testing for lung cancer and other disease types.


Realizing the Promise of Biomarker Testing in Lung Cancer and Beyond

Videos

Dr Luis Raez shares his perspectives on ways to manage thrombocytopenia in patients receiving chemotherapy for ES-SCLC treatment. 

EP 12A: Managing Thrombocytopenia in Patients receiving Chemotherapy for ES-SCLC

Luis E. Raez, MD, the medical director and chief scientific officer at Memorial Cancer Institute, Memorial Health Care System, discusses the treatment of 

 fusion-positive lung cancers in the past and the present.

 fusions are a relatively new target in the lung cancer space, says Raez. Despite their novelty, 

 fusions are important because they are changing the face of cancer treatment. The reach of 

 fusions spans 18 different adult and pediatric cancers, he explains.

The original data around the TRK inhibitor, larotrectinib (Vitrakvi) showed that patients will respond to TRK inhibition. This research was revolutionary for lung cancers and other solid tumors because it further solidified the role of genetic testing and targeted therapy for these patient groups.

Luis E. Raez, MD, discusses the treatment of TRK fusion-positive lung cancers in the past and the present.

TRK Inhibition Continues to Advance the Lung Cancer Field

 fusions has been very revolutionary because, first of all, we have discovered 1 more type of fusion that we have therapy for now, despite the fact that a lot of people ask us lung cancer doctors, “This is a very uncommon genetic alteration. Why would you worry about that?” We have so many lung cancer patients in the United States: around 225,000, and a few more every year. Even if only 0.3% carry this genetic alteration, there is a significant number of Americans who have benefited from that. Worldwide, we believe that more than 8000 to 10,000 patients may carry these genetic alterations and can benefit from new treatments. That was 1 point.

The other point is the fact that we’re using tumor-agnostic therapies. This is the beginning of tumor-agnostic therapy, and it is amazing that in the papers, there were 17 different types of tumors responding. Not only were the tumors different, but there were also tumors in adults and in children. We never crossed over before, we never gave the same treatment to adults and children. These are 2 different sciences. Pediatric oncology and adult oncology were very separated, but not anymore. If we do tumor-agnostic therapy, we’ll be able to treat patients, regardless if they are adults or children.

The other important things we learned about tyrosine kinase inhibitors are their quality of life, tolerability, and low toxicity profile. We’re providing patients with cancer therapy that may do very well for them. It does not impair their quality of life, and they can stay on it longer. In lung cancer, we always said that we are trying to make this a chronic disease. Certainly, these types of treatments are helping us to make lung cancer a chronic disease because we monitor these patients maybe once a month. But the survivors don’t like to come in. After 2 or 3 years, they say, “Oh, nothing happens, so I will wait 2 or 3 months until I need to do my scan.” That’s amazing. In our lifetime—most of us have been treating lung cancer for 20, 25 years—it’s amazing to see this difference. That’s all with good quality of life.

Given all these aspects, I think the treatment of these 

 oncogenes is very important and has been impactful because we have used this example to look for other types of tumor-agnostic therapy, such as with 

 and other genes. That’s why I think it’s a very amazing, very successful story.

We are not going to find these patients if we don’t use testing and education. We’re empowering the patients to request to be tested. Even if, for example, the testing comes back negative because it’s tissue based, we can use liquid biopsies, and these 

 alterations can be found even in liquid biopsies. That’s why I think doing this is very good for our patients, for the doctors, and for education.

For me, the most important unmet need is to do the testing. Our statistics show that we aren’t testing all patients yet, and they need to be tested. Our statistics show that not all the patients tested with positive oncogene results are getting targeted therapy because of several different problems: access to the drug, problems with the payers, insurance, and things like that. Sometimes, test results take 2 or 3 weeks, and the patient becomes impatient. They are already waiting months to meet with a medical oncologist. By the time they get a chest x-ray and meet with the medical oncologist, it may be 2 or 3 months.

When you’re talking with the patients and saying, “Let’s wait 3 weeks for your results,” the patients sometimes say, “No, I want my chemotherapy tomorrow.” There are many of these aspects that we need to work together to improve. Patients need to understand, for example, that it’s worth being tested for these alterations. They can attain not only several extra months of life but also a very good quality of life. That is why for me, the most important thing is to increase testing and increase access to these drugs.

 Fusion-Positive Metastatic Non-Small Cell Lung Cancer

A 67-year old man presented with a 2-month history of cough and dyspnea on exertion

PMH/SH: hypercholesterolemia, never smoker

Chest X-ray showed a right-side mass ~2.5 cm

Chest/abdomen/pelvic CT showed a 2.7-cm solid pulmonary lesion in the right lobe, ipsilateral mediastinal lymph node involvement

CT‐guided core needle biopsy of the lung lesion and lymph node revealed lung adenocarcinoma, grade 3

Contrast‐enhanced MRI of the head showed a small lesion (0.6 cm); indicating CNS metastasis

Larotrectinib 100 mg PO BID was initiated; treatment was well-tolerated

Stereotactic radiosurgery of the brain was deferred due to location and increased risk of post-operative morbidity

Imaging at 2 months showed stable disease; sustained response upon follow-up

Imaging at 18 months showed decreased size of pulmonary and brain lesions

Larotrectinib: A Tumor-Agnostic Therapy

We repeat molecular profiling when patients progress, especially patients who have fusions like 

. We do that because there is very good documentation that these fusions suffer mutations. These mutations are creating resistance to the tyrosine kinase inhibitors. In the specific case of 

, we have a whole library of well-known resistance mutations that arise while these patients are treated with tyrosine kinase inhibitors. We learned that from the 

 patient history, and now we’re learning the same of these patients treated with larotrectinib or entrectinib. By the time we had all these data published, we had already seen that several of these patients treated with larotrectinib or entrectinib developed resistance mutations. For that reason, it is necessary to document the resistance mutations to try to find the next treatment.

resistance mutations, because in the case of 

 we already have 5 FDA-approved agents and 2 or 3 drugs being researched. If you have a patient with an 

 alteration who develops resistance, you have so many options for him. We really need to retest. The question is how you retest these patients. It depends. If it’s convenient, you can perform a tissue biopsy. For example, if the patient develops a new, single liver metastasis and you are going to use some form of local therapy, maybe it’s convenient to take a biopsy before you administer local therapy like stereotactic radiation or radiofrequency ablation.

If you don’t have a large volume of tumor, maybe the easiest method is to use a liquid biopsy, sequence DNA in the blood, and try to identify the resistance mutation and get more information from these patients. That’s why I think repeating the genomic profiling of the patient is very important. Of course, it is more focused. However, we know that the patients are going to develop mechanisms of resistance, such as 

 amplification. That’s why it’s very important to do the genomic profiling. That is a controversial topic. A lot of people will say, “Oh, we are not ready. Why are you doing that? Just put them on chemotherapy, and forget about this.” But this is something that is evolving as we speak, and when we are doing research, it’s very important that we repeat the molecular profiling for all these genetic fusions in lung cancer.

For NTRK-targeted therapies, we already have some resistance mutations that have been well described, not only in lung cancer but also arising in patients with other cancers. We have treated a lot of fibrosarcomas and other types of tumors that carry these 

 fusions. That’s why we have been developing an agent called LOXO-195. Other companies have other potential agents that can help us treat these patients to overcome resistance. There are already presentations of LOXO-195 that show the drug is able to rescue patients with resistance mutations. That is why I’m very optimistic about the future. At least we now have a second-generation NTRK inhibitor that will be able to rescue patients who fail the first line of defense.

The role of next-generation sequencing [NGS] is very important because that’s what we use now. Everybody agrees that we have to use next-generation sequencing and DNA testing at least once in every patient with lung cancer. There is a little bit of controversy about using NGS at progression. It’s important to understand that because of 

 patients have different variants that may not be captured by the DNA sequencing. It’s necessary that we add the RNA sequencing to complement that and be able to discover the genetic alterations that we cannot discover when we analyze only DNA.

We know that we can use, in specific cases, immunohistochemistry. The pan-TRK antibody seems to be good. As I said, we know more or less which genetic alteration we’re going to find. If I know for certain, for example, that this is a patient subset with a high incidence of 

 genetic alteration and secretory breast carcinomas, I can pinpoint and look for that genetic alteration, and I don’t have to worry about all the other 

That’s why there is a little bit of room to be more flexible and incorporate pan-TRK immunohistochemistry. I understand, you cannot use next-generation sequencing so often because it’s a very expensive test. However, the cost is hopefully going to go down like everything else in science. It’s amazing. We will be able to use it more often, but until then, we have to find other ways to work. Certainly, we would love to see accurate pan-TRK immunohistochemistry so that all of us can use it in any part of the United States in any small hospital in the most cost-effective way.