Mark A. Socinski, MD

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

, experts discuss the impact of chemotherapy induced myelosuppression in patients being treated for extensive-stage small cell lung cancer and review current treatment options. Chemotherapy induced myelosuppression (CIM) can be a significant consequence for patients receiving chemotherapy for the treatment of extensive stage-small cell lung cancer (ES-SCLC). Mark A Socinski, MD, a medical oncologist specializing in thoracic malignancies, defines chemotherapy induced myelosuppression (CIM) and discusses the challenges faced when treating CIM. Dr Socinski explains the rationale for using trilaciclib in patients who develop CIM for ES-SCLC and also provides insight into how the data from the post-hoc analyses of trilaciclib for CIM in patients with ES-SCLC will impact clinical practice.

Targeted Oncology™: What are the currently available treatment options for patients with extensive stage small cell lung cancer (ES-SCLC)?

: The currently available treatment options for patients with extensive-stage small cell lung cancer really were framed by two trials, the IMpower133 trial and the CASPIAN trial. What these trials did is take the doublet of platinum plus etoposide, which has been a standard of care for decades, [and] essentially in the case of IMpower133 added atezolizumab onto that platform. In the case of CASPIAN, [it was] durvalumab. Both of these trials were positive for overall survival [and the overall survival was] consistent between these two randomized trials. [These trials] really transformed the standard of care from platinum-etoposide to the addition of either atezolizumab or durvalumab with very similar outcomes and benefits. With hazard ratios for overall survival in the 0.7 to 0.75 range, [there was] a significant improvement in overall survival.

Targeted Oncology™: Briefly define chemotherapy induced myelosuppression (CIM), and how does it manifest?

 Regarding chemotherapy induced myelosuppression, we know that the regimen of platinum-etoposide does result in myelosuppression that can be quite significant. When we say myelosuppression, we are really talking about the three lineages of blood cells, namely neutrophils, platelets [and] red blood cells. Chemotherapy-induced myelosuppression can be detected on blood tests that we would conduct on a routine basis [or at] other times when patients present with fever and neutropenia, or when they develop extreme fatigue and are found to be anemic, or they have bleeding complications due to platelets. The spectrum of the way in which chemotherapy induced myelosuppression can occur can be quite wide.

Targeted Oncology™: What are some risk factors that may predispose patients to developing CIM?

: One of the risk factors is aging [since] elderly patients have less bone marrow reserve. [Another risk factor is if the patient has had] prior treatments, particularly radiation treatment that may have been delivered to bones that have a lot of the bone marrow where these three [cell] lines are made, [or] other concurrent treatments or history of treatment in the past. [Also,] certain comorbidities that may have affected the bone marrow in the past could predispose patients to it [chemotherapy-induced myelosuppression]. The consequences can be quite significant and can be quite varied. It's important to be aware of the complications of chemotherapy induced myelosuppression and to anticipate them by [monitoring] blood counts during the course of treatment.

Targeted Oncology™: How do you typically treat CIM in patients with extensive stage small cell lung cancer (ES-SCLC)?

: In the past, we have typically treated chemotherapy induced myelosuppression in the setting of extensive-stage small cell lung cancer in a reactive fashion. We would allow patients to become neutropenic or become anemic or thrombocytopenic, and then we would react to that either with transfusions or the use of growth factors, whether they would be white cell growth factors or red blood cell growth factors. Typically in the past it would be kind of a reactive strategy to these sorts of things.

Targeted Oncology™: What are some challenges seen when treating CIM in patients with ES-SCLC?

 The consequences and some of the challenges in treating [CIM] is that patients often have consequences of the chemotherapy induced myelosuppression before you treat it. Therefore, we were allowing our patients to have a sequela of chemotherapy induced myelosuppression and then reacting to it. It would be much better to take a more proactive [approach and] that's really the rationale for using trilaciclib in patients who are receiving chemotherapy for extensive stage small cell lung cancer. Trilaciclib is a CDK 4/6 inhibitor. In this case, it's given intravenously over a short infusion. [Trilaciclib works by] arresting the bone marrow progenitor cells in the resting phase of the cell cycle G0, [so] these cells are not dividing and therefore they are protected against the cytotoxic effect of the chemotherapy when it is delivered. Because of the intravenous infusion and the short duration, the effect is very transient. Trilaciclib is administered only on the day of chemotherapy. [Trilaciclib] arrests the stem cells in the dormant phase to help protect the cells against the effect of chemotherapy.

Targeted Oncology™: Please review the post-hoc analysis of the impact of trilaciclib on CIM from the randomized trials in patients with extensive stage small cell lung cancer. Which trials were evaluated? Which CIM events were assessed and how were they defined?

 As I mentioned, trilaciclib is a CDK 4/6 inhibitor [that] is given IV and is short-acting. [Trilaciclib] earned its FDA approval and indication in the setting of reducing the occurrence of chemotherapy induced myelosuppression across the three [cell] lineages, neutrophils, red blood cells, and platelets. This data was demonstrated in three phase 2 clinical trials that were placebo controlled [and] all of them in extensive-stage small cell lung cancer. Two [of the clinical trials were in] the first-line setting, [while the third clinical trial] was in the second-line setting, although there were a few patients that had received two prior regimens. We recently saw a post-hoc trial analysis that was really done to further assess the impact of trilaciclib on the occurrence of both, single as well as concurrent multi lineage chemotherapy induced myelosuppression events. [The analyses looked] at [the events] separately in terms of line of therapy, dividing it into first-line as well as second-line trials. In two of the first-line trials, [trilaciclib] was given with etoposide, carboplatin and atezolizumab in the first trial [and] just etoposide-platinum by itself in the second trial. Again, [the trials] were placebo controlled. Then in the second-line [and] third-line trial, [trilaciclib was given] with topotecan [and this trial was also] placebo controlled. The aim of the study was to look at the proportion of patients with single and concurrent multi lineage chemotherapy induced myelosuppression events and to estimate that per cycle and what happened over the first four cycles of chemotherapy. What was assessed was really the severe grade three or higher events of neutropenia, anemia, and thrombocytopenia.

Targeted Oncology™: How was concurrent CIM defined in this post-hoc analysis?

 Concurrent chemotherapy induced myelosuppression events were defined as having two or three lineage-specific events that overlapped by at least a day or more. The results were pretty consistent with what we had seen in prior trials. When you compare trilaciclib to the placebo arm, fewer patients that were receiving trilaciclib had single lineage events with regard to chemotherapy induced myelosuppression [and] fewer patients had concurrent events in either two or three lineages during cycles 1 to 4 of the first-line trials. [There was a] similar trend seen in a second-line trial, although this was a smaller number of patients. Severe chemotherapy-induced events occurred more frequently in earlier cycles [and] that was true of neutropenia. As we typically see, severe anemia and thrombocytopenia tended to occur a little bit later. The conclusion of this post-hoc analysis was that those patients with extensive-stage small cell lung cancer receiving trilaciclib had fewer single lineage as well as concurrent multi lineage chemotherapy events compared to the placebo arm. This was a nice reinforcement of the initial data set that we saw from these trials in the original FDA approval.

Targeted Oncology™: What are the clinical implications of these post-hoc analyses of trilaciclib from randomized clinical trials?

How do we integrate the information from the post-hoc analysis into day-to-day practice? Now, some of us, like myself, had adopted the use of trilaciclib based on the original data [that] we saw from the registrational trial. I like to take the proactive approach rather than the reactive approach. My experience with using trilaciclib concurrently with chemotherapy has been pretty positive. I am convinced that it abrogated the complications of neutropenia [and I am] impressed [to see a] reduction in the occurrence of anemia. I think anemia is one of the driving factors that really impacts patient's quality of life.

Targeted Oncology™: Might the results of these post-hoc analyses change your clinical practice?

 The post-hoc analysis really did not necessarily change my practice or my feeling about trilaciclib, [but] it reinforced it. Using [trilaciclib] reduces the single or concurrent suppression of the three lines of blood cells. I do think that that allows patients to have a more tolerable chemotherapy course. I would like to think it is a better quality of life since there is less fatigue, [and] less complications of anemia, which is a major issue from my perspective. [Also,] less complications with neutropenia [and] a lower rate of severe neutropenia, which would reduce the likelihood that you are going to have an episode of neutropenic fever in this setting. Again, like many of these post-hoc analyses, it really reinforced the initial messaging that we got from the trials. It just builds confidence that trilaciclib is an agent that does have a supportive care effect in this particular setting by reducing the risk of complications of chemotherapy induced myelosuppression.

Videos

In this companion article, Dr Mark Socinski provides insights into the use of trilaciclib for the management of chemotherapy-induced myelosuppression in patients being treated for extensive -stage small cell lung cancer. 

Episode 10B: Impact of Trilaciclib on Chemotherapy Induced Myelosuppression (CIM) in ES-SCLC 

Dr Mark Socinski reviews the challenges faced when treating chemotherapy induced myelosuppression and discusses the impact of trilaciclib on CIM and how that will impact clinical practice.  

EP. 10A: Impact of Trilaciclib on Chemotherapy-Induced Myelosuppression in Patients with ES-SCLC

Mark A. Socinski, MD, medical oncologist and executive medical director of the AdventHealth Cancer Institute, discusses the safety profile of tepotinib (Tepmetko) that was observed in the VISION trial (NCT02864992) of patients with advanced or metastatic non–small cell lung cancer (NSCLC) with 

As of July 2020, 255 patients in the phase 2 VISION trial had received tepotinib for a median of 5.1 months. The primary end point of objective response rate as assessed by an independent review was 45.2% (95% CI, 36.0-53.6).

Grade 3 or higher adverse events (AEs) related to tepotinib were reported in 25.1% of the safety population, including 7.5% who experienced grade 3 peripheral edema, according to Socinski. Peripheral edema of any grade was observed in 138 patients (54.1%) in the safety population. Socinski notes that it is a common AE of other MET inhibitors including capmatinib (Tabrecta) and is not life-threatening but can cause discomfort for patients.

Other serious AEs included gastrointestinal (GI) toxicity, general edema, and pleural effusion, while lower-grade AEs such as nausea and diarrhea were also common. The tolerability was relatively high overall, according to Socinski. Treatment was discontinued by 27 patients (10.6%) due to treatment-related AEs.

When you look specifically at the [AEs] that one would see, the most common one was, as I mentioned previously, peripheral edema. This occurred in nearly about half the patients, but in only 8% of the patients was it grade 3. So, grade 3 would be more significant than grades 1 or 2. [There were] other things such as GI toxicity, some grade 1 to 2 nausea, some low-grade diarrhea. There were other low-grade alterations of liver function tests, and these sorts of things. They should obviously be monitored for when patients are on treatment. Overall, I think tepotinib is a relatively well-tolerated agent.

The 1 issue as I mentioned before, is this issue of peripheral edema. It's not unique to tepotinib; we see it with pretty much any 

 inhibitor. So, it really is a class effect of these agents, the rates of peripheral edema are very similar across comparing capmatinib to tepotinib. Again, I don't know that we have a good understanding of the mechanism of action, nor do we have a good understanding of the best way to manage it. And again, it's not a life-threatening AE, but it tends to be very bothersome to patients.

Mark A. Socinski, MD, discusses the safety profile of tepotinib that was observed in the VISION trial of patients with advanced or metastatic non–small cell lung cancer with MET exon 14 skipping mutations. 

VISION Trial Shows Favorable Tolerability of Tepotinib in NSCLC

Mark A. Socinski, MD, executive medical director at the AdventHealth Cancer Institute and member of the Thoracic Oncology Program in Orlando, Florida, discusses the patient population of the trials targeting 

 exon 14 skipping mutations in non–small cell lung cancer (NSCLC).

 exon 14 skipping mutation is a biomarker that is an oncogenic driver as well as a therapeutic target for NSCLC. It occurs in 3% to 4% of patients with NSCLC, which is more frequent than other known biomarker mutations, according to Socinski.

The phase 2, single-arm VISION trial (NCT02864992) of tepotinib (Tepmetko) investigated 153 patients who had a detected 

 exon 14 skipping mutation, 66 of whom had the mutation positively identified by liquid biopsy, 60 by a tissue biopsy, and 27 by both methods. According to Socinski, the patient population of the VISION trial was similar to the overall patient population, though the study recruited less symptomatic patients with an ECOG performance score of 0 or 1. The same was true of the phase 2 GEOMETRY Mono-1 trial (NCT02414139) of capmatinib (Tabrecta), which studied both 

 amplification. The VISION trial’s patient population had a relatively high median age of 74, and 46% had a history of smoking.

Both tepotinib and capmatinib showed efficacy and safety in patients with the 

 exon 14 skipping mutation and both drugs have been approved by the FDA for use in these patients.

 exon 14 skipping population tends to be a little bit older than the average driver mutation population. It also is likely to occur in smokers as well as non-smokers, so smoking status shouldn't necessarily be a criterion for testing or not. They almost always have adenocarcinoma of the lung; however, it has also been described in squamous [histology]. It's important to be aware of that when you're deciding on who to test for and who not to test for. Again, this occurs in roughly 3% to 4% of all of lung cancer, so it tends to be more common than we might see [in], say 

 fusions, and these sorts of things. So this should definitely be on the radar screen of any practicing oncologist to make sure that adequate testing is done here.

Specifically looking at the clinical trials for both tepotinib as well as capmatinib—these trials, since you're selecting patients based on a biomarker that's a molecular alteration—I think the patients in the trials of all of these agents were relatively representative of what you would see in practice. There was nothing unusual about it. Of course, these are patients that had to have good performance status. These were ambulatory, relatively asymptomatic, or minimally symptomatic patients. So, I think both in the VISION trial as well as the [GEOMETRY mono-1] capmatinib trial, the patients that you see and the outcomes that were described in these trials should be the expected outcomes that you would see in practice, again, because these patients are chosen for the clinical trial based on a molecular alteration.

Mark A. Socinski, MD, discusses the patient population of the trials targeting MET exon 14 skipping mutations in non–small cell lung cancer. 

Characteristics of the MET Exon 14 Skipping Mutation NSCLC Population

Socinski, mentions a few adverse events, such as fatigue, skin rash, and diarrhea, but then explains that most of these are grades 1 and 2. Very few are grades 3 and 4, but Socinski urges oncologists to be aware of the different toxicities and know how to treat them.

Socinski believes this trial is significant because it presents another monotherapy, other than docetaxel, and it happens to be better in terms of overall survival.

Mark A. Socinski, MD, professor, Medicine and Cardiothoracic Surgery, director, Lung Cancer Section, Division of Hematology/Oncology, clinical associate director, Lung SPORE, co-director, UPMC Lung Cancer Center of Excellence, co-leader, UPCI Lung Cancer Program, University of Pittsburgh, discusses the adverse events, as well as the overall significance, of nivolumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC).

Mark A. Socinski, MD | Authors

Articles

Episode 10B: Impact of Trilaciclib on Chemotherapy Induced Myelosuppression (CIM) in ES-SCLC

EP. 10A: Impact of Trilaciclib on Chemotherapy-Induced Myelosuppression in Patients with ES-SCLC

VISION Trial Shows Favorable Tolerability of Tepotinib in NSCLC

Characteristics of the MET Exon 14 Skipping Mutation NSCLC Population

Adverse Events of Nivolumab in Patients With Advanced, Non-Squamous NSCLC