A Pharmacist’s Perspective on the Evidence for Lurbinectedin

As new options emerge for the treatment of small cell lung cancer (SCLC), lurbinectedin (Zepzelca) has received both accelerated approval from FDA and a recommendation on the National Comprehensive Cancer Network (NCCN) guidelines. But what do clinical pharmacists have to say about this option for second-line treatment in relapsed/refractory SCLC?

The American Journal of Managed Care® (AJMC®)recently spoke with David J. Reeves, PharmD, BCOP, an associate professor at Butler University and clinical pharmacist at Franciscan Health in Indianapolis, Indiana, about an evidence review on lurbinectedin in the September 2021 issue of Annals of Pharmacotherapy,¹ for which he was seniorauthor. Of note, the review received no outside funding.

This interview has been edited lightly for clarity.

AJMC®: You and your colleagues recently published an evidence review for lurbinectedin, which was approved last year in relapsed/refractory small cell lung cancer. Can you discuss the overall findings?

Reeves: When we first saw this was approved, it was exciting because it fills a hole in therapy for small cell lung cancer. It’s an additional option for treatment, where there really weren't that many options for patients, especially after immunotherapy had been moved from the second line largely to the first line for extensive stage small cell lung cancer (ES-SCLC). So, we reviewed the evidence that looked at lurbinectedin use in small cell lung cancer.

Essentially, there were multiple studies. But the main one that led to its approval was a basket trial that included 105 patients with small cell lung cancer.² One caveat was that they excluded patients with CNS [central nervous system] involvement, which can be problematic considering that a lot of the patients with extensive stage small cell lung cancer have CNS metastases. So, it does roll out a large population of patients with small cell lung cancer; we don't know exactly how they'll respond to this medication. But when they looked at the results in this group of patients in the basket trial, it showed that they had about a 35% overall response rate. When you look historically at the other agent that we use in this setting, topotecan, that response rate was around 15%; some [results] showed it was up to 25%. So, [lurbinectedin] looks to be promising, although it's hard to tell, because it wasn't a head-to-head trial. The duration of response was around 5 months, and the overall survival was around 9 months. Again, this is maybe a little bit better than what they saw with the topotecan, which is probably going to be somewhere around 8 months.

No complete responses were observed. However, this is just phase 2 data. When we look at other trials that have other agents, complete responses are very rare in small cell lung cancer in the second-line setting; one interesting finding that they [examined] was looking at patients who were more refractory—those who had progressed within 90 days of their first line setting or first-time treatment, and they showed that those patients, although they did worse, they still had somewhat of a response—the response rate was around 20% in those patients, whereas in patients who had greater than 90 days lapse from their first-line therapy, their response rate was around 45%.

The investigators also looked at patients who were platinum sensitive. In the study, there's a small group of patients who are platinum sensitive, meaning that it was greater than 6 months since their first-line setting or first-line treatment, and they showed that the overall response rate was around 60%. The standard of care in these patients is to repeat their first-line regimen. However, this does offer an option in patients who aren't able to tolerate their first-line therapy again.

This was only a phase 2 study, so it's hard to tell how it would hold up head to head with something like our historical therapy topotecan. And another thing: when they were doing the study, immunotherapy wasn't really the standard of care and the first-line setting, so only a few patients—I believe, 8 patients—had immunotherapy in the first-line setting, while now pretty much every patient with ES-SCLC is going to have immunotherapy in the frontline setting.

Overall, the safety was pretty decent; it's it was comparable to our other agent, topotecan. One thing that was nice about the study is that they included patients up to a performance status of 2, so that's generally what we're going to see in those small cell lung cancer patients. The adverse effects were myelosuppression, which was the most common, and then other there was some nausea and vomiting, fatigue, stuff like that. They did not use G-CSF [granulocyte colony-stimulating factor] up front with these patients. Growth factors were only used if patients developed febrile neutropenia while they were on it. They used it as secondary prophylaxis.

AJMC®: You discussed that lurbinectedin has been studied alongside the rise in the use of immunotherapy. Why is it so important to have lurbinectedin during this period of increased use of immunotherapy?

Reeves: There are a few points here. First, until recently, immunotherapy was an option in the second-line setting. Now that it's moved to the first-line setting, it increases your overall survival. But it does decrease our toolbox for that second-line setting. So, [having lurbinectedin] as an option there, this does give us an option. And [with] these patients, the only problem is that we don't really know how patients would respond after receiving immunotherapy getting lurbinectedin because so few of those patients were included in that phase 2 basket trial.

The other interesting thing about immunotherapy is that there's been some interest in looking at combinations of lurbinectedin and immunotherapy due to some belief that there could be some synergy between the 2 types of agents. And so, there are studies underway looking at combinations. How that is going to play out now with using the immunotherapy first line, we don't know. Also, there's studies looking at potentially moving lurbinectedin into the first line setting into combination therapy. So, there's still a lot of moving parts when it comes to immunotherapy and the role of lurbinectedin.

AJMC®: Can you tell us about the importance of dose adjustments and drug interactions when administering lurbinectedin?

Reeves: There are some drug interactions that we have to be concerned about. It is a 3/4 substrate, so you need to try to avoid inhibitors and inducers. And if you can't avoid an inhibitor, then there are dose reductions that are recommended. There have been studies looking at the impact of giving inhibitors in [these] patients. And in looking at patients who received the 3 or 4 inhibitor, grade 3 neutropenia was increased by about 10%. So, it does have a clinical impact in patients who have who are receiving the lurbinectedin. One thing of that we need to take this consideration is that a lot of the patients continue to have nausea and vomiting, despite receiving a 5-HT3 antagonist and the steroids. So around 20% of the patients in the study had vomiting; despite us giving them our typical therapy for moderately emetogenic chemotherapy, they're still breaking through. There might be a role for upping that prophylactic regimen in these patients. One concern would be that many of the agents that we use when we up to the next level would be 3 or 4 inhibitors, [such as] aprepitant/fosaprepitant. … So, an option would be olanzapine, which has been shown to decrease nausea.

If the patient has adverse effects, such as neutropenia, febrile neutropenia, [or] hepatic toxicity, there are dose reduction schemes available in the prescribing information. The nice thing is that they're not necessary in patients who have baseline renal dysfunction, or hepatic dysfunction. So, for patients with liver [metastases], you can likely still use this medication; the study had a cut off of bilirubin 1.5. For renal function, creatinine clearance of [worse] than 30 [mg/g] was excluded from the trial. So, anything above that we can use—so someone who has maybe some moderate renal dysfunction from a prior therapy in their first-line setting could still be a candidate for this medication.

AJMC®: Are there any other considerations from a pharmacist’s perspective when using lurbinectedin?

Reeves: One thing that I was a little bit concerned about when looking through the study is that this basket trial excluded patients with cardiac comorbidities. They didn't show that there was any concern in that trial, [as well as] the phase 3 trial that's up and coming also excludes these patients; this is to be expected because it includes doxorubicin, which is also cardiotoxic. But when you look at the related medication, trabectedin, which is used in sarcoma, those patients who have received that have around a 5% risk of cardiomyopathy. So, if you look at our small cell lung cancer patients, these are often long-term smokers who have a lot of cardiac comorbidities—those patients were actually excluded from the trial. So again, it leads to some questions as to how safe this medication is in our patients with a lot of comorbidities. That’s one thing that I always was thinking about when I was looking at these trials. The other thing is when they're combining it and the phase 3 trial with doxorubicin, are they going to see any significant markers for cardiotoxicity? It'll be interesting to see when those results come out.

AJMC®: Can you describe your experience with the reimbursement landscape for lurbinectedin?

Reeves: From what I've seen, and the patients that we've had on it, we have not had any issues getting it approved, which is good. I think that it being in the NCCN guidelines helps, because a lot of the insurers rely on that—as well as the FDA approval—specifically in small cell lung cancer, and the fact that there really aren't that many alternatives. If the insurance is not going to cover lurbinectedin, then really, we don't have any other alternatives besides topotecan. So, I think those [factors] help us as far as getting it approved [by insurers].

AJMC®: What trials in lurbinectedin are ongoing? What results are you waiting to hear?

Reeves: There is an ongoing trial in the first-line setting. There's a phase 3 trial in the second-line setting, still looking at doxorubicin plus lurbinectedin as a combination therapy and comparing it to either topotecan or cyclophosphamide doxorubicin and vincristine. This is exciting; however, it does lead to additional questions:

• First, if it comes out to be positive, how does that compare to single agent lurbinectedin, which is currently approved?
• And if it comes out negative, would lurbinectedin suffer the same fate as a monotherapy compared to these agents if [lurbinectedin] is negative in the combination?

It’s going to be interesting to see what those results show. But I don't think it's going to answer all of our questions, and it's likely going to lead to more questions in the future. One other thing is that with combination therapy, especially in this population of refractory disease, a lot of patients have a poor performance status. So, the tolerability is going to go down.

References

1. Shinn LT, Vo KA, Reeves DJ. Lurbinectedin: a new treatment option for relapsed/refractory small-cell lung cancer. Ann Pharmacother. 2021;55(9):1172-1179. DOI: 10.1177/1060028020983014
2. Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol. 2020;21(5):645-654. doi: 10.1016/S1470-2045(20)30068-1.