Lurbinectedin for SCLC Treatment in the Second-Line Setting

EP: 1.Overview of SCLC and Importance of Early Diagnosis

EP: 2.Use of the TNM Staging System in SCLC

EP: 3.Progress in the Treatment and Management of SCLC

EP: 4.Patient Profile 1: A 68-Year-Old Male with SCLC and Brain Metastases

EP: 5.Frontline Therapy for SCLC: The CASPIAN Trial of Durvalumab + Chemotherapy

EP: 6.Management of Adverse Events Associated with Durvalumab + Chemotherapy

EP: 7.IMpower 133 Trial and Patient Selection for Durvalumab + Chemotherapy vs Atezolizumab + Chemotherapy

EP: 8.Ongoing Trials and Real-World Studies in Frontline SCLC

EP: 9.Patient Profile 2: A 60-Year-Old Man with SCLC Progressing on First-Line Therapy

EP: 10.Second Line Treatment Options in SCLC and Selecting the Appropriate Therapy

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EP: 11.Lurbinectedin for SCLC Treatment in the Second-Line Setting

EP: 12.Patient Profile 3: A 70-Year-Old Man with SCLC Receiving Chemotherapy in the Second-Line Setting

EP: 13.Choosing the Appropriate Treatment in the Second Line Setting in SCLC

EP: 14.Investigational Agents in SCLC in the Second Line Setting and Beyond

EP: 15.Clinical Practice Pearls and the Future of SCLC

Charu Aggarwal, MD, MPH: Vivek, may you please walk us through the data that led to approval for lurbinectedin?

Vivek Subbiah, MD: Absolutely. Thank you so much for that question. Lurbinectedin is a new agent. It’s a marine biologic derived from under the sea.It's an interesting agent. It has an interesting mechanism of action. And preclinically, it showed activity in multiple small round blue cell tumors like ewing sarcoma and other small round blue cell tumors. It is a selective inhibitor of oncogenic transcription. And this study recruited this first part of a basket study that recruited multiple small round blue tumors, and the small cell lung cancer cohort consisted of 105 patients. Between October 2015 and Jan 2019, 105 patients were enrolled with post platinum treated with- and were enrolled and treated with lurbinectedin at a flat dose of 3.2 mg per meter squared. The median follow-up here was 17.1 months. And the overall response rate by investigator assessment in this case was seen in 37 patients, which comes to 35.2% in terms of objective response rate. Again, what they saw in this study as with other studies with lurbinectedin was the same in toxicities of hematological toxicities, anemia, leukopenia, neutropenia, thrombocytopenia, and serious adverse events occurred in 10% of patients with neutropenia and febrile neutropenia, and no treatment-related deaths were reported. Based on this study, lurbinectedin was shown has active second-line agent in small cell lung cancer. Again, as we all know, this small cell lung cancer has been devoid of treatments for 2 to 3 decades, especially in the second-line setting. It's always good to have a new kid on the block to have something in our back pocket to give our patients. This was encouraging. And based on this data, the drug lurbinectedin received US [United States] FDA accelerated approval. And this is another option for our patients.

Charles Rudin, MD, PhD: It may be important to think about what accelerated approval means. I don't know if we want to talk about that, but, as you said, it's a new kid on the block. It is an active agent. To me, the benefit over the prior standard of care, topotecan, is not on the activity side as much as it is the tolerability side. It does have a better adverse effect profile. The accelerated approval based on single-arm Phase 2 data essentially allows the drug to be given and sold to our patients with small cell lung cancer, but it is contingent on subsequent data that needs to be forthcoming to give a full FDA approval, and that data is still pending.

Charu Aggarwal, MD, MPH: Jared, are there specific patients that you will not consider suitable for lurbinectedin?

Jared Weiss, MD: In standard of care use, not really. If there's a patient who's available for treatment, their performance status, their values are such that they want treatment, I don't think there's anything bad. Lurbinectedin has the very important property of not being topotecan. But I would say there's one major exclusion in my practice for someone I wouldn't give lurbinectedin to, which is if the patient is open to and eligible for clinical trial. Lurbinectedin is my preferred option second line outside of the context of a clinical trial. However, this is still an agent with limited efficacy and significant toxicity. And if there's a trial available of real promise, I'm offering that to the patient first.

Charu Aggarwal, MD, MPH: You would say that routinely, if there isn't a trial, most of the patients would be able to receive this treatment in clinic. And I often find that sometimes myelosuppression is an issue requiring dose reduction. Charlie, have you witnessed that? And how do you manage it in your practice?

Charles Rudin, MD, PhD: Myelosuppression is always an issue. It's less so with lurbinectedin than it is with topotecan. We do have GI [gastrointestinal] advere effects with lurbinectedin as we do with many chemotherapy agents. Lurbinectedin is an alkylating agent, which is an old class of drugs. It has adverse effects that are associated with that.

Jared Weiss, MD: If I might add a thought to that, there's some data that maintaining dose intensity may be more important with lurbinectedin than with some of our older drugs. In trying to explain the differential outcome of the fees one expansion and the Atlantis trial, which was a negative trial combining lurbinectedin and doxorubicin. There are a lot of attempts to understand that. To my mind, the most convincing one was an analysis of the relationship between response rate and AUC exposure, and it's rather sigmoidal at the 3.2 mg per meter squared dose. And it may be more important with this agent to try to maintain exposure than with some of our other small cell drugs, where there has not been traditionally a relationship between dose intensity of chemotherapy and in clinical outcomes.

Charu Aggarwal, MD, MPH: And that's exactly where I was going. Do you routinely come in with growth factor support to try and maintain that dose, or would you let cycle one pass, and then come in with those adjustments? Taofeek, maybe you can comment?

Taofeek Owonikoko, MD, PhD: In my own practice when I use lurbinectedin, given the fact that we know that it's substantial. Proportion of patient will need growth factor support, rather than waste time on insurance denying the approval for growth factor use after we started the treatment, I tend to just plan to use it as I initiate treatment for the patient. And the- When you do that, you see that you are able to maintain the dose of 3.2 mg per meter square without having to dose reduce. And I think that is important in this disease. Of course, we don't have a very clean study to look at, the reduced dose versus the full dose of 3.2. But from the phase 1, we also know from there that, that dose intensity going to 3.2 was associated with a higher rate of response. The other place where I always want to use growth factor is in those patients with chemotherapy refractory disease because that's where you want to maintain that intensity. If they are going to benefit from it, I want to make sure I go in with the full dose and give the patient all the support they need to be able to stay on.

Charu Aggarwal, MD, MPH: How do you define response in a patient on lurbinectedin, and are you happy with stable disease? How long do you keep treating?

Taofeek Owonikoko, MD, PhD: In my approach, and this is in line with how the study was designed, is I look more at clinical benefit as opposed to clinical response because as we know, when we do scans, we don't sit down, the radiologist doesn't do all the risk measurement that we go through a clinical trial to say you have 30% reduction or 20% growth to say whether or not the tumor is growing. The first thing is how the patient is feeling. If the patient is getting better in terms of their symptoms, they do not have a lot of adverse effects, they are not ending up in the hospital, and they're tolerating the treatment, they're on schedule as planned, I know that that is helping them. Then the second is the objective measurement as best we can, which is with the cross-sectional imaging. If based on the scan, the radiologist looks at data and I look at the report and confirm that this is under control, I go by disease control as opposed to disease response in this setting. It's the combination of the objective measurement with the scan, as well as the patient's objective reporting, that allow me to decide whether the patient is benefited. I do not prescribe a defined number of cycles for a patient when I stop patient I always discuss, "We're going to continue this for as long as it's helping and you're not having bad side effects." I continue until we must change to something. That's why the patient decides that they need a break.

Charu Aggarwal, MD, MPH: That's important to understand and recognize that we're not coming in trying to limit therapy but actually prolong as much time as they can safely remain on treatment. And, Charlie, you pointed out that this is just an initial approval. We are waiting for certainly more data. What do you do in your practice after lurbinectedin failure? What is your post-lurbinectedin strategy?

Charles Rudin, MD, PhD: It's a great question. As you pointed out in the NCCN [National Comprehensive Cancer Network] guidelines, there are lots of drugs listed, and all of them are based on, I would say, small datasets, mostly, and datasets that have response rates that we would consider disappointing. But these are active drugs. I'm not a huge fan of the taxanes. I don't like- Despite my hair, I don't like hair loss. I don't like the neutrophil- The numbness and tingling that comes with peripheral neuropathy, that can be long-lasting, I find those drugs are often not great for quality of life. I use a fair bit of temozolomide which has activity in the 20-25% response range. And we see some durable responses with it. It tends to be quite well tolerated, relative to other agents. It's oral, patients can take it at home. And it has very good CNS [central nervous system] penetration, very good brain penetration. For a disease that often goes to the brain, we like temozolomide. It is not an FDA-approved indication. It's approved for the use in brain tumors like glioblastoma, but it's clearly an active agent, small cell lung cancer. It's a dealer's choice, to be perfectly honest. There's a long list and ask the patient, if they have good performance status, and they are up for further therapy, we will sort of cycle through those. But those are some of the things that I think about.

Transcript edited for clarity.