Videos

The panel shares clinical pearls for community oncologists treating small cell lung cancer.

Clinical Practice Pearls and the Future of SCLC

Taofeek Owonikoko, MD, PhD, highlights investigational agents and ongoing clinical trials in SCLC he looks forward to.

Investigational Agents in SCLC in the Second Line Setting and Beyond

Experts provide insights on choosing the optimal therapy in patients with small cell lung cancer in the second line and beyond.

Choosing the Appropriate Treatment in the Second Line Setting in SCLC

Jared, why don't you take us through the next case? I understand you have a case of third or second line.

 All right. Our third patient profile. This is a 70-year-old man diagnosed with small cell a year previously. He had a 35-pack-a-year smoking history and presented with severe shortness of breath and cough to the emergency room. Get a chest X-ray that showed pneumonia and a central chest mass. CT subsequently showed a bulky central lung mass, hilar and mediastinal lymphadenopathy compressing both the SVC and multiple central airways. He had an endobronchial ultrasound, transbronchial fine needle aspirate, that showed small cell lung cancer. And because we're in the US, [United States] he had a PET [positron emission tomography] and that showed bone metastases as well. He had an MRI without brain metastases. This frontline treatment was a first cycle was of carboplatin and etoposide was given inpatient. This led to rapid improvement in his symptoms and discharge from the hospital within a week. And that's fairly typical, not an exceptional case. He received 3 additional platinum doublet cycles, with atezolizumab grafted on starting in cycle 2 on the outpatient basis. Chemotherapy was complicated by fatigue, nausea, alopecia, multiple episodes of febrile neutropenia, despite the use of secondary prophylaxis with Neulasta,® [pegfilgrastim] which was itself complicated by bone pain. Again, not an atypical or extreme profile. But happily, he did have a complete response and was treated with maintenance atezolizumab. His quality of life notably improved over the ensuing months. There are 2 things that harm our patients' physical quality of life, the most, the cancer and the things we do to them. And this was a cytotoxic free period and a period free of cancer symptoms. Intentionally not giving you a total duration here to provoke conversation, but he sees you in consultation because his cancer has progressed while on maintenance atezolizumab. He was nearly due for imaging when he became short of breath, started to cough, he received his CT just a bit early that showed progression in his central chest, as well as possibly in bony metastases, and he had a new liver met evident. He did have a repeat brain MRI, which remained negative for metastasis. In summary, this is a patient who's significantly suffering from his cancer, from symptoms of progression of his cancer, but also afraid of chemotherapy adverse effects because of how badly it went the first time for adverse effects. Options are discussed, amongst these are multiple clinical trials. Clinical trial of lurbinectedin with trilaciclib added was discussed, a CAR-T trial was discussed, traveling for a tarlatamab study was discussed. But as is typical of many patients with small cell in the US and a barrier sometimes to our development of new agents, the patient was not able to travel due to the large financial burden of doing so. He noted that a relative would have to take the day off from work and that- even the cost of the tank of gas would be a very big deal of the significant financial toxicity for the patient. And in this case, a recommendation was made for repeating carboplatin and etoposide, this time with proceeding trilaciclib as Charlie and Taofeek were recognizing where this was going to go because they know me. There was a low threshold recommended. This was a patient treated then back in the community to have a very low threshold to add pegylated filgrastim back for secondary prophylaxis. If cycle 1 didn't go well with trilaciclib, recommendations were given for aggressive antiemetic support, a recommendation was given to consider calcium, vitamin D and denosumab for the bone- brain- bone metastases, and the patient was provided gas cards and connected with a local advocacy organization to help with some of the financial burdens and barriers to treatment.

Dr Jared Weiss presents the profile of a 70-year-old male patient with SCLC who received chemotherapy in the second line setting for discussion to the panel.

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

Vivek, may you please walk us through the data that led to approval for lurbinectedin?

: 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.

: 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.

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

: 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.

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?

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.

: 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.

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?

: 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.

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

: 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.

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?

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.

Dr Vivek Subbiah explains the clinical trial data that led to the approval of lurbinectedin for SCLC treatment.

Lurbinectedin for SCLC Treatment in the Second-Line Setting

Vivek, can you talk to us about some of the adverse events that were observed on this study, especially when durvalumab was combined with chemotherapy and how do you usually manage them in practice?

That was a great question because in the context of ASCO [American Society of Clinical Oncology] 2022 the Caspian PLO data was presented. Again, for everyone here, what is PLO? PLO is patient report outcomes and there is this NCI defined patient report outcomes criteria called PLOCTCE, which is the patient reported outcomes, common terminology criteria for adverse events. In this Caspian study, they ask patients these questions 164 of the 537 on all patients were asked these questions. And it was interesting. They ask questions directly from patients. It's not doctor reported outcomes, it's patients, self-reported outcomes. They ask for presence or absence of rash, pain, swelling, redness, again, a frequency of arm, like swelling, pain in the abdomen, shivering or shaking or chills, and severity. Severity of the itching, severity of the numbness or tingling in the hand, mainly from the platinum-based agents. And is it going to be an exacerbated by immunotherapy or mouth source, throat source from the chemotherapy and immunotherapy combination and handful syndrome in addition to dry mouth. These were the patient reported outcomes adverse events were asked to patients and they were asked to fill up. Interestingly, what the data showed the self-reported data from patients showed in the Caspian study that the 11 adverse events examined during the 24 weeks after starting treatment as reported by minority of patients in both the arms, mostly with rare events rates and patterns of adverse events, the adverse events over time were similar in both the arms, again, it could be that this is a trial population, motivated patients pre-selected population, but we don't see any differences in terms of adverse events by adding an immunotherapy checkpoint. I don't know if you see that in the real world as well. Maybe Jared can answer that.

The effects that we don't understand our patient experience very well, right? Every PLO study ever done tells us that the most remarkable finding is always the difference between the patient reported outcomes and the clinician reported outcomes, because if you don't ask in a busy clinic, you don't know. The PLOs are very useful for bringing that out. And they're complimentary to the physician provided data. Our patients suffer from fatigue a lot more than we recognize. And the mouth sores and rashes are often a lot worse than we recognize.

Charlie, could you talk to us about real-world data on chemotherapy plus durvalumab that was recently presented at ELCC [European Lung Cancer Conference]. They were trying to see what actually happens when these drugs are administered in the real world.

That data was reassuring. It's quite similar to the clinical trial data to Vivek’s point. This wasn't it of course, was a selected trial population with good performance status to start out, but as was pointed out, patients with small cell lung cancer often present with poor performance status because of disease and rapidly improve actually with initiation of therapy and real world data, looking at patients treated with chemo, immunotherapy actually had very similar outcomes in terms of progression-free survival and early data with survival as was seen in the clinical trials. These are robust results.

They reflect what Taofeek was talking about also that it didn't seem to matter if you went above 4 cycles of chemotherapy, you had toxicity, but maybe we don't get that much bang for the buck in terms of efficacy. It affirms our current practice, affirms what we saw in clinical trials. It's reassuring.

Vivek Subbiah, MD, analyzes adverse events observed with durvalumab plus chemotherapy in patients with SCLC and how they can be managed.

Management of Adverse Events Associated with Durvalumab + Chemotherapy

Charles M. Rudin, MD, medical oncologist, chief, Thoracic Oncology Service, co-director, Druckenmiller Center for Lung Cancer Research, Sylvia Hassenfeld Chair in Lung Cancer Research, Memorial Sloan Kettering Cancer Center, discusses the safety and efficacy of single-agent rovalpituzumab tesirine (Rova-T) in patients with recurrent or refractory small cell lung cancer (SCLC).

This is the first-in-human, phase I clinical trial examining the novel antibody-drug conjugate targeted at DLL3, which is often expressed in SCLC cells, Rudin explains. Once the complex is internalized and released, it binds to the patient’s DNA and leads to cell death.

Results of the trial showed that the agent was safe and appropriate doses were determined for patients. Encouraging findings were also found regarding efficacy, Rudin adds.

Charles M. Rudin, MD

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