 Hi. My name is Ticiana Leal. I’m a medical oncologist and a thoracic oncologist at the University of Wisconsin Carbone Cancer Center. I’m the lead on our thoracic oncology program. Today we’ll be talking about a case of a patient who is a 61-year-old man with small cell lung cancer. Here is our initial presentation.

This is a 61-year-old man who presented with cough, fatigue, and progressive shortness of breath. His past medical history is unremarkable. Social history is significant for a 25-pack-year smoking history and social alcohol use.

On physical exam, his vitals are stable. There is some wheezing in the right lower lobe auscultation and axillary lymph node enlargement. Labs demonstrate that his renal and hepatic function are within normal limits, as well as his CBC [complete blood count]. Sampling of the axillary lymph node demonstrates small cell carcinoma. Staging included a CT scan of the chest, abdomen, and pelvis, which showed a large 7.1-cm mediastinal mass with invasion into the right main and lobar pulmonary arteries, 2 small left pulmonary nodules, and hypermetabolic activity of the lymph node in the axillary region.

Additional imaging included a PET [positron emission tomography] scan, which showed large focal hypermetabolic activity in the mediastinum and small hypermetabolic activity in the surrounding area and the axillary lymph node. Contrast-enhanced MRI of the head showed no CNS [central nervous system] metastatic disease. This patient was staged to have stage IV small cell lung cancer or extensive-stage disease with an ECOG performance status of 0.

His initial treatment included 4 cycles of platinum with carboplatin plus etoposide and atezolizumab followed by atezolizumab as maintenance therapy. In follow-up, this patient had treatment for 7 months but unfortunately developed shortness of breath, right upper quadrant pain, and back pain.

Follow-up imaging with a CT scan showed metastasis in the liver and right adrenal gland. This patient initiated lurbinectedin at 3.2 mg/m2 IV [intravenous] every 21 days.

This is our initial case. We’ll talk a little more about the decisions during the treatment for this patient and also their prognosis. In summary, this patient has been diagnosed with extensive-stage small cell lung cancer. Unfortunately, this is how the majority of the patients present with advanced disease; therefore, the disease is not curable. However, the disease is treatable, and this patient initiated treatment with platinum in combination with immunotherapy.

This is a very standard presentation. One good thing about this clinical case is this patient presents with good performance status and good organ function and is stable enough to maintain his initial treatment in the outpatient setting. Those are definitely good prognostic factors that allow us to treat this patient in the outpatient setting.

We can estimate the prognosis for this patient based on the data we currently have and the advancements we’ve made in the treatment of small cell lung cancer. With the regimen that this patient initially received—a combination of carboplatin-etoposide with atezolizumab—based on the phase 3 trial in IMpower133, we know that the median overall survival for this patient is approximately 10 months or 12.3 months in the durvalumab arm with a 12-month overall survival of approximately 51%. So 51% of the patients are alive at 1 year receiving this regimen.

One thing that is consistent with what we see in the data is that the median progression-free survival with this regimen is about 5 months, and this patient also had progression of his disease within that period of time.

That tells us that the majority of patients at that time point are actually faced with the decision of whether to continue on to second-line treatment. In the case of this patient, he went on to receive lurbinectedin.

Presentation of a Patient with Small Cell Lung Cancer 

 When determining the best choice of treatment for this patient, I think 1 important factor to consider is performance status. Does this patient have adequate performance status to be able to tolerate and benefit from a triplet combination, such as platinum-etoposide with an immunotherapy agent? The other important factor to consider is the clinical stability of the patient, in terms of whether this patient needs to be admitted to manage symptoms and to optimize the clinical scenario in order to receive the therapy they need.

Some of our patients present with high symptom burden, and perhaps they have organ dysfunction or SIADH [syndrome of inappropriate antidiuretic hormone] and hyponatremia that needs to be managed as an inpatient. Perhaps they have uncontrolled symptoms due to the cancer that may require admitting the patient to the hospital to optimize and manage the symptoms and then providing the inpatient chemotherapy or transitioning and providing that therapy for the frontline setting as an outpatient.

Also, organ function is very important. Does this patient have adequate CBC [complete blood count], renal, and hepatic functions? Sometimes patients present with widely metastatic disease with liver involvement, and sometimes they have elevation of their LFTs [liver function tests] and bilirubin, which may require dose modifications for the first cycle of treatment.

Obviously, it’s very important to consider the patient’s goals and wishes. If patients present with extensive-stage small cell lung cancer and they have comorbidities and an incurable cancer, it’s very important to introduce palliative care early on and have a detailed discussion about goals of care and shared decision-making so that we take into account the patient’s goals for their course of treatment.

It’s also important to consider the course of the treatment. We talked about how this patient received 4 cycles of induction therapy with carboplatin-etoposide in combination with immunotherapy followed by maintenance therapy, which in this case is monotherapy with a PD-L1 inhibitor. This patient received atezolizumab, and this is based on the data from the phase 3 trial IMpower133. There are no other regimens approved in combination in the maintenance setting. We’ll talk about the CASPIAN data, which also similarly has the combination of chemotherapy-immunotherapy with durvalumab followed by durvalumab maintenance. However, there was a study that looked at combination immunotherapy with nivolumab plus ipilimumab. We saw that the results of the CheckMate 451 study did not show a benefit of adding combination nivolumab plus ipilimumab in the maintenance setting. As of now, the frontline strategy is the combination of chemotherapy plus immunotherapy, followed by maintenance with an agent such as durvalumab or atezolizumab.

Something to think about is whether there are patients who don’t receive chemotherapy-immunotherapy in the frontline setting. Certainly, there are a few patients who may not be candidates for immunotherapy in the frontline setting. Maybe this is a patient who has a contraindication to immunotherapy. So look at comorbidities. Does this patient have a history of a transplant that immunotherapy unfortunately is contraindicated? Or do they have an uncontrolled underlying autoimmune disorder that requires immunosuppression? This is a patient who would then not be a candidate for receiving immunotherapy. Those are other patient-related factors that are certainly important to consider when making the decision to initiate therapy in the frontline setting.

Assessing Treatment Options for the Case-Based Patient 

 In the frontline setting, the data are pretty clear that we use the combination of chemotherapy with immunotherapy. We talked about using the immunotherapy agent durvalumab based on the CASPIAN data and atezolizumab based on IMpower133 data followed by the maintenance strategy.

As we talked about, the vast majority of patients are going to have progression of their disease on their frontline regimen. While it’s not very well established what and how to define platinum sensitivity or platinum resistance, we do have some clinical guidelines of how we define that. From a clinical trial standpoint, some of the trials have defined platinum sensitivity or platinum resistance using a cutoff of 90 days or greater. If patients have had their prior platinum 90 or more days ago, these are considered patients who are platinum sensitive. If they’ve had progression of their disease on their prior platinum for less than 90 days, that’s considered platinum resistant.

That’s a great measure for using that definition in a clinical trial. However, in the clinical setting as a standard of care, we generally define platinum sensitivity as greater than 180 days. If their prior platinum was greater than 180 days, we would consider rechallenging with the platinum again. If patients have good tolerability of their prior platinum-etoposide, we obviously take that into account vs if they have a hard time with their prior regimen and if they have significant complications of their prior platinum regimen. Obviously, that would be something that may sway you to move on to a second-line regimen that is different from the rechallenge strategy.

The rechallenge strategy is a relatively good strategy. It’s a better strategy when we don’t have options in second-line that are beneficial or promising or that have high toxicity. For a long time, we struggled with second-line topotecan as our next regimen given the significant toxicity—especially myelosuppression—when we used topotecan in the second-line setting. The response rate of topotecan in the resistant population is around 5% with high rates of toxicity. That would certainly sway you to perhaps rechallenge a patient in the frontline setting, especially if they had platinum-sensitive disease.

The data for platinum-sensitive rechallenge is based on a small series of patients, but it is something that we would consider again today.

Defining Platinum Sensitivity vs Resistance after First-Line Treatment in Small Cell Lung Cancer

 In terms of when you move on and what you move on to as a second-line strategy, if your patient is not a candidate for rechallenge because they are considered platinum resistant or because they have had significant prior toxicities to their regimen in the frontline setting when they used the platinum-etoposide, then we would move on to another agent. Our options at this point include topotecan as well as a new agent that was recently approved called lurbinectedin.

In terms of which agent to use, lurbinectedin is very well positioned to be our next strategy. It has a different mechanism of action. It’s a novel agent that was approved by the FDA in an accelerated fashion, and it’s a selective inhibitor of oncogenic transcription. It is a regimen that was recently approved that we started using in the clinical setting.

This agent was approved based on a global, multicenter, open-label phase 2 basket trial that included a cohort of patients with previously treated small cell lung cancer. In this trial, patients who had 1 prior line of platinum therapy—they could have received 1 prior immunotherapy agent—received lurbinectedin as a single agent for small cell lung cancer. The primary end point of this study was overall response rate, and this study did meet the overall response rate criteria that was defined statistically in the study.

Importantly, they actually treated 105 patients in the study. All these patients were previously treated. The overall response rate for patients in the second-line setting in this study was about 45% in the sensitive population and 22% in the resistant population, which is promising when you consider our historical controls. The resistant population especially shows a glimmer of hope given that the response rate with topotecan is about 5%. In the overall population, the response rate was about 35%. Importantly, they also had a duration of response that was considered promising in the order of 5 months. The median overall survival with lurbinectedin in this study was about 9.3 months in this previously treated population. The median overall survival was slightly better in the sensitive population in the order of 10 months.

This was a regimen that was studied in an initial study but led to FDA approval. It’s rolled out already to the community sites. Academic sites are also experienced with lurbinectedin to date with the number of patients we’ve treated. It has been favorable in the sense that it has been a regimen that has manageable adverse effects and has mirrored what we saw in this phase 2 study.

The main adverse effects of lurbinectedin have been related to myelosuppression. The main episodes we’re seeing that were more severe in terms of grade 3/4 events was neutropenia, but the number of episodes of febrile neutropenia was substantially lower. Certainly, you also see anemia and thrombocytopenia. About 20% of the patients did require G-CSF [granulocyte colony-stimulating factor] use in the trial because of myelosuppression.

Other potential adverse effects that are seen in 20% or greater of patients include fatigue, nausea, decreased appetite, elevation in LFTs [liver function tests], and potentially elevation in both creatinine and glucose.

Overall, the regimen seems to be well tolerated in this patient population and hasn’t shown any significant signals of prohibitive toxicity.

Analyzing the Role of Topotecan and Lurbinectedin in Small Cell Lung Cancer

 For this patient, the choice to use lurbinectedin in the second-line setting is appropriate. Lurbinectedin is an agent that has been studied in the phase 2 setting, and has been approved in an accelerated fashion given the benefits seen in the phase 2 setting with the response rate as well as duration of response. One important thing to think about if you’re moving on to second line in a patient with extensive-stage small cell lung cancer is that the number of patients who are able to receive third-line treatment is substantially lower. About half the patients are able to receive second-line treatments, and then only about 15% of the patients or less get to third-line treatment. Sometimes, when you’re faced with having that discussion with your patient, you have to really consider what the next-best line of therapy is for this patient that will impact the course of their disease. Importantly, think about toxicities and quality of life. Lurbinectedin for this patient is definitely an appropriate choice and is something I would discuss with my patient and their family. I would likely make a similar decision in this case.

My personal experience with lurbinectedin with the patients we have treated at the University of Wisconsin so far has been favorable. Specifically, the toxicities have been manageable. We talked about how myelosuppression has been the main adverse effect seen in the study, and we do see that in the clinical setting. But the treatment discontinuation and dose delays for patients have been manageable and have been something we have been able to clinically work with the patients on. It will be a learning curve as we gain more experience with using lurbinectedin.

In my own clinical practice, I’m still trying to learn more about the impact of lurbinectedin in patients who have a history of CNS [central nervous system] metastasis. In the phase 2 trial we talked about, patients with CNS metastasis were excluded so we don’t have any clinical trial data in terms of the activity of lurbinectedin in CNS metastasis and how it impacts patients with active CNS metastasis or previously treated CNS metastasis. That is also unfortunately a reason that patients have functional decline or progression while they’re being treated in the second-line setting.

The Impact of Lurbinectedin in Small Cell Lung Cancer

 We’ve made progress and had approvals of new regimens in small cell lung cancer, which has been great to see and great to be able to provide new therapies and new hope for small cell lung cancer patients. One of the questions that remains is the role of predictive biomarkers in selecting patients most likely to benefit from strategies such as chemotherapy-immunotherapy. That is something we’ll need to work more on as the new trials come out. The other important thing to work on is improving cure rates in the limited-stage setting. Patients with limited-stage disease are receiving chemotherapy radiation in combination with platinum-etoposide, and it’s going to be exciting to see if adding immunotherapy to chemotherapy radiation will improve the outcomes and cure rates for patients with small cell lung cancer in the limited-stage setting.

I’m also interested in seeing more about the molecular subtypes of small cell lung cancer. We saw some interesting results from Dr [Taofeek] Owonikoko at ASCO [American Society of Clinical Oncology Annual Meeting] showing that patients with 

 expression seemed to have an inflammatory signature, and perhaps these patients are most likely to respond to immunotherapy. Lastly, I’m also interested in looking at PARP inhibitors and the 

 story to see if this is a biomarker that will help select patients for therapies. I’m interested in seeing the combinations of PARP inhibitors and immunotherapy in small cell lung cancer and what kind of outcomes and improvements we can see in that.

Lastly, I’m really interested in seeing CAR [chimeric antigen receptor] T-cell therapy targeting 

 and if that will show some promising and interesting activity in small cell lung cancer. There’s a lot of work to be done. We certainly have seen improvements with the addition of immunotherapeutic chemotherapy in the frontline setting. We are seeing what appear to be clinically meaningful benefits with the addition of lurbinectedin in the second-line setting. But we need to have more studies showing better outcomes and greater and meaningful benefits for patients.

In terms of 1 of the ways to answer all these questions, 1 of the important things for all of us treating patients with small cell lung cancer in the community or academic centers is to continue to work together and try to enhance and increase accrual of patients to clinical trials. [Then we can] get the clinical trials completed and have these answers for our patients. Thank you very much.

Evaluating Current Treatment Options for Small Cell Lung Cancer

A 61-Year-Old Man With Small Cell Lung Cancer

Ticiana Leal, MD, presents a case of a 61-year-old man with small cell lung cancer.

A 61-Year-Old Man With Small Cell Lung Cancer | Case Based Peer Perspectives

EP 1: Presentation of a Patient with Small Cell Lung Cancer

EP 2: Assessing Treatment Options for the Case-Based Patient

EP 3: Defining Platinum Sensitivity vs Resistance after First-Line Treatment in Small Cell Lung Cancer

EP 4: Analyzing the Role of Topotecan and Lurbinectedin in Small Cell Lung Cancer

EP 5: The Impact of Lurbinectedin in Small Cell Lung Cancer

EP 6: Evaluating Current Treatment Options for Small Cell Lung Cancer