Hossein Borghaei, DO

 In places like major academic centers and a lot of the cancer centers around the country, there’s this recognition that we need better treatment options for patients with small cell [lung cancer]. Fortunately, as opposed to 5 or 6 years ago, there are a number of clinical trials ongoing in this space. There’s been a tremendous amount of interest in defining small cell, a little better from a biological point of view, meaning that we all realize that this is again a heterogeneous patient population. Some patients do well with checkpoint inhibitors; some don’t. We’re trying to identify these patients by doing some sophisticated patient-derived tumor samples and evaluating the transcription factors that could further subdivide small cell into categories that might make it easier to develop specific drugs or regimens for particular patient populations. What we’re doing with non–small cell lung cancer is based not on molecular subtypes but on other biological criteria.

At Fox Chase [Cancer Center], we have 2 phase 1 clinical trials specifically for patients with small cell. Some of these are showing early promise, but I must emphasize it’s rather early in the clinical development of these drugs. Nonetheless, we’re getting some interesting results.

Given the increase in a number of clinical trials and a better understanding of this disease, I’m very hopeful that in the next 5 or 10 years we’ll make significant progress in this disease and we will have better treatment options for our patients. But it’s going to take a lot of work. It’s going to take participation in trials and participation in biomarker studies to better define this disease. But at this point, we have to rely on the available clinical data starting with chemotherapy plus a checkpoint inhibitor at the time of initial diagnosis. And then at the second line, perhaps we’ll consider a drug like lurbinectedin, always keeping in mind that this patient population could benefit the most by participating in clinical trials. Thank you for your attention.

Videos

Hossein Borghaei, DO, shares insights regarding future directions and current unmet needs in extensive-stage small cell lung cancer. He provides advice to researchers about the importance of clinical trials in the setting of extensive-stage small cell lung cancer.

Unmet Needs and Future Directions in Extensive-Stage SCLC

In ATLANTIS, which was a randomized trial, patients received lurbinectedin at a different dose from what we discussed, so not the 3.2 mg. This was a 2-mg dose, in combination with doxorubicin in relapsed small cell. Now doxorubicin might sound like an odd choice for patients with small cell, but based on preclinical data and earlier data, that combination was taken to a phase 3trial.Based on the press release, we know that the primary end point wasn’t met.

We’re hoping that the study will be presented at 1 of the major meetings and therefore will get to dive into the details of the study to see what exactly was going on, including the adverse effects and why the study didn’t meet its primary end point.

An expert oncologist, Hossein Borghaei, DO considers safety and efficacy data from the ATLANTIS study of lurbinectedin in combination with doxorubicin in relapsed/refractory small-cell lung cancer.

Use of Lurbinectedin-Doxorubicin Combination in Relapsed SCLC 

 The clinical evidence for the use of lurbinectedin comes from a single-arm study that included around 100 patients. Patients in the study had ECOG PS [performance status] of around 0 to 2. They must have had at least 1 prior chemotherapy. Immunotherapy use was allowed, but patients with active CNS [central nervous system] metastases were excluded from the study. A dose of 3.2 mg/m2 was selected as the standard dose for this particular agent, a single drug given by IV [intravenous] once every 3 weeks. And the study was a single-arm trial.

In patients who are chemotherapy-sensitive, using that 90-day marker as our reference, patients who had chemotherapy-sensitive disease ended up having a 45% response rate vs about 22% for those who were defined as chemotherapy resistant, which is better than many of the drugs—especially for the chemotherapy-sensitive patient population—we’ve had access to. The antitumor activity and duration of response and all that were good, and this was a single-arm study, so it’s hard to say how the drug compares with another arm. But we know from historical data that topotecan would not give us this level of response.

The median duration of response in the chemotherapy-sensitive patient population was roughly around 6 months, and in a chemotherapy-resistant patient population it was close to 5 months. The median overall survival was almost 12 months in the group that was defined as having chemotherapy-sensitive disease vs about 5 months in chemotherapy resistant. The drug compares favorably with other drugs that we have in this category.

In my clinical practice, I’ve used lurbinectedin on a handful of patients with metastatic small cell following chemoimmunotherapy with evidence of disease progression. My experience has been rather positive. It’s a drug that does have some myelosuppression associated with it, so following these patients closely is absolutely needed. I know that it goes without saying, but we’re giving drugs with potential adverse effects, so obviously the monitoring has to be rigorous. But the myelosuppression part is something that has caught my attention in terms of monitoring the red blood cell count and possibly discussing the need for the use of a growth factor, like G-CSF [granulocyte colony-stimulating factor], to maintain the red blood cell to help with that.

Like many other drugs that we use in this category, other adverse effects such as fatigue can be seen. But overall, it’s a simple drug. It’s once every 3 weeks, so it makes it a little more convenient to use than topotecan. We’ll have to wait for subsequent studies to see if the results of a single-arm study can be confirmed.

A thought leader in lung cancer, Hossein Borghaei, DO, reviews safety and efficacy data from the phase 2 basket trial of lurbinectedin in selected advanced solid tumors.

Safety and Efficacy of Lurbinectedin as a Second-Line Treatment for SCLC 

 What happens when there’s evidence of progression? In our case, roughly 5 months after starting treatment, patients began to complain of some fatigue. He felt that he had wheezing. There was unintended weight loss, increasing shortness of breath, some right upper-quadrant pain, and back pain. CT confirmed that the liver metastases were unfortunately progressing, indicating the patient was no longer responding to the checkpoint inhibitor that the patient was receiving as maintenance therapy.

The question is what can be done and what should be our standard approach. This gets to be a bit of a discussion. We have drugs that are approved in this setting. Some of these drugs are familiar to you. Topotecan has been around for a long time. We have lurbinectedin, another drug that’s been FDA approved and can be used in a setting like this. We also get into this discussion of chemotherapy-sensitive vs chemotherapy-resistant disease in small cell [lung cancer]. The definition is an old 1, goes back many years, and it has to do with how long after initial chemotherapy a patient was able to maintain a response. This 90-day, 3-month a time frame has emerged as an indication whether somebody has chemotherapy-sensitive or chemotherapy-resistant disease. The definition matters because for patients who unfortunately have chemotherapy-resistant disease or patients with metastatic small cell who have treatment-refractory disease, that means that despite the best treatment that we have, the first CT shows evidence of disease progression. Unfortunately, they don’t do well with subsequent standard treatment options that we have right now, so the response rates tend to be a little bit lower.

Chemotherapy-sensitive patients, if you go by the 90-day time frame, can have a better response rate to subsequent treatment as opposed to chemotherapy-resistant patients. At least before the era of having checkpoint inhibitors in immunotherapy drugs, a chemotherapy-sensitive patient could sometimes get a repeat of the same chemotherapy they got in the beginning. The question is do we go back to that, and that’s a practice decision everyone has to make in conjunction with all the other data available: Is the patient healthy enough to get another platinum-based treatment? What are the real data around that?

For the purpose of our discussion, I’d like to suggest that in this case, given all the symptoms, I would like to move on to another form of treatment. As I said, that’s based on what we have available. The options are topotecan vs this newer drug, lurbinectedin. Topotecan we all have worked with in the past. It’s an inconvenient drug to use. It requires repeat visits to the infusion room and is highly myelosuppressive. The outcomes, unfortunately, haven’t been all that good. Lurbinectedin is a newer drug. It has an interesting mechanism of action. It has been postulated that it could have a couple of ways of affecting the tumor or the tumor microenvironment, making it a drug that we might have an interest in, for the development and what to do with it down the road in terms of combination studies.

What do we do in a case like this, and how do we proceed in second-line treatment? If we don’t rechallenge with the initial chemotherapy, the option of using a drug like lurbinectedin makes sense.

Hossein Borghaei, DO, reviews the second-line treatment options in the setting of extensive-stage small cell lung cancer: topotecan or lurbinectedin. 

Second-Line Treatment Recommendations for ES-SCLC 

 How do we go about managing this patient in 2021? There are at least 2 phase 3 studies that have shown efficacy of a combination of chemotherapy and immunotherapy in this patient population. As many of you are aware, for a long time, for close to 2½, 3 decades, the standard treatment for patients with metastatic small cell [lung cancer] was a combination of a platinum agent plus etoposide in the first-line setting. Unfortunately, the overall survival and prognosis of patients with this diagnosis with this treatment was rather poor.

With the introduction of the checkpoint inhibitors into clinical practice in many malignancies, including non–small cell lung cancer, there was an intense interest to investigate the role of the available checkpoint inhibitors in management of patients with small cell lung cancer. Most of the studies were initially done in patients who had had chemotherapy and had evidence of disease progression. They had immunotherapy-based studies in the maintenance setting, which unfortunately didn’t show significant clinical activity until IMpower 132 was presented.

In IMpower 132, patients with similar characteristics as our patient discussed here, with metastatic small cell lung cancer, were randomized to carboplatin-etoposide with or without atezolizumab. Then patients who were having evidence of a response after about 4 cycles of the 3-drug combination were offered atezolizumab in a maintenance setting and patients were followed. The study confirmed that both PFS [progression-free survival] and overall survival was superior in the patient population that received the atezolizumab. Improvement in survival was about 2½ to 3 months. That’s not a spectacular improvement; however, it’s enough to indicate that the standard of care now should be a combination of chemotherapy plus a checkpoint inhibitor, in this case atezolizumab.

CASPIAN is another study, also conducted in patients with metastatic small cell. It had a very similar design except that in CASPIAN there were 3 arms, including an arm where patients were treated with a combination of a durvalumab and tremelimumab. Tremelimumab is an anti-CTLA4 antibody, but the initial presentation of CASPIAN concentrated on analysis of patients who had received standard chemotherapy vs same chemotherapy with durvalumab. This phase 3 randomized study also confirmed that the patients who received chemotherapy with a checkpoint inhibitor had an improvement in overall survival, in the order of 2, 2½ months, indicating and confirming that the standard of care for this patient population is a combination of chemotherapy and immunotherapy followed by immunotherapy.

Toxicities of this triple combination in both studies were actually quite manageable, meaning that there was not a significant increase reported in the immune-related adverse events in this patient population. Obviously, with the combination of the 3-drug regimen, you expect a little more toxicities. But the ones we worry about in terms of pneumonitis, renal dysfunction, or immune-related adverse events did not appear to be significantly worse. Keep in mind that in CASPIAN, treatment in a maintenance setting with the checkpoint inhibitor continued until disease progression and the case was similar in IMpower133—basically patients who were responding but continue to receive the checkpoint inhibitor.

Now we have a new standard of care. Most of our patients are offered treatment with a 3-drug combination that includes the old-fashioned, usually in the United States anyway, carboplatin plus etoposide with a checkpoint inhibitor, in this case atezolizumab or durvalumab, and then patients are followed.

Hossein Borghaei, DO, reviews the currently accepted first-line treatment recommendation for extensive-stage small cell lung cancer: a triple combination of carboplatin, etoposide, and a checkpoint inhibitor (atezolizumab or durvalumab). He provides an overview of the IMpower and CASPIAN trials.

First-Line Treatment Recommendations for ES-SCLC 

 Hello, everyone. I’m Hossein Borghaei. I’m a thoracic medical oncologist at Fox Chase Cancer Center in Philadelphia, [Pennsylvania]. Thank you for joining us to discuss a case of a patient with extensive-stage small cell lung cancer and management of this patient population.

Our case is a 59-year-old man who has been diagnosed with small cell lung cancer. His past medical history is significant for hypertension, which is medically controlled. Patient has a 32 pack-year smoking history and does not drink alcohol. On physical exam at the time of initial presentation, the patient has decreased breath sounds in the left lung and evidence of cervical lymph node enlargement. Laboratory evaluation showed that most of the labs are within the normal range, and the patient does have axillary lymph node that’s palpable. A biopsy of the axillary lymph node shows small cell lung cancer.

The patient then undergoes the usual staging studies, such as CT of chest, abdomen, and pelvis. Unfortunately, the CT shows evidence of large mediastinal mass with invasion into the right main and lobar pulmonary arteries and 2 small left pulmonary nodules. Hypermetabolic axillary lymph node was seen on PET [positron emission tomography] scan, and he also had a palpable node that was biopsied. Unfortunately, based on the CT and PET scans, the patient has evidence of liver metastases. A contrast-enhanced MRI of the brain is negative for brain metastases, and the patient has a really good [ECOG] performance status around 0 or 1, so he’s relatively asymptomatic.

A thoracic oncologist, Hossein Borghaei, DO, provides an overview of the initial presentation, clinical work-up, treatment, and follow-up of a 59-year-old man with extensive-stage small cell lung cancer.

Hossein Borghaei, DO | Authors

Articles

Unmet Needs and Future Directions in Extensive-Stage SCLC

Use of Lurbinectedin-Doxorubicin Combination in Relapsed SCLC

Safety and Efficacy of Lurbinectedin as a Second-Line Treatment for SCLC

Second-Line Treatment Recommendations for ES-SCLC

First-Line Treatment Recommendations for ES-SCLC

Case Overview: A 59-Year-Old Man With ES-SCLC