Activity Transcript

Jared Weiss, MD: Hello, I'm Jared Weiss. I'm an Associate Professor of Medicine at UNC's Lineberger Comprehensive Cancer Center and a Thoracic Oncologist, and it's my pleasure today to talk to you about three cases in extensive stage small cell lung cancer (ES-SCLC). In this program, we'll discuss the following: strategies to improve clinicians' ability to manage patients with extensive stage small cell lung cancer; and three cases that are all real but also carefully chosen to empower discussion of new data, followed by a brief discussion of supportive care advances.

Our first case is that of a first-line therapy in a patient with rheumatoid arthritis. Our patient is a 60-year-old woman with 30 pack year smoking history. She has mild type II diabetes, and she has rheumatoid arthritis that is currently asymptomatic and last required treatment five years ago. She's diagnosed initially with a chest x-ray, showing a central mass, and then gets cross-sectional imaging, a CT then a PET, showing FDG (fluoro-2-deoxy-D-glucose ) avidity of the mass and multiple FDG avid masses in multiple nodal stations, bilateral lungs, and liver. MRI (magnetic resonance imaging) of her brain is clear with no brain metastasis. She has a biopsy and it shows small cell lung cancer. Her performance status is good and her values are oriented towards life-prolonging therapy.

How should we treat this patient? Or perhaps, what treatment should we recommend to this patient? So, frontline therapy has evolved over the years, but until very recently, that evolution was really more about side effects than it was about survival. The move from CAV (cyclophosphamide, doxorubicin, vincristine) to platinum etoposide, as you can see at left, was not accompanied by an improvement in survival, but we finally in recent years has gotten our survival improvement with the addition of PD-L1 inhibition to carboplatin and etoposide. You're looking right at the IMpower data, adding atezolizumab to carboplatin and etoposide, and for the first time showing an improvement in the frontline treatment of extensive small stage, small cell lung cancer.

Before I move on, I want to say that that was repeated with durvalumab. This is important not only for adding durvalumab as another option for the addition to carboplatin and etoposide, but also for confirming the story that PD-L1 inhibition is indeed helpful here. Now, unfortunately, many patients including ours would have been excluded from these trials. The trials of immunotherapy from the beginning have excluded patients with auto-immune diseases, but over the years in the real world, checkpoint inhibitors are not so new anymore. In the real world, we've started expanding the indication, giving checkpoint inhibitors to patients who would have been excluded to these clinical trials. And what we've learned over time is that with one exception, really all of these contraindications are relative and not absolute. The one clear ongoing absolute contraindication to checkpoint inhibition as an allograft. PD-1, PD-L1 is the rejection pathway, and so if you give a patient an allograft, a PD-1, or PD-L1 inhibitor, they will lose that allograft.

Now if that allograph is, say, a double lung transplant, you can't ever consider it. I did have a patient with a renal allograft who I had considered this contraindicated, and the patient was the one who expressed the point that she can live without kidneys. There is dialysis, but if her cancer grows through her, she can't live. That's of course her choice to make, but she in the real life case, the patient did get a checkpoint inhibitor. She did lose her allograft and she's alive with beautifully suppressed cancer two years in.

Now, what about things other than an allograft? So there are a variety of inflammatory and auto-immune conditions that our patients come to their cancer with. This particular patient here has rheumatoid arthritis, but I'm going to show for reference in subsequent slides some of the other conditions mostly so that when you have an individual patient in your practice, you'll have a reference here from this and the two following series if your patient has something other than rheumatoid arthritis.

So, you see other conditions here, but let's talk about what happened to these patients. Overall, 55% had an exacerbation of their auto-immune disease or a new immune-related adverse event. Interestingly, a quarter overall had exacerbation and 38% had an immune related adverse event. Now as a clinician, what are you thinking about when you're considering treating a patient such as this? What are you worried about? At least I'll admit what I tend to fear is a severe exacerbation, right? I'm afraid I have a patient with a smaller, moderate problem, and I'm going to make their auto immune disease go crazy. That's not what the data speaks to here. Here, the rate of grade 3-4 reactions was 11%. Interestingly, that's not different from what's been seen in the numerous clinical trials that would have excluded this patient.

Looking specifically at rheumatoid arthritis in this series, there were 13 patients, six of whom had a flare, all of which were easily managed. This is consistent with the next few series and others I'll show you. The second series...sorry, before I move on again, mostly for your reference, this is all the patients who had a flare, how they were managed or what happened. The theme here is that they were mostly very easily managed and didn't require permanent discontinuation of drug. Again, mostly for your reference.

Continuing the theme of slides that are mostly for your reference, this one is because it included patients with ipilimumab. If you're using ipilimumab your practice, say for melanoma or occasionally used for some other conditions, this may be helpful to you to see. Ipilimumab does have more immune related adverse events in general compared to the PD-1 (programmed cell death protein-1) inhibitors, and so it's not unexpected, as you see here, a greater extent of flare and you're looking at the rheumatoid arthritis specific data here. There is a broader table in the paper reference below.

Okay. So, we're now looking at a third series here. Again, a broader series with many auto-immune diseases on it. For rheumatoid arthritis, there were 20 patients in this series. Sixty percent had a flare up their existing disease, almost all grade 1 and 2, and importantly, because it's a helpful measure of just how meaningful the events were, only 15% discontinued their therapy for it.

So, let's come back to the actual patient. In practice, her doctor recommended treatment with carboplatin, etoposide, and the PD-L1 inhibitor after counseling about the risks of exacerbation of rheumatoid arthritis and other immune-related adverse events. The patient shows treatment with just carboplatin and etoposide for fear of exacerbation. She had a response in these disease progression four months later, and in the real world case, it's a very fresh case. The patient is consulting with a rheumatologist concerning the risks of PDX inhibitory therapy for consideration in second or third line.

It's worth pointing out here that this consultation can be extremely productive. There are even people obviously, mostly at large academic centers, but they're even people whose entire practice is made up of consulting on management of immune-related adverse events and the risk of treatment with PDX inhibitors in patients with rheumatologic and other disorders. In my practice, I have found this to be an extraordinarily helpful resource. When patients come to me for a second opinion with this as the primary question, I do my best to try to arrange back to back consultations with the relevant specialists, most commonly rheumatologists.

Let's move on to our second case. Our second case is that of a second line therapy in a patient with recurrent disease, more than three months but less than six months after first-line therapy. And if that seems like funny phrasing, I want to point out why this case was chosen. In the U.S., we tend to use a chemo-treatment-free interval of six months as where we define platinum sensitive. Our European colleagues tend to use three months in their studies. The reality is there probably is not a regression discontinuity but that's why this case was chosen as such. So, the patient was treated in frontline with carboplatin, etoposide, and durvalumab for extensive stage disease. The cancer progressed four months after the last dose. The patient is physically fit, performance status is 1, and his values are oriented towards life extending therapy.

The question is, what treatments are available to this patient? One question we often think about is the repeat of the platinum doublet. The data that you're looking at here are from a European trial. Thus, the chemo treatment free interval of 90 days as the inclusion criteria. As a phase three trial, patients were randomized to either repeat the platinum etoposide, or to topotecan. What you can see at left is that the doublet resulted in a significantly longer PFS. It also resulted in a significantly longer response rate than the topotecan, but unfortunately what you can see at right is there was no improvement in survival. No harm, either. The most frequent grade 3-4 adverse events were hematologic in both groups, and they were roughly similar. Repeat a platinum doublet, either with etoposide or a different partner agent such as irinotecan, is one valid option for this patient.

The most standard answer is probably topotecan. Topotecan has been extensively studied in various contexts and across time. The results here are mostly for your reference, but I would summarize this busy table by saying that the drug is active, but not as active as we would like it to be, and perhaps more toxic than we would like it to be, particularly for hematologic toxicity and their downstream sequelae.

With this data dissatisfaction with topotecan, a new agent has recently entered the marketplace: lurbinectedin. Lurbinectedin is a selective transcription inhibitor. Most of its mechanism of action is probably as an alkylating agent, and it was studied here as single agent in phase 1 in an expansion study in 105 patients. You're looking here at the waterfall plot, and what we see here is a 35% overall response rate. Interestingly, we divide these patients out by their chemo treatment-free interval. We see the same theme we've seen for pretty much all other similar studies that the response rate is better in those with a longer keep chemo treatment for interval, 45% percent, for those who are at least 90 days and 22% for those were under it.

Survival, as well, divided out by chemo-treatment-free interval. In those with the shorter chemo-treatment-free-interval, in dark blue here we can see that there is disease activity but survival is only five months. For those with the chemo-treatment-free interval that is longer, their survival is almost a year. The adverse events are mostly in-line with the mechanism of action of an alkylating agent, and as you can see hematologic toxicity is quite common. Then other things, like fatigue and nausea, are mostly low grade that we expect with chemotherapeutic.

Lurbinectedin has also been studied in a randomized phase three study. Here, the design was the combination of lurbinectedin and at a lower dose combined with doxorubicin. This combination was chosen based on preclinical synergy data, but it did come at the expense of reducing that lurbinectedin dose. Something that I'm going to come back to in a moment. These were randomized against dealer's choice of topotecan or CAV with a primary endpoint of survival. We know by press release that this was a negative study, survival was not improved, and we look forward to seeing presentations or publications of more detailed data. In explaining the nature of the failure, the best hypothesis out there, and I believe it to be true based on some data presented at World Lung, was that this was really about dose.

It turns out that if you look at AUC (area under curve) exposure of lurbinectedin, there's a sigmoidal shape on a curve of response rate versus exposure. So, it may be very important for the drug to be active to get to an adequate exposure. At the higher dose, the drug does remain approved as a single agent. In my clinical practice for a patient who wants next line therapy and who is not a candidate for, or does it want a clinical trial is, is my preferred agent.

So, let's move on to our final case. Our final case is that of third line therapy in a patient with response then progression on platinum etoposide and a PD-L1 inhibitor and lurbinectedin. Our case is that of a 50-year-old woman. She was previously treated in the first line with carbo-etopo-atezo with trilaciclib proceeding and her cancer read the textbook. It had a partial response followed by progression four months later. Second line was lurbinectedin and again, a partial response and again, a duration of four months and her cancer progressed again. She's physically fit, she's motivated for further therapy, and since she's an educational case, she doesn't want one of our clinical trials.

So, what standard of care options should be recommended to her? I showed you earlier data on why a CAV was replaced from platinum etoposide in the frontline. Historically, it then moved to second line where it was subsequently replaced by topotecan based on the data shown here. In randomized study, survival was similar, time to progression was similar, response rate was a whiff higher with topotecan, but critically there was better disease symptom improvement with topotecan.

We think about quality of life. I think it's the most important thing to most of our patients. We treat cancer for survival improvements and for improvements in quality of life, and we have to keep in mind that quality of life is driven in part by the side effects of our drugs and in another part by suffering related to cancer growth.

At least in terms of physical cancer related quality of life, these are the two dominant factors, and that's how we got to topotecan as the standard second line drug. So, I think in considering a patient like this, if you're considering topotecan versus hospice in trials' best supportive care, it's important to note that there is data on that question. This is an older randomized study of topotecan plus for supportive care or best supportive care alone. Survival was improved on a relative basis. It was a large improvement. It has a ratio of 0.61 on an absolute basis from 14 weeks to 26 weeks. Perhaps much more importantly than a 12 week survival improvement, there was a slower deterioration in quality of life with topotecan. While it does have many adverse events, small cell is even more brutal than topotecan, and just as with other datasets, the outcomes were better in the patients with the chemo-treatment-free interval of at least 90 days.

So, to put topotecan, is one option for this patient. We've already discussed that. We've already discussed CAV. We've discussed repeating chemo in case two, repeating doublet in case two. This patient had a chemo-treatment-free interval of four months, so repeating platinum etoposide or platinum with a different partner agent remains a valid option here. Other agents that are active in this space are irinotecan, either alone or with platinum, a taxane, gemcitabine, vinorelbine, or temozolomide.

For teaching purposes, I made this patient uninterested in clinical trials. If you bring it back to the real world, there's a lot of exciting stuff coming down the pike in small cell lung cancer, and so I would encourage for patients whose values are interested in it and whose resources are such that they can travel for it, to at least be offered clinical trials. And, of course for patients whose values are oriented in a different direction, hospice is always an option available to the patient.

Now, in our final time before moving on to questions, I want to talk about adverse events of chemotherapy and I want you to consider for yourself for a moment, what do you think are the most common high-grade side effects with carboplatin, etoposide, and atezolizumab? Now, parenthetically states the same answer for carbo-etopo-durvalumab, topotecan, or lurbinectedin.

And the answer is that with small cell lung cancer treatment in general, the toxicity is dominated by hematologic adverse events. Here highlighted for you in the... I don't know. Is that the taupe, the beige? Whatever that color is on this table.

So, not all of the adverse events. Of course also have alopecia, nausea, fatigue, gastroenterological side effects, but both at overall toxicity and high-grade toxicities, hematologic toxicities from count suppression and their downstream sequelae. Fatigue is in part a downstream sequalae of count suppression, as an example, really are rather common in our patients. I think we don't think about these that much, because until very recently there wasn't a whole lot we could do about it, particularly for anemia and the fatigue that can be downstream of it. Now that there is a drug that can do something about it, I hope that this is a stimulus, not only to consider that agent that I'm about to show you, but also to take a step back and think more about these quality of life driven by hematologic adverse events in general, and not take for granted that it just the cost of business of your patients with cytotoxics. With that, I'll get off my soapbox and show you the actual data.

So, I want to start with there were actually three randomized phase two studies. The data looks rather similar in all of them, and so I show you the data for perhaps the most relevant to your practice, which is carbo-etopo-atezo, with or without trilaciclib. Now, the primary end points of this study were median duration of grade four severe neutropenia in cycle one, or patients with grade four severe neutropenia. Well, you can see at a glance it's a dramatic improvement in both of these measures that did reach statistical significance. What you can see for everything else that you might expect for an agent aimed at multi lineage myeloid preservation, that there were trends in the individual study is all in the right direction. So, these trends are in the production in febrile neutropenia adverse events, patients getting G, severe anemia, red blood cell transfusions. I don't know who's still using ESA's (erythropoiesis-stimulating agents), but people were, and their use was reduced, and reduction in severe neutropenia.

I want to point out here that the movement here from mechanism of action to numeric count preservation to reduction in hematologic adverse events is rather clean. So, our mechanism of action is a CDK 4-6 inhibitor, short acting IV CDK 4-6 inhibitor. In plainer English, what we're doing is holding the bone marrow progenitors out of cycle while the chemo is washing by, so that it doesn't poison them.

Here for you is the pooled data from the three studies, and really the themes are exactly the same except that with the greater patient numbers what were trends before mostly become significant now. Now, that progression I described for you from mechanism to count suppression, to count preservation, to reduction hematologic adverse events, frankly wouldn't mean much to me if it were not accompanied by the most downstream and most important effect, which is quality of life, and by PROs (patient-reported outcomes) that did happen. In my clinical practice, the event that I feel least well equipped to help my patients with and that they suffer the most from is fatigue, and so for me that's the most impactful of the PROs here is patient reported fatigue.

Now, safety and most studies is the toxicity table. Here toxicity kind of flips on its head, right? Toxicity was decreased. That was the whole point of this drug. It's a quality of life drug. The only real adverse events that I wanted to describe to you are infusion related reactions. They fit the theme of irritation at the infusion site. If in your practice, you use ports, this is not an issue for you. If in your practice, you use peripheral IVs, you can slow the infusion. You can rotate sites. The other supportive care maneuvers that you're used to work just fine. The only other thing really worth pointing out from the toxicity standpoint is a reduction in alopecia which is not surprising given the mechanism of action. Small cell is more common in men, more common in older patients. So, some patients may not care for those who do. I find it interesting.

But safety for me here has flipped on its head. The question for safety isn't whether toxicity is worse than it wasn't, it's whether a survival or PFS (progression-free survival) was harmed. Now, small cells are obligate RB-null, so you wouldn't expect any improvement or harm to PFS or OS (overall survival), and that's exactly what seen here, the pulled data shown for you. It is purely a supportive care agent in the context of small cell.

In summary, for eligible patients the PD-L1 inhibitors durvalumab or atezolizumab should be added to carboplatin and etoposide for a survival advantage. We shouldn't have said "and." Durvalumab or atezolizumab. Lurbinectedin is an exciting new option for second-line extensive stage small cell lung cancer. Trilaciclib may be added to carboplatin and etoposide, carboplatin etoposide and atezolizumab, or to topotecan to reduce myelosuppression.

I thank you for your kind attention.

This is a verbatim transcript and has not been copyedited.