Mastering the Evolving Treatment Paradigm in SCLC: Expert Case Discussions to Aid Integration of Immunotherapy and Novel Targeted Therapies Small-Cell Lung Cancer  

 

So this is a high grade neuroendocrine carcinoma When I was a fellow which was a long time ago it used to be almost 20%-25% of all lung cancers Right now it accounts for about 13% So in that 5%-15% range The outcomes in terms of survival are very poor. The major region for the reduction is the reduction we have seen in smoking in the United States, which is the major risk factor for this. And this is a disease that is characterized by alterations in tumor suppressor genes as well as transcription factors and no clear targetable genetic driver.

 

[00:37:03]

 

SCLC: Staging and General Approach to Treatment  

We have lapsed into the old VA staging system, which again is a little bit lazy in my opinion. About a third of patients have this limited-stage disease, which is a tumor that will fit within a reasonable radiation port. The technology in radiation has changed quite a bit since this definition, but traditionally, we have treated this with concurrent chemoradiotherapy. This is a potentially curable, although we do not cure the majority of patients. Many of them still recur historically. However, it is a potentially curable stage of the disease.

 

Most of the patients we see, about two-thirds, have extensive-stage disease. This is essentially stage 4. We have a standard of care of chemotherapy with immunotherapy. We will review that data briefly. This is, as I say to my patients, a treatable but not a curable stage of the disease.

 

[00:37:56]

 

Paradigm Shifts in LS-SCLC Treatment  

We wrote this paper back around 2007-2008 or so looking at paradigm shifts in limited-stage disease. And all of them have been done by our radiation oncology colleagues. The integration of concurrent chemotherapy, more intensified radiotherapy, early delivery of radiotherapy as well as the role of PCI.

 

[00:38:18]

 

Establishing Standards for LS-SCLC  

This was Drew Turrisi's paper published in the late 1990s in the New England Journal of Medicine. This is an interesting paper. I think this paper was presented at this meeting the first 2 times, back in the 1990s, as a negative trial. It was only when the 5-year survival came out and the tail on the curves were different that it was considered a positive trial, with about a 10% difference in absolute survival at 5 years.

 

Increased local control with the BID radiotherapy. Again, this was 45 gray once a day vs 45 gray twice a day. There was a cost increased toxicity, namely grade 3 esophageal toxicity.

 

[00:39:01]

 

RT Fractionation With Concurrent Chemo in LS-SCLC  

That prescription 45 gray BID was used in 2 subsequent trials the CONVERT trial and then the trial by the CALGB. You can see the twice daily radiotherapy. What this explored is just higher doses of radiotherapy given once a day, 66 gray in the case of CONVERT or 70 gray in the case of the CALGB trial.

 

[00:39:24]

 

LS-SCLC: Once-Daily vs Twice-Daily RT  

Both had overall survival as the primary endpoint. Both of them were negative trials showing no difference between the higher dose once a day vs the 45 gray BID.

 

[00:39:36]

 

Final Results: Phase II Trial of High-Dose (60 Gy) vs Standard-Dose (45 Gy) Twice-Daily Radiotherapy in LS-SCLC  

There have been a couple of attempts to look at more intensified BID radiotherapy. This paper was first presented at this meeting, ASCO, a couple years ago. It was a look at 45 gray BID as the control arm vs 60 gray in 40 fractions BID. It was a phase II trial. It was not a large trial. By phase II standards, it was positive. You see the overall survival curves in favor of the 60 gray.

 

[00:40:10]

 

TRISS: Twice-Daily SIB RT vs Standard RT in LS-SCLC  

The TRISS trial was recently published. This was a multi-center open-label randomized phase III trial done exclusively in China. This was using 45 gray as the control arm BID, but using a simultaneous integrated boost to a 54 gray to the tumor volume. This was again in limited-stage disease. It cut the age of patients at age 70. The primary endpoint was overall survival. This was terminated by the DSMB early because of the difference in overall survival. You can see the median OS hazard ratio was 0.55. You see a difference of 20 months in overall median survival between the 2 arms.

 

It brings us back to the importance in the quality of radiotherapy that we see in this stage of the disease.

 

[00:41:13]

 

Current Clinical Guidelines on Primary Treatment for LS-SCLC  

Here are the NCCN guidelines, they are pretty straightforward. We use 4 cycles. They do say the preferred regimen is cisplatin, as I mentioned. Consolidation therapy with durvalumab is mentioned. There are other recommended regimens shown here. Carboplatin is mentioned here, but at least how I see the data, the carboplatin data does not seem to be as robust as the cisplatin data. Most of that is because the patients are not as robust as patients who get cisplatin. However, to keep that in mind, shown here.

 

[00:41:48]

 

ADRIATIC: Consolidation Therapy With Durvalumab for LS-SCLC  

What has changed after all the radiotherapy advances, there were no chemotherapy advances. We still use standard does cisplatin-etoposide. It was not really until the immunotherapy era that we saw a change. Last year at at this meeting at the plenary session, we saw the first presentation of the ADRIATIC trial. Essentially, what this did was graphed durvalumab as consolidation therapy after the completion of chemoradiotherapy in this limited-stage setting.

 

There were 2 primary endpoints PFS by blinded review as well as overall survival compared to a placebo control arm. You can see the secondary endpoints are shown there.

 

[00:42:32]

 

strong>ADRIATIC: Baseline Characteristics  

The patients were pretty well-balanced. I will just point out a couple of things. You can see most of the patients received once daily to the higher dose. There was about a quarter or so of patients that got twice daily. Two-thirds got cisplatin, a third got carboplatin, show here. Again, pretty typical male domination, which we typically see in small-cell trials.

 

PCI was allowed on this trial, slightly more than 50% shown here, in balance between the 2 arms got PCI.

 

[00:43:05]

 

ADRIATIC: OS and PFS (Coprimary Endpoints)  

Here are the 2 primary endpoints. This was a positive trial. The overall survival is on the left, PFS to the right. The hazard ratios shown here, 0.73 for overall survival and 0.76 for progression-free survival. You see the median overall survival on the durvalumab arm at nearly 56 months. So, impressive positivity shown here.

 

[00:43:32]

 

ADRIATIC: OS Subgroup Analysis  

All groups seem to benefit. Remember, these are not individually statistically powered to show statistical difference. A couple of observations. Here is why I use cisplatin. It seemed to be greater benefit, although carbo did seem to benefit. And let me say on the PACIFIC trial in non-small-cell, if you start immunotherapy earlier, you seem to get a greater advantage of it, as shown here.

 

Now, again, the question is because the patients had less toxicity, maybe smaller tumor volumes were able to start and did not have esophagitis that took a couple weeks to clear up? These things we do not know. However, at least in my practice, I try to start it as quickly as possible after completion of chemoradiotherapy.

 

[00:44:20]

 

ADRIATIC: Most Frequent AEs  

The adverse events are shown here. Radiation pneumonitis, or what was called radiation pneumonitis, is a balance between the 2 arms of the trial. Pneumonitis slightly more common, shown to the bottom. Pneumonia and pneumonitis slightly more common as shown here on the durvalumab arm. Typically, what we would see for some of the IO-related events, hypothyroidism, diarrhea, these sorts of things were slightly higher, and that is obviously not surprising when you are using an active IO agent in this setting.

 

[00:44:56]

 

ADRIATIC: Pneumonitis/Radiation Pneumonitis  

Specifically looking at pneumonitis and radiation pneumonitis, here you can see like we saw in the PACIFIC trial. Any-grade about 30-38% of the patients shown here, but grade 3/4 was essentially 3% on both arms. Slightly higher rate of leading to treatment discontinuation on the durvalumab arm. Only a single death attributed to it on this particular trial. So I would argue pretty safe treatment in this setting.

 

[00:45:28]

 

ADRIATIC: Conclusions  

So this ADRIATIC trial showed a statistically significant, and I think clinically meaningful improvement in OS and PFS after completion of concurrent chemotherapy. I gave you the numbers before, durvalumab was, in general, given. I forgot to mention this, this was different than the PACIFIC trial. It was given for 2 years vs 1 year that we seen in non-small-cell.

 

Really no new safety signals shown with durvalumab therapy. I think this is the slide used in the presentation and declared a new standard of care, and has been integrated into the NCCN guidelines.

 

[00:46:10]

 

Ongoing Immunotherapy and ChemoRT Trials in LS-SCLC  

There are several other ongoing immunotherapy trials in limited-stage disease.

 

[00:46:17]

 

NRG-LU005: Addition of Atezolizumab to CRT for LS-SCLC  

We saw at ASTRO last October the first presentation of the NRG-LU005 trial. This looked at another PD-L1 drug, atezolizumab, in a randomized phase III trial, shown here in limited-stage disease. Although, in this case, it was given from cycle 2 during the chemoradiotherapy portion. Again, one could either use the 45 gray BID or the 66 gray once daily. The primary endpoint of this trial was overall survival. Atezolizumab was continued for 1 year after completion of treatment.

 

[00:46:55]

 

NRG-LU005: Baseline Characteristics  

A busy slide, but essentially well-balanced between the arms here. You can see again, most of the patients got cisplatin. A surprisingly high number got BID treatment. Almost half the patients were treated with BID. Only about 45% of patients got PCI, which was allowed on the trial.

 

[00:47:18]

 

General Review of Radiation Therapy  

I think the quality of radiation therapy is always important. I think in this trial, as you should see here, per protocol, +80% of patients acceptable variation in about 15% of patients. The unacceptable deviation you can see was quite low. I think the quality was quite good.

 

[00:47:38]

 

NRG-LU005: OS (Primary Endpoint) and PFS  

Unfortunately, this was a negative trial, with overall survival being the primary endpoint. And you can see those curves essentially overlapped in this setting, as do the PFS curves shown here.

 

[00:47:50]

 

NRG-LU005: Safety  

The safety again, there were more grade 3 immune-related adverse events, as one would expect, shown here. Pneumonitis also more common here. You can see that the reporting of this window was different on the 2 arms. The reporting window for the control arm was 30 days post-chemoradiotherapy, where on the atezolizumab arm it was 90 days post-atezolizumab. So really an assessment period of 11 weeks vs 15 months, so you would expect to see more events in that particular setting.

 

[00:48:28]

 

Active Phase III Trials in LS-SCLC  

Again, we have a number of active phase III trials going on here. I will not go through them in detail in the interest of time. However, you can see the completion dates, so we should expect to see much more data in this arena over the next 3-4 years.

 

[00:48:41]

 

LS-SCLC: Testing, Primary Treatment, and Adjuvant Therapy  

I do not want to forget limited-stage disease. I was trained to treat based on TNNM, to treat small-cell the same way we treat non small-cell. In the new NCCN guidelines, they talk about something we do not see very often which is stage 1 and 2A or T1 to 2. They should be staged in the mediastinum. If the mediastinum is negative, then resection is recommended. And we see this occasionally with patients with limited-stage small-cell lung cancer.

 

Now, let us go back to a question

 

 

[00:49:10]

 

Patient Case 1: Treatment for LS-SCLC  

So back to the question. Here is the lady again, my lady with the limited-stage disease. She undergoes concurrent chemo and radiation with cisplatin. Has a good response, no toxicity.

 

[00:49:32]

 

Posttest 1: What is the most appropriate next step for this patient's treatment plan?

 

So at this point, what is the most appropriate next step for this patient's treatment plan

 

1. Close observation with surveillance imaging every 3 months;
2. PCI without further systemic therapy;
3. Durvalumab consolidation after completing chemo-rads; or
4. Second-line chemotherapy with topotecan.

 

So we will vote.

 

100%. Cannot do better than that. Thank you.

 

Speaker: [Inaudible 00.50.15 – 00.50.19]

 

Dr Socinski: I do not have an explanation for that. Again, it was a different trial design. I do not know if my colleagues have a good reason. I do not think anyone has a good reason.

 

Dr Johnson: The current approach, the fact that LU-005, the atezolizumab was given concurrently with radiation. We have seen that in other studies including in PACIFIC-2 and also in head and neck trials where the concurrent approach seems to eliminate the lymph node drainage of the mediastinum, and perhaps that has negative impact on response to immunotherapy. I think it is pretty clear in lung cancer that a concurrent approach with radiation is not the way to go. So, sequential. I do not think the problem was the atezo itself, it was a concurrent approach with radiation.

 

Maximizing First-line Therapy for ES-SCLC

 

[00:51:12]

 

Phase III Trials: Addition of Anti–PD-L1 Checkpoint Inhibitors to First-line Platinum + Etoposide in ES-SCLC  

Dr Socinski: To follow up on your question, we are switching gears to extensive-stage disease. Now, we all know the IMpower133 and CASPIAN trials were phase III trials that changed the standard of care in extensive-stage disease. Here are the 2 trial designs, simply grafting to the left atezolizumab onto our old friend carbo-etoposide, and then to the right, essentially the same trial design on the bottom 2 arms with grafting of durva on this trial.

 

There was a stratification if you plan to use either carbo or cis on that. Both had primary endpoints of overall survival, although IMpower133 also had a PFS as a coprimary endpoint.

 

[00:52:00]

 

IMpower133 and CASPIAN: OSIMpower133 and CASPIAN: OS  

The results of the 2 trials were remarkably similar.

 

You can see the hazard ratios, 0.76 and 0.75 in this analysis of these 2 curves. Really, it changed the standard of care in this particular setting.

 

[00:52:15]

 

FDA Approvals for 1L ES-SCLC: Updated Analyses  

When you line up the variables in terms of median survival, the hazard ratio, as I have mentioned, the survival at 1 year and 2 years, and these sorts of things had remarkably consistent data between these 2 trials.

 

Again, it really changed the standard of care in early-stage disease.

 

[00:52:35]

 

Current NCCN Guidelines on Primary Treatment for ES-SCLC  

Obviously, it was rapidly incorporated into the NCCN guidelines, and you can see here a number of options using either ateo or durva in the guidelines in either with cis with durva or carboplatin-based therapy, which is what I think most of us do in the extensive-stage disease setting.

 

[00:52:53]

 

Overview of Key Studies of ICIs in ES-SCLC  

Those are the 2 trials we talk about. There are a number of other trials. You can see the listed drugs there, nivo on down. Again, this rarely do we see such consistency of data.

 

If you look, just scan down the median PFS, the median overall survival, and the hazard ratios are remarkably consistent. Obviously, the 2 agents that are currently FDA-approved are the 2 top ones, but you can see the impact of these others, some of which are PD-1 vs PD‑L1 is remarkably consistent and similar across the 2 arms.

 

[00:53:27]

 

ASTRIDE: Serplulimab + Chemotherapy in ES-SCLC  

There is a comparative study ongoing with serplulimab, a head-to-head phase III trial looking at a direct comparison. We do not have any of these comparisons with all these other agents, so we lapsed into the cross-trial comparisons when we have to. The primary endpoint here is overall survival.

 

[00:53:54]

 

SKYSCRAPER-02: Atezolizumab + Chemotherapy ± Tiragolumab in Untreated ES-SCLC  

Now, there was a lot of excitement in the thoracic field for what is the next step after PD-1, PD‑L1. Yes, we had CTLA-4. Has not made a huge splash, but TIGIT, and tiragolumab is an anti-TIGIT antibody. We saw this trial presented at ASCO a couple of years ago and then published in the JCO, essentially taking the IMpower133 regimen and grafting tiragolumab on during the induction as well as maintenance treatment with the atezolizumab.

 

[00:54:31]

 

SKYSCRAPER-02: PFS and OS in Full Analysis Set  

And unfortunately, again, this is a completely negative trial as shown here. No seeming value in this particular setting.

 

[00:54:39]

 

Biomarker for Response to ICIs: The Search Continues  

Biomarkers for response, I mentioned early on that we really are dealing with a situation of tumor suppressor genes and transcription factors, and we do not really have reliable biomarkers, and we do not really have genomic targets like we have in non-small-cell lung cancer.

 

There was an early bit of optimism that perhaps tumor mutation burden would be a predictor of response. This is some early data from Matt Hellman at Memorial Sloan Kettering, looking at the combination of nivolumab plus ipilimumab, and you can see at least in the high expression that there seemed to be a benefit with an overall response rate of about 46%, and a very nice 1-year overall survival of 62%. Of course, these are inpatients who make it to the middle of Manhattan and get on a clinical trial.

 

So highly selected patients in this particular setting.

 

[00:55:41]

 

TMB Does Not Predict OS Benefit From Atezolizumab + Chemotherapy  

When this was looked at in the IMpower133 trial, you can see down here that tumor mutation burden, no matter how you cut it here, really was not a discriminating factor between high and low, however you defined it in that particular setting.

 

[00:56:00]

 

PD-L1 Status Does Not Correlate With Response in SCLC  

Likewise, PD-L1 status, we use it as a biomarker in non-small-cell. I would not say it is a perfect biomarker, but it does have practical use in non-small-cell. It really does not correlate with any of the outcomes that we see in small-cell lung cancer, and this is shown in the CASPIAN and IMpower133 trial, as well as the Keynote 604 trial.

 

[00:56:27]

 

SCLC Biology: Molecular Subtypes by Expression of Key Transcriptional Regulators  

There was some early excitement looking at the expression of transcriptional factors. Shown here, there was kind of a subsetting of the small-cell population into 4 different categories. Shown here, you can see to the bottom left how they are distributed. This is namely 70% of the cases fall into that first bucket there.

 

There is a differential expression of some of the genes shown at the bottom, the MYC as well as BCL2 and DLL3. There was some initial excitement about looking at this inflamed subtype. This was analysis, again, of the 133 where there was a suggestion.

 

Now, you have to kind of squint your eyes a little bit to the left there, but maybe there was a subgroup that you might find would have a better outcome with IO-based therapy, this so‑called inflamed subtype. You can see to the right there did not seem to be any separation. Now, to me, is this enough separation to be excited about? Personally, I had my doubts in this particular setting.

 

[00:57:40]

 

Better OS for SCLC-I "Inflamed Subtype"  

You know that old saying, you never met an analysis you did not like? This is a meta-analysis of PCI that was published, again, in 1999.

 

This was 7 randomized trials that were done prior to that time, obviously, in patients with small-cell lung cancer. The forest plots over here look at relative risk of death. You can see there was about a 16% decrease in the risk, as well as relative risk for brain metastases, a much bigger effect on the local control in the brain.

 

There did not seem to be a dose effect, as the doses were different across these 7 randomized trials.

 

[00:58:21]

 

Prophylactic Cranial Irradiation  

Brain mets, obviously, are a common problem in small-cell lung cancer. The majority of patients will develop them if they live long enough.

 

PCI has been an option for quite some time, based upon that meta-analysis. In extensive-stage disease, we have conflicting data. There was some initial excitement in ERRTC data that suggested a benefit.

 

However, a probably better designed and more controlled Japanese trial suggested actually quite the opposite. There is a lot of ongoing trials on the role, what role PCI should play. I think I have it on the next slide. The bottom bullet there, brain surveillance, is a reasonable option for patients with extensive-stage disease.

 

[00:59:12]

 

Select Ongoing Trials on PCI  

You can see the select ongoing trial is shown here, listed to the left there. You can see on the treatment arms, a trial through SWOG and the MAVERICK trial, looking at MRI brain surveillance alone vs surveillance plus PCI.

 

Then some other trials looking in the middle one, an IMRT/CRT comparison, as well as the bottom one, looking at patients with brain meds in the role of stereotactic radiosurgery vs whole brain with supportive care. Ongoing trials, I am not quite sure of the timeline of when these will be complete.

 

[00:59:54]

 

Phase III Randomized Controlled Trial of TRT in ES-SCLC  

Likewise, several years ago, Ben Slotman published this paper initially in the Lancet. Nearly 500 patients looking at the role of thoracic radiotherapy in this setting. These were, again, 500 extensive-stage patients that had responded to platinum-etoposide were randomized to thoracic radiotherapy, 30 gray in 10 fractions plus PCI vs PCI alone. The primary endpoint was overall survival at one year, which was actually not different.

 

I will show you the curve on the next slide. There seemed to be a late effect. I do not know how the statistics were done here, but the 1 year was not statistically significant. The 2-year was. PFS seemed to be better, and intrathoracic control seemed to be better, which we would expect.

 

[01:00:43]

 

Phase III RCT of TRT in ES-SCLC: OS  

Here are the force plots shown here.

 

Looking at the curves here, again, there might be a late effect shown here. There may be patients. The question is, how do you select these patients?

 

[01:00:55]

 

Role of RT in ES-SCLC  

Which brings me to one of my favorite trials from, again, from 1999. This was the Jeremic trial that really categorized patients based upon their intrathoracic and extrathoracic response to chemotherapy. He is defining the chemosensitivity of patients across these 5 groups.

 

Then they go on to get PCI as well as chest radiotherapy. You can see here in the population that seemed to have a CR at intra and extrathoracic sites actually did the best. Important to be aware of this data, as it certainly has influenced me and my practice in terms of who I would offer or think about using thoracic radiotherapy in this setting.

 

[01:01:44]

 

Role of TRT in ES-SCLC in the IO Era  

There does not appear to be any increased toxicity. That is unexpected. There are some retrospective and propensity scored matched analysis suggesting an overall survival advantage to adding thoracic radiotherapy.

 

There are 2 ongoing randomized trials exploring this, the TRIPLEX as well as the RAPTOR trial shown here.

 

[01:02:07]

 

IMforte: Lurbinectedin + Atezolizumab as First-line Maintenance Therapy in ES-SCLC  

Now we are going to get some new data that will affect the extensive-stage small-cell lung cancer population in the IMforte trial. Melissa Johnson is going to cover this in as much detail as we have right now, since the presentation is not until late Monday afternoon.

 

We will come back to the IMforte data on Melissa's trial presentation.

 

[01:02:35]

 

SCLC: Summary  

In summary, this really has been a model for multidisciplinary care in this setting, as has non-small-cell. Obviously, integration of radiotherapy and more aggressive radiotherapy has changed outcomes in both limited and extensive-stage disease.

 

As shown, the addition of immunotherapy to standard chemotherapy has improved outcomes in both extensive as well as limited-stage disease. There still is a clear need to understand the biology of this disease better than we currently do that will hopefully give us some predictive markers in terms of how we direct our treatments to individual patients.

 

With that, I am going to invite Melissa to the podium to talk about navigating options for relapsed small-cell.

 

Navigating Options for Relapsed ES-SCLC

 

[01:04:20]

 

Patient Case 2: Relapsed ES-SCLC After Initial Response to First-Line Therapy  

 

Dr Melissa Johnson (Sarah Cannon Research Institute): Thanks, Mark.

 

This is a similar patient to Mark's. I think this is also a female 56-year-old who had been diagnosed with extensive-stage disease 6 months prior, received chemoimmune therapy with dirvalumab for 4 cycles and then dirvalumab maintenance for 3 months. After 3 cycles of dirvalumab, the patient had a PET scan that you see on this slide that showed recurrent FTG Avid disease, both in the chest wall, in the mediastinal lymph nodes as well as in the liver. There was a brain scan that showed 2 sepsonometer asymptomatic brain metastasis. The patient was still working full-time, had no symptoms from her recurrence.

 

[01:05:08]

 

Pretest 2: Which of the following systemic treatment options would you select for this platinum-refractory patient?

 

So the first pretest question is, which of the following systemic treatment options would you select for this platinum refractory patient in the second-line?

 

1. Lurbinectedin;
2. Tarlatamab;
3. Ifinatamab deruxtecan;
4. Lurbinectedin or tarlatamab;
5. I-DXd or lurbi?

 

We have a mixed audience this evening. Some voted for lurbi, some voted for tarla, some voted for both, and a few voted for the novel I-DXd. So we will see what the right answer is as we go.

 

[01:06:06]

 

Current Guidelines on Subsequent Systemic Therapy for Recurrent SCLC (May 2025)  

So this is the NCCN current guidelines for subsequent systemic therapy. I would say compared to the frontline small-cell guidelines, these are a little bit skinnier, a little lean. There are fewer options for our small-cell patients. This is a prime clinical trial category. I do want to point out that to date in the NCCN guidelines, patients are still separated based on their chemotherapy-free interval at 6 months. So that is 180 days.

 

So for patients that relapse after 6 months or 180 days, it is reasonable to re-challenge with platinum. However, for patients that relapse in under 80 days and certainly under 90 days, those are patients we call relapsed/refractory in whom we are looking for other things to treat with the second time.

 

[01:07:10]

 

Lurbinectedin  

So what about lurbinectedin? This is a new kid on the block. Maybe not the newest kid anymore.

 

It is a selective inhibitor of oncogenic transcription. Translation and transcription are vital to a rapidly growing cancer, and so it makes sense that this is a chemotherapy that slows down that process. It also turns out, as you see on the right-hand side of the slide, that lurbinectedin has some immunogenic properties and restores antitumor immunity in a few ways in the tumor microenvironment of the cell.

 

lurbinectedin was initially studied in a phase I trial, all solid tumors, and in a basket trial that included small-cell lung cancer. There were 105 small-cell lung cancer patients in this small phase II trial that were treated with a dose of 3.2 mg/m² once every 3 weeks and the primary endpoint was investigator-assessed objective response.

 

[01:08:21]

 

Phase II Study of 2L Lurbinectedin in ES-SCLC: Efficacy  

You see on the left-hand side of the slide the objective response shown at the very top of those columns. 35% for all patients, a little bit less in the patients that had a chemotherapy-free interval less than 90 days, and a little more in the patients whose chemotherapy-free interval was more than 90 days, so what we would expect.

 

However, the data started to get more interesting for many of us as it matured. You see the duration, the median PFS, and the median overall survival. On the right-hand side of the slide, in particular, the duration was what caught many people's attention for small-cell. Small-cell is rapidly progressive at recurrence. It can shrink easily but grows back quickly.

 

The duration of 5 months was improved over topotecan, the standard of the day. These responses were even a little better in the bottom column, those patients with platinum-sensitive disease.

 

[01:09:27]

 

Phase II Study of 2L Lurbinectedin in ES-SCLC: Safety  

The main toxicity that we see with lurbinectedin is hematologic.

 

On the left-hand side of the screen, I have bolded the various percentages. There are some grade 3 leukopenia and neutropenia, so these patients are susceptible to infections. On the right, you see that fatigue is also a common side effect, and even some grade 3, so it can be clinically significant for our patients.

 

Nevertheless, for some patients, lurbinectedin is super well tolerated. Just like every chemotherapy that we give, there is a range of tolerance.

 

[01:10:04]

 

ATLANTIS: Combination Lurbinectedin and Doxorubicin vs TPC of Chemotherapy in Relapsed SCLC  

Lurbinectedin received a conditional approval based on that phase II data, and the pivotal trial, ATLANTIS, was launched combining lurbinectedin with another chemotherapy, doxorubicin, vs treating physician's choice TPC of chemotherapy for relapsed small-cell.

 

Some of you are saying, wait a minute, when did we start using doxorubicin for our small-cell patients? We just do not, but there was preclinical data that suggested impressive synergy between lurbinectedin and doxorubicin used in breast cancer, used in sarcomas, and so that was the chemotherapeutic that was chosen.

 

Patients were enrolled in the second-line and beyond 1 prior line of platinum-based chemotherapy to receive Doxorubicin and lurbinectedin at a dose of 2.0 mg/m² day 1 of a 3-week cycle vs topotecan or CAV, another historical regimen that we do not use very much for refractory small-cell anymore. It has similar efficacy to topotecan.

 

[01:11:22]

 

ATLANTIS: PFS and OS  

The primary endpoint of this pivotal trial was overall survival. Here you see the PFS on the left and the overall survival on the right.

 

These curves are superimposable whichever way you slice it, and so maybe doxorubicin was not the right choice for this trial, but nevertheless, at that point by the point that the Atlantis trial read out, investigators that take care of small-cell patients were liking lurbinectedin. They were using lurbinectedin, and so it has not been, the indication was not pulled. Still probably one of the choice regimens in the second-line now.

 

[01:12:02]

 

LAGOON: Lurbinectedin ± Irinotecan vs Topotecan or Irinotecan in SCLC  

And so it has been studied and is being studied in other phase III trials. LAGOON shown here, this is lurbinectedin and irinotecan, another topoisomerase inhibitor vs topotecan or irinotecan in small-cell lung cancers.

 

So those are the standards in the second-line, topo or irino, and we have lurbinectedin alone or with irino as the 3 arms, which is hopeful that this will assess both contribution of components as well as the efficacy of a modern day lurbinectedin vs a historical control like topotecan. This trial is ongoing, continues to mature for the primary endpoint of overall survival.

 

[01:12:52]

 

Phase I/II LUPER: Lurbinectidin + Pembrolizumab in SCLC  

Now, this looper trial is a I/II trial.

 

It is a small data set, but nevertheless provocative and interesting, in which patients were treated after 1 line of platinum with lurbinectedin in combination with pembrolizumab for small-cell lung cancer. So we see that in the phase II portion, small trial, 28 patients, half were platinum-resistant and half were platinum-sensitive. You see the objective response rates at the bottom in the table.

 

Particularly provocative for those platinum-sensitive patients, a response rate of 60% and a duration of response of 12 months. PFS, 8 months, suggesting that there may be some synergy when immunotherapy is added to lurbinectedin. So that will, of course, require additional work.

 

However, nevertheless, lurbinectedin has survived to fight another day.

 

[01:13:59]

 

IMforte: Lurbinectedin + Atezolizumab as First-line Maintenance Therapy in ES-SCLC  

And so that next day is IMforte. That is the trial that we will hear the results of on Monday.

 

This is a frontline maintenance trial in which patients who have been treated for first-line extensive-stage small-cell with carboplatin, etoposide, and atezolizumab after 4 cycles of induction are randomized to continued atezolizumab, which was the standard of care Dr Socinski told us about, in combination with lurbinectedin or atezolizumab alone.

 

This was both a bold and an intelligent trial because it is these patients with extensive-stage disease where I cringe when I stop the chemotherapy because PD-L1 inhibitors alone just does not control the disease in small-cell the way it does in non-small-cells. So this was, in my opinion, a great idea for a study.

 

Coprimary endpoints, PFS, and overall survival. So spoiler alert, the abstract's online.

 

[01:15:05]

 

IMforte: Efficacy  

Here are the results.

 

You can see that lurbinectedin added to atezolizumab improved both PFS and overall survival. Median overall survival improved by 3 months. Remember, the immunotherapy added to chemotherapy improved overall survival for extensive-stage disease by 2 months, so 10-12 months.

 

And now we have gone from 10 months with atezolizumab alone to 13 months here. So maybe one of the criticisms will be that with atezolizumab the median overall survival was only 10 and not 12 months. However, nevertheless in this trial the hazard ratio was 0.73 with a significant P value. And so we will see Professor Luis Pazarez present this data on Monday afternoon. And many believe because of the positive overall survival result that this will change our standard of care.

 

[01:16:09]

 

Practical Considerations on Dosing Lurbinectedin  

So this is a nice slide for clinicians in the audience.

 

Just some practical considerations for dosing your lubi 3.2 mg/m² Q3 weeks. This is an IV infusion.

 

And the NCCN it is a preferred treatment for patients whose chemotherapy free intervals less than 6 months not to say that if it is more than 6 months it is not condoned. You can give it there too.

 

Tarlatamab: DLL3 x CD3 Bispecific T-Cell Engager

 

[01:16:44]

 

DLL3 T-Cell Engager Mechanism of Action  

So switching gears to the second spoiler. Let us talk about tarlatamab. At this meeting a year ago, this DLL3 CD3 bispecific had just been approved for the treatment of relapsed refractory small-cell patients. Again, an accelerated approval.

 

[01:17:03]

 

Rationale: DLL3 Expression in Neuroendocrine Cancers  

The way I explain this drug to my patients is that this by targeting DLL3 on the tumor and targeting CD3 on the T-cell we can bring the T cells to the cancer in a way that atezolizumab or durvalumab does not because it is only active in the bloodstream.

 

DLL3 is super important in neuroendocrine cells. You see the prevalence of DLL3 expression across a number of neuroendocrine neoplasms including small-cell lung cancer where it is expressed as highly as 85%.

 

[01:17:42]

 

DeLLphi-301: Tarlatamab in Relapsed ES-SCLC  

So tarlatamab was approved based on the DeLLphi-301 trial which enrolled patients. This was an open-label phase II trial.

 

Patients had had at least a platinum-based regimen and 1 other treatment immunotherapy for most. The median lines of therapy was 1 to 8. So this was a heavily pre-treated group of patients and patients were randomized to 2 doses of tarlatamab.

 

So everybody gets there is a step dose with tarlatamab. Everybody gets 1 mg the first time that they get it and then the step dose was the randomization here. Either from 1 mg to 10 mg or 1 mg all the way up to 100 mg. A bigger step for those patients randomized to 100 mg. And the primary endpoints were objective response.

 

[01:18:36]

 

DeLLphi-301: Intracranial Antitumor Activity  

This trial showed that the step from 1-10 mg had equivalent efficacy to 1-100 mg, but with a better safety profile and so that is the dose that was selected for filing and for other investigation.

 

One question, remember our patient had 2 subsodometer brain mets. What do we do about those if we wanted to give tarlatamab? It turns out in DeLLphi-301 all patients had to be treated for their brain disease before they were allowed to go on, but nevertheless the investigators from that phase II experience looked at the 17 patients that had brain mets when they went on to the trial.

 

You will notice on the left-hand side of each of these swimmer lanes there is a little box, and it is either orange if they got whole brain radiation before they went on the trial and red if they got SBRT or SRS before they went on the trial and the degree to which it is to the left of that black line shows how far before they went on trial was the radiation. Nevertheless, you see here that there were patients that had tumor shrinkage irrespective of whether they had had whole brain or SRS. I think the colleagues were trying to show here that even for patients that had limited brain radiation before they went on trial there was at least stabilization and sometimes response in the brain. And so we have this general idea that tarlatamab has CNS activity, even though it has not been studied very robustly yet.

 

[01:20:30]

 

DeLLphi-301: Tarlatamab Toxicities—CRS and ICANS  

Let us talk about the unique side effects of tarlatamab. CRS and ICANS because this is of course a bispecific stimulating your immune system. That was the side effect that many of us were the most concerned about when we started these trials.

 

This slide shows the CRS on the left and the ICANS on the right, both in cycle 1 and cycle 2 for the CRS in particular. So you see the majority of CRS was happening in that first cycle and actually in the first 2 weekly doses and then very little in cycle 2. So that is important for the clinicians in the audience and the other thing is you know ICANS is still a work in progress, but it happens in minimal patients and when it happens, it happens early in the administration time and the farther out you go the less likely you are to see it.

 

[01:21:26]

 

Most Common Tarlatamab-Related AEs Over Time  

The main side effects from tarlatamab other than CRS are pyrexia, decreased appetite and dysgusia is a big one.

 

These patients just cannot find anything that tastes good, so it is not that they do not want to it is not that they are losing weight because they are wasting. It is not cachexia, but it is that nothing tastes good, and so they do not eat as much, which is tragic because otherwise they feel pretty darn good on this medicine.

 

These 2 side effects are new for solid tumor oncologists so we will talk about management of either 1 for just a minute.

 

[01:21:56]

 

Pretest 3: For a patient with recurrent SCLC receiving a DLL3 x CD3 bispecific antibody with grade 2 CRS with fever and hypotension, which of the following initial management steps would you recommend?

 

In a patient with recurrent small-cell receiving a bispecific antibody with grade 2 CRS meaning fever and hypotension, which of the following would be the initial management step you would select?

 

1. I would give anakinra or siltuximab;
2. I would give dexamethasone and IV fluids;
3. Dexamethasone and anakinra;
4. Dexamethasone and tocilizumab.

 

Okay. A little bit of an across the board. Actually, you guys would just throw dexamethasone, tocilizumab, siltuximab. Actually, the front line for tarlatamab is just dexamethasone.

 

Now grade 2 CRS, meaning hypotension, definitely would give fluids. But the take-home point and something I want you to walk out of here with is for the very most part you can treat all tarlatamab side effects with dexamethasone.

 

CRS and ICANS With Bispecific Antibody Therapy: Grading and Management

 

[01:23:25]

 

Practical Considerations on Dosing Tarlatamab  

Here we have the practical considerations for dosing. We talked about the dose and schedule, but it is outlined in the top right box.

 

So patients get weekly therapy for the first cycle. Day 1, day 8, and day 15. And then the treatment goes to once every other week. And it is again 1 and then 10 mg to follow.

 

[01:23:56]

 

DeLLphi-303: Tarlatamab + PD-L1 Inhibitor as First-line Maintenance in ES-SCLC  

So just finishing up quickly with the ongoing tarlatamab trial slot schemas that may change our standard of care. DeLLphi-303 is tarlatamab and a PD-1 inhibitor as first-line maintenance.

 

I have learned today actually that this trial is fully enrolled. Amazing how fast this trial has gone. This is the phase I trial that showed that you could do this. And so both atezolizumab and durvalumab were used. Importantly, again, these little graphs show that the CRS is happening in the first week and the second week of cycle 1. And likewise, and that was whether you added the tarlatamab to the atezolizumab or added durvalumab to the tarlatamab.

 

And so actually durvalumab was picked as the partner for further trials.

 

[01:25:20]

 

ASTCT Consensus CRS Grading  

And just a reminder, you can see in Clinical Care Options, you can look up the grading of CRS. However, really grade 1 CRS is a fever without hypotension, without hypoxemia. We manage that every day, all day long, in our clinics for which we would give Tylenol. Grade 2 is hypotension in combination with fever not requiring vasopressors or hypoxemia and fever requiring nasal cannula but not high flow oxygen. So you can see here that a lot of these things we manage in the clinic even though the CRS that we are accustomed to seeing with CAR T-cell therapy for example is much more in the grade 2/3 range where you have got hypoxia, hypotension, and fever happening repeatedly to patients where an intensive hospitalization would be more necessary.

 

[01:26:26]

 

Consensus Guidelines: CRS Management  

So here is a consensus guideline for a patient that has been treated with tarlatamab that is at home with a fever grade 1 or a fever with hypotension or hypoxia. You might be able to treat at home with oral hydration, checking vital signs regularly. With either hypotension and certainly with hypoxemia, however, a health system evaluation is a good idea even if it is just in the ER to probably give dexamethasone and use supplemental oxygen. Typically, that reverses within 24 hours.

 

For the sake of time I am eating into the next section, so I will just finish quickly with the ongoing trials.

 

[01:27:14]

 

DeLLphi-305: Tarlatamab ± Durvalumab as First-line Maintenance in ES-SCLC  

Tarlatamab and durvalumab in frontline maintenance was the trial that I mentioned that is closing because it is accrued fully, and so we will wait for maturity of this trial.

 

[01:27:28]

 

DeLLphi-304: Tarlatamab vs SoC in SCLC Following Progression on Platinum-Based Chemotherapy  

DeLLphi-304 is another trial that is tarlatamab vs standard of care in patients with small-cell lung cancer who have progressed on platinum.

 

[01:27:45]

 

And this is the trial that will also be reported on Tuesday. Tarlatamab we know from a press release has been reported to significantly improve overall survival, and so we really look forward to the results of this trial that, we think, will substantiate the use of tarlatamab in the second-line.

 

[01:28:04]

 

Summary Data for FDA-Approved Agents for Relapsed ES-SCLC  

So in summary, here are the drugs and the data that we have discussed tonight.

 

[01:28:15]

 

Patient Case 2: Relapsed ES-SCLC After Initial Response to First-Line Therapy  

And just to revisit our case of this platinum-resistant patient with recurrence.

 

[01:28:23]

 

Posttest 2: Which of the following systemic treatment options would you select for this platinum-refractory patient?

 

What would you now choose as the second-line option for this platinum-refractory patient?

 

All right. Excellent. We have got improvement. The right answer is lurbinectedin and/or tarlatamab, and we would use dexamethasone to treat our grade 2 CRS.

 

[01:29:08]

 

Conclusions  

So in summary, lurbinectedin is a new maintenance option can also be used in the second-line. Tarlatamab is a new second-line option for patients with small-cell and with both of these options we are able to prolong disease-free recurrence in our patients with extensive-stage small-cell beyond the second year.

 

So thank you very much.

 

Mastering the Evolving Treatment Paradigm in SCLC: Charting the Course for the Future in SCLC

 

[01:29:38]

 

Dr Ticiana Leal (Georgia Society of Clinical Oncology): Okay. So I will dive right in to the future in small-cell lung cancer and certainly Melissa gave us an overview of the current ongoing phase III trials, and we will talk about early phase trials in small-cell lung cancer in future directions.

 

[01:29:54]

 

Patient Case 3: 72-Yr-Old Woman With Shortness of Breath and Chest Pain  

So let us first start with our patient.

 

This is a 72-year-old female, shortness of breath and chest pain who presented with an irregular heart rhythm and decreased breath sounds in the left lower field. No significant laboratory abnormalities except you do see here that there is hyponatremia and elevated alk/phos which is not unusual for our patients who present with small-cell lung cancer.

 

[01:30:17]

 

Patient Case 3: Staging Workup With PET/CT  

This patient was admitted but ultimately underwent a PET scan which demonstrated a left suprahilar mass, a left upper lobe pulmonary mass concerning for lung cancer with FDG avid pleural mets as well as multiple osseous lesions consistent with metastasis.

 

[01:30:34]

 

Patient Case 3: Clinical Course  

This patient underwent a left thoracic synthesis with drainage of 1,600 ml and the cytology showed suspicious cells, bronchial and EBUS was done showing small-cell lung cancer. The brain MRI was negative for metastatic disease.

 

[01:30:48]

 

Poll 4: Considering current guidelines and clinical evidence, which of the following options would be an optimal treatment for this patient?

 

So thinking about our current guidelines and clinical evidence of what you heard, which of the following options would be an optimal treatment for this patient, and this is what is your preferred strategy?

 

1. Cisplatin/etoposide;
2. Carboplatin/etoposide/PD-L1 inhibitor;
3. Carboplatin/etoposide/PD-L1 inhibitor/CTLA-4 inhibitor; and then
4. Clinical trial with carboplatin/etoposide/PD-L1 inhibitor and a T-cell engager.

 

Okay, so 63% said PD-L1 inhibitor, 26% decided to go with the clinical trial.

 

[01:31:43]

 

Pretest 4: Which of the following outcomes was reported from the Phase II IDeate-Lung01 trial evaluating ifinatamab deruxtecan (I-DXd) in patients with previously treated extensive-stage SCLC?

 

Okay, our next one. Which of the following outcomes was reported from the phase II IDeate-Lung01 trial evaluating I-DXd, an antibody drug conjugated in patients with previously treated extensive-stage small-cell lung cancer?

 

1. An overall response rate of 50% at a dose of 12 mg/kg;
2. A median PFS of 12 months at a dose of 12 mg/kg;
3. Minimal evidence of CNS activity at any tested dose; and
4. No evidence of ILD/pneumonitis at any tested dose.

 

Okay, overall response rate of 80% Okay.

 

[01:32:44]

 

DLL3 T-Cell Engagers in Development  

So let us talk about DLL3 T-cell engagers in development. Here I have included the ones that are in clinical development at various stages of development, still including tarlatamab here because as you saw from Melissa's talk, tarlatamab is still in development in terms of moving up to earlier lines of therapy including the first-line maintenance setting and other strategies as well.

 

Obrixtamig is another T-cell engager that is bispecific targeting CD3 and DLL3 that is in development. And then MK-6070 which a trispecific T-cell engager targeting here CD3 on the T‑cell, DLL3 on the cancer cell, and then the anti-albumin domain for half-life extension. And then the QLS31904 the status of this 1 is currently unknown on clinicaltrials.gov, but we also have the RO7616789, which is a trispecific here targeting DLL-3 on the cancer cell and then CD3 and CD137 binding domains.

 

[01:33:45]

 

Obrixtamig (BI-764532), a DLL3/CD3 Bispecific Antibody in DLL3-Positive Tumors  

Our first study to review is the early phase study of obrixtamig, which is a DLL-3, CD3 bispecific antibody, and the strategy here in the first in-human study was to include patients with positive DLL-3 on tissue. The study also included the stepwise dosing approach during the first 3 cycles to reduce the risk of CRS and infusion-related reactions, and the primary endpoint here is MTD.

 

This study is actually still ongoing, but as you can see here, at the time of this reporting, which was WCLC 2023, there were 168 patients, and of these, they had 49% with small-cell lung cancer, but they also took the strategy of including other high-grade neuroendocrine cancers, such as extra-pulmonary neuroendocrine carcinomas of different primaries, and then large-cell neuroendocrine carcinoma, so 42% and 8% respectively, and again, the majority of these patients were heavily pretreated, with 51% also receiving prior PD-1/PD-L1 therapy.

 

[01:34:49]

 

Phase I Study of Obrixtamig: Responses  

And overall, the response rates here are about 18% in this early-phase study, but this data set is actually still evolving, and we will hear more. We actually saw higher response rates presented at WCLC last year in the large-cell neuroendocrine carcinoma population, but the numbers are still small.

 

[01:35:07]

 

Phase Ib DAREON™-9: Obrixtamig + Topotecan in R/R SCLC After Platinum-Based CT (Interim Analysis)  

Additionally, we are seeing now obrixtamig in combination with topotecan in the Phase Ib, DAREON-9. This is actually presented today by Dr Wermke, and it actually showed very promising response rates in patients in the dose escalation. What we are seeing here is an unconfirmed response rate of 70%, confirmed response rates of 69%, the disease control rate of 87% and a median duration of not reached. The related adverse events related to obrixtamig, 92% of any-grade, 20 or 8% grade 3 or higher, no grade 5 AEs, and then topotecan-related AEs, 84% grade 3 or higher.

 

The rates of CRS here seem consistent with the monotherapy experience. I think overall, in my opinion, as we move tarlatamab and drugs like obrixtamig in earlier phases of development, I am not sure this combination will hold, but to me, this was interesting to think about as we have ADCs targeting TOPO1. Is this finally an opportunity to get rid of carboplatin-etoposide in the frontline if this really continues to look this favorable in terms of these responses and the median duration of response with further follow-up if it is promising?

 

[01:36:24]

 

Phase I DAREON™-8: Obrixtamig + SoC for ES-SCLC  

We also have the Phase I DAREON 8 study. This is now moving obrixtamig to the frontline standard of care for extensive-stage small-cell lung cancer. This is an ongoing international open-label dose escalation and dose expansion trial of IV obrixtamig in combination with carboplatin-etoposide and atezolizumab, and it is currently in dose escalation with the primary endpoint here of safety and DLTs.

 

[01:36:51]

 

Ongoing Trials of Obrixtamig in SCLC and Other NETs  

There are multiple ongoing strategies for obrixtamig, not only in small-cell lung cancer, but I think also really important for these other extrapulmonary neuroendocrine carcinomas as well as large cell neuroendocrine carcinomas.

 

[01:37:05]

 

First-in-Human Phase I/II Trial of Gocatamig (MK-6070) in Patients With SCLC and Other Neuroendocrine Cancers  

Another strategy has been the TRITE, which we talked about before, the MK-6070, which is an agent that is also currently in Phase I in development, and as you can see here, it is also being investigated in small-cell as well as other neuroendocrine cancers, and here the strategy is investigating the DLL3 expression as a predictive biomarker for the other neuroendocrine cancers, given that it is so highly expressed in small-cell lung cancer. With the coprimary endpoints here of safety and tolerability, and pre-limb antitumor activity.

 

[01:37:38]

 

Phase I/II Trial of Gocatamig (MK-6070): Efficacy/Safety Summary  

And again here we are seeing promising response rates of 39% in 28 patients, and the other neuroendocrine neoplasms, 46%. Again, the tolerability here is similar to what we have seen with the other T-cell engagers, with the most common side effects being consistent with the mechanism of action of this agent, and again, this does require priming doses to reduce the risk of CRS.

 

[01:38:00]

 

Phase I/II Trial of Gocatamig (MK-6070): CNS Antitumor Activity  

There is also some preliminary antitumor activity in the brain. In patients with a history of brain metastasis, they actually saw a median time to CNS progression of 3.1 months, and a medium time on treatment of 6.3 months, and they actually saw PR with CNS progression in 4 patients of 14%, and a CR in the brain of about 25%, and no progression in 24 patients without history of brain metastasis. So this was an exploratory analysis, again, suggesting here some preliminary activity of MK-6070 in the brain.

 

[01:38:35]

 

Future Directions: Phase Ib/II Trial of Gocatamig (MK-6070) Plus I-DXd  

Future directions of MK, there is an ongoing international study evaluating the safety of efficacy of MK-6070, now in combination with an ADC, I-DXd, that we will talk about further.

 

[01:38:51]

 

ADC Mechanism of Action  

And that leads us to talking about ADCs, another promising class of drugs that we are seeing in multiple tumor types, approved in other tumor types, moving along also in development in small-cell lung cancer. So an ADC basically has an antibody that binds to a highly expressed antigen on the surface of the tumor cells, forming a complex, and then after binding, this is internalized, processed, and releasing the ADC payload. And the classical mode of action is cytotoxicity, but there can also be bystander killing effect.

 

[01:39:24]

 

Select ADC Targets Under Investigation in SCLC  

And there are multiple ADC targets under investigation in small-cell lung cancer, and here we are showing some of the ones that are in development for small-cell lung cancer with the target of B7H3 for I-DXd, as well as HS20093. TROP2 with sacituzumab govitecan, moving along in development. Rova-T was a DLL3-targeting ADC that was initially developed, and although promising, the development was hampered by toxicity, but this remains an important target, and there are other ADCs beyond Rova-T that are currently in development in very early phase for DLL3 as well. And then lastly, the SEZ6 target here with development of ABBV-706.

 

[01:40:10]

 

Summary of ADCs in SCLC  

So here is a summary of the data that we have seen for these ADCs in small-cell lung cancer. The first one in the column is I-DXd, and I will show you the early phase data for the 12 mg/kg dose, and we are seeing here the target of B7H3 with, again, across the board, really high response rate, 54.8% for I-DXd, for HS-20093, 61.3%, for SG, 35% in the resistant population, 47.8% for the sensitive population, and then 61% for ABBV-706. Again, high response rates, which we have seen before in small-cell lung cancer, but really the question is, is there durability in this response? Will there be a benefit in longer-term, including median PFS and OS? And some of these are tracking along with promising median duration of response, as you are seeing here in this table, with deferring toxicities depending on the payload.

 

[01:41:09]

 

IDeate-Lung01: I-DXd in Patients With Pretreated ES-SCLC  

So the first study that I want to highlight is IDeate-Lung01, which is the I-DXd B7H3 targeting ADC, and in this open-label randomized Phase II study, patients that had 1 or more prior line of therapy, including platinum-based chemotherapy, and 3 or fewer lines of systemic therapy, good performance status, asymptomatic brain metastasis were allowed, they had a dose optimization of I-DXd at 8 mg/kg IV every 3 weeks, or I-DXd at 12 mg/kg IV every 3 weeks, with the primary endpoint of overall response rate.

 

[01:41:43]

 

IDeate-Lung01: Efficacy With I-DXd  

And here what it showed was very promising overall response rate. We are seeing here the response rate, most promising in I-DXd 12 mg/kg, with a confirmed overall response rate of 54.8%, and a disease control rate of 90.5%, which is the dose chosen for further development of I-DXd in future studies.

 

[01:42:05]

 

IDeate-Lung01: Intracranial Efficacy  

Also, here, showing here some promising CNS overall response rate, in the subset of patients with brain target lesions with I-DXd at 12 mg/kg, a confirmed CNS overall response rate of 50%.

 

[01:42:20]

 

IDeate-Lung01: Safety Summary  

And the safety summary here demonstrating that when you use the 12 mg/kg, you are seeing a bit more toxicity. However, the rates of grade 3/4 toxicities actually were relatively low. So again, I think, thinking about risks and benefits, the 12 mg/kg was the 1 chosen for development.

 

The most common side effects, mostly grade 1/2, have been nausea, decreased appetite, anemia, neutropenia, and fatigue. We are also seeing ILD or pneumonitis. However, as you can see here, low rates of grade 3 or higher pneumonitis, but something to monitor patients for.

 

[01:43:01]

 

IDeate-Lung02: Relapsed SCLC After 1 Prior Line of Platinum-Based Therapy  

And this is now the IDeate-Lung02. This study is in relapsed small-cell lung cancer after 1 previous line of platinum-based therapy in documentation of progressive disease. Patients here are randomized to I-DXd at 12 mg/kg IV every 3 weeks.

 

And then the standard of care arm allowing investigators' choice of the regimens that are noted here, topotecan, amrubicin, or lurbinectedin. And the coprimary endpoints here are overall response rate and overall survival.

 

[01:43:31]

 

ARTEMIS-001: HS-20093/GSK5764227 in ES-SCLC  

The next agent is ARTEMIS-001, the study, investigating HS-20093, another agent targeting B7H3.

 

And here in this dose expansion and dose escalation study with a primary endpoint of overall response rate.

 

[01:43:48]

 

ARTEMIS-001: Response in SCLC  

Again, showing high response rates, response rates in the order of 50-60%.

 

[01:43:51]

 

ARTEMIS-001: Safety in SCLC  

And in terms of the toxicities here.

 

Again, related to the payload, we are seeing myelosuppression as the main toxicity. And some of these, for example, in the 10 mg/kg, high rates of myelosuppression, grade 3 or higher.

 

[01:44:07]

 

Future Directions: Phase III Trials of HS-20093  

These are the future directions of HS20093. So there is an ongoing study comparing to topotecan and also another study in the limited-stage setting, including HS-20093 vs active surveillance, which may be outdated now that we have the approval of durvalumab.

 

[01:44:26]

 

TROPiCS-03 ES-SCLC Cohort: Study Design  

The next one is now exploring sacituzumab govitecan in this Phase II study, looking at the primary endpoint of overall response rate.

 

[01:44:33]

 

TROPiCS-03 ES-SCLC Cohort: SG After Platinum-Based Chemotherapy and Anti‒PD-1/PD-L1 Therapy  

Showing here an overall response rate of 41.9%, a median duration of response of 4.7 months, the median PFS of 4.4 months, and a median overall survival in a heavily pretreated population of 13.6 months, where we generally see survival of less than 6 months.

 

[01:44:51]

 

TROPiCS-03 ES-SCLC Cohort: Safety  

Thinking about the safety, in terms of the safety of the grade 3 or higher, treatment-emergent adverse events were 74.4%, serious treatment-emergent adverse events were 51.2%, leading to dose reduction, 37.2%. When you look at the grade 1/2, the majority of them were actually grade 1/2 in nature, and the most common ones are diarrhea, fatigue, and you are seeing constipation and nausea. So, GI side effects are the most common ones. And then, importantly here, with sacituzumab govitecan, there is no reported ILD or pneumonitis.

 

So kind of a differential here on this TROP2 ADC.

 

[01:45:31]

 

Future Directions: Clinical Trials of SG  

So future directions, there is an ongoing frontline study of chemo plus pembro, followed by pembro plus SG, and the EVOKE small-cell lung cancer 04, which is a Phase III study of SG vs standard of care and second-line extensive-stage small-cell lung cancer.

 

[01:45:46]

 

Phase I Study of ABBV-706 in SCLC  

The last 1 is ABBV-706 in small-cell lung cancer.

 

Again, this is also an early development in the Phase I study, and here the payload is also a TOPO1 inhibitor.

 

[01:45:58]

 

Phase I Study of ABBV-706: Efficacy  

And what we are seeing here, again, high response rates of 60.9%, and the majority of these patients were highly pretreated.

 

[01:45:05]

 

Phase I Study of ABBV-706: Safety  

I think it is important to note, again, that we do need further follow-up to really understand sort of the durability of these responses, which typically have correlated with longer-term outcome for small-cell lung cancer.

 

And in terms of the grade 3 or higher treatment emergent-adverse events, 77% with the most common ones being anemia and fatigue. The MTD was 3 mg/kg, and the most common serious adverse events are pneumonia and disease progression, which is obviously unrelated to the treatment.

 

[01:46:33]

 

Targeted T-Cell Engagers and ADCs in ES-SCLC: Takeaways  

So my takeaways from the development of T-cell engagers and ADCs in extensive-stage small-cell lung cancer is that the bispecific and trispecific T-cell engagers have demonstrated antitumor activity in small-cell, and also in other DLL3 positive malignancies, including large-cell neuroendocrine carcinoma, which has been a disease that has been typically understudied.

 

The frontline setting has the potential to shift by adding these T-cell engagers, not only as first-line maintenance, but perhaps seeing them to shift to the frontline. And ADCs are promising as a therapeutic strategy. However, it is important to understand target expression and how to optimize that in terms of not only sequencing, but perhaps which one is best for each patient.

 

Thank you very much.

 

[01:47:25]

 

Pretest 4: Which of the following outcomes was reported from the Phase II IDeate-Lung01 trial evaluating ifinatamab deruxtecan (I-DXd) in patients with previously treated extensive-stage SCLC?

 

So let us go back to our posttest. Which of the following outcomes was reported from the Phase II IDeate-Lung01 trial evaluating I-DXd in patients with previously treated extensive-stage small-cell lung cancer?

 

5. An overall response rate of 50% at a dose of 12 mg/kg;
6. A median PFS of 12 months at a dose of 12 mg/kg;
7. Minimal evidence of CNS activity at any tested dose; and
8. No evidence of ILD/pneumonitis at any tested dose.

 

Excellent, we had a little bit of an increase. That was correct, overall response rate of 50% at the dose of 12 mg/kg. 81.8%, doing better.

 

[01:48:43]

 

Poll 5: Do you plan to make any changes in your clinical practice based on what you learned in today's program?

 

Do you plan to make any changes in your clinical practice based on what you learned in today's program?

 

1. Yes;
2. No;
3. Uncertain.

 

[01:49:19]

 

Poll 6: Please take a moment to enter 1 key change that you plan to make in your clinical practice based on this education.

 

And then please take a moment to enter 1 key change that you plan to make in your clinical practice based on this education.

 

Okay, now we will move on to Q&A.

 

Q&A

 

Dr Socinski: I wanted to ask Melissa a clarification. I am under the impression on the IMforte trial that those survival figures are from the time of maintenance.

 

Dr Johnson: I believe you are right. Did I explain it wrong?

 

Dr Socinski: No, I do not think you did. However, the difference of, I think it was 10-13 months.

 

Dr Johnson: Is from the time of maintenance, yes.

 

Dr Socinski: So you can add another, at least 3 months to those figures. So with the maintenance, I do not think I have ever seen an extensive-stage small-cell lung cancer median survival of 16-17 months, right?

 

Dr Johnson: Right.

 

Dr Socinski: So I think that that is quite remarkable. We have questions from the audience. We have a couple of minutes, I think here, about 10 minutes or so for questions.

 

We will have a microphone. Yes, we have a question here.

 

Speaker: [Inaudible 01.50.45 – 01.50.55]

 

Dr Leal: Well, not at this point, in my opinion. However, you know, if you saw the poster today by Wermke, which was looking at topotecan, which has a TOPO1 payload in combination with obrixtamig, it looked very promising with response rates of 70%. And the duration of response was not estimated.

 

So at this point, no. However, I think as we move these T-cell engagers, if they really move up to frontline, you know, topotecan, etoposide, these are all TOPO1 inhibitors. So if the combination is strong enough and if there is synergism, perhaps with more data, that could be a possibility.

 

Again, it would have to also be sort of in light of what the toxicities are. Topotecan, I think, is a more toxic drug in terms of myelosuppression. However, perhaps a better tolerated ADC could offset that toxicity and be a gain. So we will have to see. Right now, premature.

 

Dr Johnson: I think the I-DXd progression-free survival is just shy of 6 months. And so the idea of I-DXd taking the place of etoposide, which is in the design of a lot of the current ongoing trials, is an interesting and provocative question.

 

We have been giving carboplatin and etoposide for 30 years. And so to what degree the carboplatin vs the etoposide is responsible for the response rate of 70% and the PFS 6 months or more, I do not know. So it is a provocative question. And I think Ticiana's point is a good one that the hypothesis of a T-cell engager added to the ADC, the T-cell engager will give the duration and the ADC will give the early response.

 

Dr Leal: And I think it is also important to note as we move these therapies to earlier stages, we are piling 4 drugs. And carboplatin-etoposide by itself is pretty myelotoxic. There are risks associated with that.

 

I think what are the drugs that are really going to drive the survival? The high response rate is really important in first-line when you think about how symptomatic patients are. They get that symptomatic relief. However, what you really need is the durability of that response that will translate into overall survival. And carboplatin etoposide is not able to do that. We know that.

 

So if we move the T-cell engager to frontline, we have to think about which combinations will provide that longer-term survival, but also importantly reduce the toxicities. Because I think it is really hard to pile multiple drugs in a very sick patient with small-cell lung cancer. And think about these are trial patients.

 

The patients that we really see in clinical practice may have multiple comorbidities. They may be older, they may be more frail. And the challenge of 4 drugs in an older patient that is frail is a different, I think, clinical situation that we will still have to encounter depending on how these approvals happen.

 

Speaker: Yes, I have a question. Thank you. What bothers me is both cystisplatin and etoposide are very immunosuppressive.

 

So essentially, you are giving this drug for 4 or 6 cycles, you really beat down the patient's immunity. So you put the patient not in a favorable position to get like a T-cell engager. I wonder because right now, all the T-cell engager data is after using the second-line, after cystisplatin and etoposide.

 

So if you move the T-cell engager to the front line, I wonder whether the response or duration response will be better.

 

Dr Leal: Yes, I think that is an important question. Thankfully, the addition of immunotherapy did not add to the myelosuppression and the T-cell engagers overall seem to have low rates of myelosuppression. So the toxicities are not overlapping.

 

However, I do think that, again, people have to have a healthy immune system to be able to respond to these therapies.

 

Dr Johnson: There is an interesting phenomenon we noticed in the Phase I trial with the DLL3/CD3 bispecifics where the immune system and in particular the neutrophils will extravasate out of the blood. So it looks like you have this transient drop in your neutrophil count, but it is really just the T-cells. Or we like to imagine it is the immune cells tracking to the cancer and has not been associated with febrile neutropenia or the other things that we associate with carboplatin and etoposide.

 

Dr Socinski: Other questions? There are a few questions here. We can answer one of them if we can remember the design of the ADRIATIC trial because the question is, if you use durva's consolidation treatment after in limited-stage disease, what is the best time for the PCI?

 

The best time would be how they did it in ADRIATICs, but I cannot remember.

 

Dr Johnson: PCI was allowed.

 

Dr Socinski: Yes.

 

Dr Johnson: And I think it happened before the durva was initiated.

 

Dr Socinski: So you are really going to have to be coordinated with your radiation oncologist because they had to start it within 42 days, right?

 

Dr Johnson: Yes.

 

Dr Socinski: On Adriatic. So yes, it requires collaboration, communication, coordination.

 

Dr Johnson: And PCI can take 3 weeks.

 

Dr Socinski: Right.

 

Dr Johnson: So it is not just one dose of SBRT.

 

Dr Socinski: Right. Another question we had, none of us are radiation oncologists. I consider myself or did consider myself an amateur radiation oncologist early in my career.

 

The thoracic radiotherapy that I was referring to, the question is, was it SBRT? Was it targeted radiotherapy? In the data that I showed looking at the thoracic radiotherapy, I do not think that was the case.

 

In fact, I know it was not the case. What would SBRT be used for? What situations it would be used for? I can imagine there might be situations where you would do SBRT as thoracic radiotherapy, but again, I am not, I do not have the expertise to know.

 

Dr Leal: However, even in the RAPTOR trials, the NRG trial, they are using in that experimental arm, the thoracic radiation or radiation to residual disease in combination with IO, but they are using lower doses than SBRT. So right now, SBRT I think would be more for palliative purposes, for like bony sites of metastatic disease, not really to the chest. And I do think there needs to be some concern there of synergizing immunotherapy with thoracic radiation using high doses of having toxicity.

 

We have also seen some trials in small-cell when you use IO plus radiation to the chest that you could have significant toxicity as well.

 

Dr Socinski: There is one other question, and I guess we would be fortunate if we were in this situation.

 

So if you use durvalumab for limited-stage disease, and we would give it for 2 years. If that patient relapsed afterwards, what would you do? Let us say they relapsed a year later.

 

Dr Leal: A year after stopping durvalumab?

 

Dr Socinski: Yes, so 3 years later.

 

Dr Leal: I think I would retreat.

 

Dr Socinski: With carboplatin.

 

Dr Leal: Carboplatin-sensitive, and IO-sensitive potentially.

 

Dr Socinski: Yes, so go back to the first-line.

 

Dr Johnson: Yes, I might use the other, if I had used durvalumab before, I might use atezolizumab.

 

Dr Socinski: Did you read the question? Because they asked if you would switch to atezo.

 

Dr Johnson: For no reason other than it just would treat my anxiety.

 

Dr Socinski: Okay.

 

Dr Leal: I do not necessarily think I would propose a switch, but I guess I think it depends on where the data is. However, I think, thinking about immunotherapy resistance in small-cell is actually something that is going to be very relevant as we move these regimens. Yes, that is a good point.

 

Dr Johnson: Yes, that is a good point.