Current and future directions in small cell lung cancer (SCLC) clinical management — Dr Rudin

DR RUDIN: Today I’m really happy to present a little bit on current and future directions in the management of small cell lung cancer.

Of course, the biggest advance in small cell lung cancer has been the introduction of immunotherapy into our first-line treatment for extensive-stage small cell lung cancer. And this is largely based on 2 studies, the IMpower133 trial that added the PD-L1 inhibitor atezolizumab to standard carboplatin and etoposide. And then in the subsequently published CASPIAN trial, very similar in design in that it added a PD-L1 inhibitor, in this case durvalumab, to platinum/etoposide, again, for first-line treatment of extensive-stage small cell lung cancer.

We’ll go through some of the differences between these trials, but you can see the outcome is very, very similar with the blue curves representing the addition of PD-L1 inhibitor to prior standard of care, and the other curves representing platinum/etoposide. Both curves demonstrating a statistically significant superiority in overall survival for the addition of a PD-L1 inhibitor here.

So, let’s think about these 2 trials and think about a few of the similarities and differences between then. They’re both designed as first-line extensive-stage studies looking at platinum/etoposide with or without the addition of a PD-L1 antibody as immunotherapy. Importantly, they’re both positive Phase III practice-changing studies with an overall survival endpoint and both led to FDA approvals in this space.

The differences between them, a few of the key differences I’ve indicated here, the CASPIAN trial allowed asymptomatic, untreated brain metastases –– patients with those asymptomatic brain metastases to enroll on trial. The IMpower133 trial did not. They required patients who had a brain metastases to have that treated and stable prior to enrollment.

The CASPIAN trial also allowed dealer’s choice for the clinician in terms of the platinum. You could choose carboplatin or cisplatin. This may not be as relevant for the United States practitioners but it is important around the world where cisplatin may be the preferred agent for financial reasons. And the most important difference probably is CASPIAN was actually a 3-arm trial looking at chemotherapy alone versus chemotherapy with durvalumab, the PD-L1 inhibitor, or chemotherapy with both durvalumab and tremelimumab, the CTLA4 inhibitor.

This is the design of the CASPIAN trial with a little bit more detail in terms of the enrollment criteria, again patients with asymptomatic stable brain metastases were allowed. Good performance status was required on both trials. These are the 3 arms. And in all of these trials the immunotherapy was combined in combination with the platinum/etoposide but then also continued thereafter with the arms reflected here.

The third arm in the CASPIAN trial actually was not a success, so this is updated data from ASCO 2020, showing the 3 arms of this trial in terms of overall survival. The red curve is the control arm of platinum/etoposide and the dark blue is the successful arm with the addition of durvalumab. The arm that included durvalumab and tremelimumab is the light blue arm in the center here. And as you can see, it doesn’t separate as well from the red curve. Ultimately, the benefit of addition of durvalumab is achieved on that arm, but there was more toxicity on that arm and it was not statistically superior to the control arm. So the success here was really the addition of durvalumab and the addition of a CTL4 inhibitor really did not help in terms of outcome.

I think an important lesson from both of these trials and also the KEYNOTE-604 trial which was very similarly designed with pembrolizumab, a PD-1 inhibitor in this space, is that although these changed the standard of care, the benefit is fairly minimal, that is about 10% of the patients seem to have durable response to these agents and really benefit from the addition of PD-L1 inhibitor in this context. But 90% of the patients really don’t benefit from this type of therapy. So, clearly, there’s plenty of room for improvement in the treatment of small cell lung cancer patients.

So first-line immunotherapy, good proof of principle. These drugs are important for us to think about in this context, but not good enough. And we need to think about where additional improvements might be made in the treatment of small cell lung cancer.

There’s also, of course, the immunotherapy trials in recurrent small cell lung cancer. And I’ll point out a couple of the important trials here. One was the CheckMate 032 trial that looked at nivolumab, a PD-1 inhibitor, with or without the addition of ipilimumab, another CTLA4 inhibitor. And here you can see similarly, I think about 10% of the patients really have durable benefit from either nivo or ipi/nivo together, but the majority of patients, unfortunately their disease progresses and they do recur.

Similarly, pembrolizumab has been looked at in recurrent small cell lung cancer in the KEYNOTE-028 and KEYNOTE-158 trials. These are combined data sets presented here. And again I’ll point out the flattening of the curve at about 10% of patients really having a durable response in terms of benefit in progression-free and overall survival, but the majority of patients recurring.

Both of these trials led to FDA accelerated approvals for pembrolizumab or nivolumab in third line and beyond for treatment of small cell lung cancer. One of the difficulties, you don’t really know what to do with those approvals now because of the introduction of immunotherapy into the first-line setting for small cell lung cancer. I think the probability of response to a PD-1 inhibitor in the context of a tumor that has progressed on PD-L1 inhibitor is pretty low. So I don’t know how much use these will actually get. I think the combination of nivolumab and ipilimumab remains interesting for patients with recurrent small cell lung cancer and may have a role. But we really need to look at that in the context of patients who have progressed on first-line therapy with immunotherapy.

So the challenges in terms of immunotherapy for small cell lung cancer, where we go from here? I think there are a number of options. And when we think about IO/IO combinations I would say one lesson from the CASPIAN trial again is that CTLA4 blockade was, overall, I think, a little bit disappointing. I didn’t point out the first-line trial that looked at an introduction of CTL4 inhibitor alone, but that trial was stone cold negative. So I don’t know that CTLA4 really has many legs here in terms of a target for intervention. But there are other immunologic targets that are relevant. TIGIT has raised a lot of interest now and there’s an ongoing clinical trial looking at that. And then there are other cell types that may have relevance in the immune system. NK cells, which may have an important role in the treatment of small cell lung cancer, or macrophages.

There’s also interest in combining immunotherapy with targeted therapies and those were included, in particular, DNA damage response inhibitors, where we know there’s potential sensitivity in small cell lung cancer. Those can also play a role in immune activation. And epigenetic priming may also be important for small cell lung cancer in terms of stimulating antigen presentation by the tumor for the immune system.

And finally, I think we really need to think about biomarkers of response. Who are those 10% of the patients who really benefit from immunotherapy? And who are 90% where we need to figure out better approaches?

One of the things we’ve been really interested in, in terms of thinking about small cell lung cancer is are there small cell lung cancer subtypes that have biological relevance? When we think about lung adenocarcinoma, of course, we think about mutationally defined subsets, EGFR, ALK, and others. It turns out small cell lung cancer doesn’t have that driver mutation directed subsets. But if you look at the RNA, if you look at expression, there are certain key transcription factors that seem to define difference subsets of small cell lung cancer and these include ASCL1, NEUROD1, POU2F3 and YAP1. And here, in a review that we published into 2019, we can see that these really differentiate 4 clear groups of small cell lung cancer. And we think that these subtypes of small cell lung cancer may have differential sensitivity to a number of targeted therapies. This represents a potential way forward for us in terms of targeted therapy for small cell lung cancer, which, of course, has never really been possible before.

The fourth subtype, this YAP1 subtype, it’s not clearly well defined, but there’s been recent studies and data presented by Taofeek Owonikoko at ASCO of this year suggesting that this YAP1 subtype has a T-cell inflamed signature and has upregulation of antigen presentation. This may be that 10% that actually responds well to immunotherapy. And I think that’s an interesting direction for us to begin looking at in terms of small cell therapies.

When we look at small cell under the microscope you don’t see a lot of T cells, but you see a lot of macrophages that infiltrate the tumor. And Julien Sage has shown in preclinical models of small cell cancer, that if you stimulate those macrophages by turning off this CD47 “don’t eat me” signal, that the macrophages will actually consume tumor and this can lead to really dramatic responses in preclinical models. Whether this hold up in the clinic is something that we think ought be looked at and may be a way forward for small cell lung cancer.

And finally there’s real interest in combining immunotherapy with DNA damage response inhibitors. This is data from Triparna Sen, a colleague of mine, now at Memorial Sloan Kettering. This is work that she did when she was with Lauren Byers at MD Anderson. Again, in preclinical models of small cell lung cancer where PD-1 blockade really has very little efficacy, a PARP inhibitor has very little efficacy, but the combination just flat lines these tumors. And Triparna was able to show that this is mediated through an important signaling pathway called cGAS-STING, which results in an inflammatory tumor that may react well to immunotherapy.

This is all in the preclinical space. We really need to see whether this will hold up in the clinic. The initial clinical testing of that concept combining a PD-L1 inhibitor with a PARP inhibitor, durvalumab and olaparib, in patients with relapsed small cell lung cancer, I would have to say was initially disappointing. This is data from Anish Thomas at the NCI looking at this combination. And yeah, there’s a couple of pretty dramatic responses here with a complete response. But really this is data that we might expect with durvalumab alone in this context.

So it’s not clear how to best combine these therapies, but I think this is an important area of research to keep an eye on.

So immunotherapy in small cell cancer, opportunities and challenges. I think first-line chemo/IO trials have shown consistence success. This is a critical milestone for the field. However, the durable benefit is really concentrated in a small minority of patients.

What are the biomarkers for this subset and how do we prime the other 90%? I think that’s an area of active, ongoing clinical research.

Preclinical research is defining new therapeutic strategies here. However, the preclinical models, as I’ve just shown you, are clearly imperfect predictors for clinical translation. And more research needs to go on in this space.

I want to talk just briefly about a new drug that just got an FDA accelerated approval in recurrent small cell lung cancer. This is a drug called lurbinectedin. This is a new drug that is actually a derivative from a sea sponge. It’s an alkylating agent and it binds in the minor groove of DNA. And there are multiple potential mechanisms by which this works. One important one, tumor intrinsic, is that it seems to inhibit certain transcription factors in binding to the DNA. And we know, again, as I showed you that small cell lung cancer falls into these subsets defined by transcriptional drivers. We think that lurbinectedin may interfere with this process leading to response in small cell lung cancer.

In addition, lurbinectedin may have effect on the surrounding microenvironment, including macrophage effect in the tumor that may be important.

In any case, lurbinectedin does show significant activity in patients with recurrent small cell lung cancer. This was a trial, single arm, Phase II trial, looking at 105 patients with recurrent small cell lung cancer. Lurbinectedin demonstrates an overall response rate of about 35%. And the overall survival here is reasonably impressive for patients with recurrent metastatic small cell lung cancer. And these data really led to the accelerated approval of this agent very recently in the United States.

Of course, our standard of care previously was topotecan for recurrent small cell lung cancer. One advantage of lurbinectedin over topotecan seems to be less heme toxicity. So if we compare lurbinectedin here to topotecan when it was used in the absence of GCSF for growth factor support, we can see much less anemia, leucopenia, and neutropenia and thrombocytopenia with lurbinectedin. Of course with growth factor support you can reduce the leucopenia and neutropenia of topotecan, but, still, lurbinectedin seems to have a favorable toxicity profile here with similar outcome in terms of survival.

And finally, I want to talk just briefly about some other targets that I think are of relevance in small lung cancer. Small cell lung cancer almost universally is deficient for p53 and Rb. And p53 and Rb, as you know, are key regulators of the cell cycle progression. And the loss of these 2 key checkpoint proteins really sets up small cell lung cancer to be susceptible to other checkpoint inhibitors in the cell cycle.

And there are a number of these that are now being explored in clinical trials and I’m just indicating a few of them here. There’s a lot of interest in PARP inhibitors in small cell lung cancer, not standard of care but I think a space to watch. And all of these targets may become relevant in the treatment of small cell lung cancer. All are in clinical trials now.

So there’s a lot of new targets in small cell lung cancer. I think in 2020 we really think there are several targets that may be important to explore. We’re interested in the epigenetic vulnerabilities in small cell lung cancer. EZH2 is an important target in small cell and there are others in this space.

DLL3 I didn’t really talk about today. It’s a cell surface protein that’s uniquely expressed in small cell lung cancer, really not expressed in normal tissue on the cell surface.

There’s a drug, a bispecific T-cell engager that’s in clinical trials that I think may show real promise in this space.

We’re really interested in immunotherapy, of course in this disease, and in all others. I think a key challenge here is thinking about how do we prime these tumors to respond to checkpoint inhibitors. There’s a number of opportunities there to explore the unique immunological landscape of small cell lung cancer.

And finally the cell cycle and DNA damage repair vulnerabilities in small cell lung cancer. I think there are unique opportunity here in tumors that really lack p53 and Rb and are kind of set up to respond to new sorts of agents.

So I’ll stop there.

Case: A man in his early 80s and a heavy smoker with extensive-stage SCLC and metastases in the liver and brain

DR RUDIN: I thought I would briefly go through a few small cell case scenarios and just present some of my thoughts about how we generally approach small lung cancer cell patients in the clinic. And I picked 3 of these that are sort of representative of different stages of disease.

The first one is the typical patient with extensive-stage small cell lung cancer. This represents about two thirds of all patients with small cell lung cancer, that is most patients present with metastatic disease at the time of diagnosis. So this particular patient, an 80-year-old, heavy smoker, presents with cough, dyspnea, weight loss. Typical presentation for lung cancer. No neurologic symptoms and a reasonably good performance status.

Staging workup in this patient demonstrates a bulky lung mass, mediastinal lymphadenopathy, evident liver metastasis, although small, a small brain metastasis without significant edema. And a liver biopsy is performed and it demonstrates small cell lung cancer.

This is a patient that I would typically treat with carboplatin, etoposide and one of the PD-L1 inhibitors, either atezolizumab or durvalumab. And it’s really dealer’s choice which of those to choose. I would choose carboplatin here. The patient is 80 years old. So, in general, in an elderly patient I would favor carboplatin over cisplatin, if possible.

Following completion of 4 cycles of combination chemotherapy and immunotherapy, I would continue the immunotherapy alone until the time of progression, if possible. Managing the typical toxicities associated with immunotherapy as we normally would with any other tumor type.

I think one of the considerations in extensive-stage disease is, is there a role for radiation? There were some trials that suggested radiation consolidative chest radiation after treatment with chemotherapy. I think that’s most important in patients who have primarily residual thoracic disease. This patient has a liver metastasis, brain metastasis. Typically I wouldn’t give chest radiotherapy to that patient. If it were patient that really had primarily chest disease and the rest of the disease really responded beautifully to first-line therapy, I think it would be a consideration, but we don’t really know how to integrate that data with now the use of immunotherapy in the first line setting, because the use of consolidative chest radiation was really done in trials that did not involve any immunotherapy.

The other thing that I’ll point out here is PCI, prophylactic cranial irradiation, which we use in small cell lung cancer, particularly for limited stage. Recent data from the Japanese really indicate that PCI for extensive-stage small cell lung cancer may not be a benefit. In my practice, and I think increasingly around the United States certainly, we’re not using a lot of PCI for patients with extensive-stage small cell lung cancer. The use of it has really been decreasing.

There are ongoing clinical trials to look at its role here. But I think as a standard of care, I’m kind of favoring not using it for my patients with extensive-stage disease.

Case: A man in his mid-50s with combined SCLC (limited stage)

DR RUDIN: The second case is the other scenario, limited stage small cell lung cancer. So this is a younger patient, a 55-year-old gentleman in my practice, a minimal smoker actually who presented with small volume hemoptysis. He’s got good performance status. No weight loss. Really minimal dyspnea on exertion. Staging workup revealed a 5-cm left upper lobe mass and associated reasonably bulky hilar and subcarinal lymphadenopathy. Biopsy by bronch at the Level 7 lymph node to the subcarinal space revealed a combined small cell lung cancer and adenocarcinoma. So this is a Stage IIIA tumor.

We would treat this with combined modality chemotherapy and radiation. We don’t yet have a role for immunotherapy in limited stage small cell cancer. Those trials are actually ongoing now and it may be in the future that we use immunotherapy in this context, but right now our practice would be to combine platinum/etoposide and radiation in this scenario.

We would generally use cisplatin in this patient for limited stage disease. That may be an advantage. He’s young. Can probably tolerate this. Good performance status. So that’s how we would approach this, platinum/etoposide with concomitant radiation, with the radiation introduced as early as possible into the treatment scenario. Usually starting in cycle 2.

There’s been data looking at twice-daily radiation and once-daily radiation. Our standard of care is twice-daily. I would say the data for both is similar in terms of outcome. And around the country many radiation oncologists are using once-daily just because that’s more compatible with their practice pattern. And that remains an open question, again one that’s being worked up in ongoing clinical trials.

Here we would consider the use of PCI. If a patient has good response to chemoradiotherapy in limited stage small cell lung cancer, they are potentially, in a curative scenario, 25% of those patients will be potentially cured with combined modality therapy. The brain is a sanctuary site where the tumor can hide out. And in this context, PCI has been shown to improve survival. So we would favor it in this context.

Case: A man in his mid-60s and a heavy smoker with resected Stage IA SCLC

DR RUDIN: The third scenario is an unusual one but occasionally occurs. This is a patient who was a heavy smoker, who happened to undergo CT screening and was found to have a peripheral spiculated lung mass. Initially, 0.6 cm, it was watched, but then 1 year later it has tripled in primary dimension at 1.8 cm now. Pretty suspicious and now showing up positive on PET scan. Staging workup reveals no distant disease. A mediastinoscopy reveals no involvement of the lymph nodes. And this patient’s suspected to have perhaps a lung adenocarcinoma. Undergoes lobectomy but surprisingly surg path reveals small cell.

So this is a patient who presents with a resected Stage IA small cell lung cancer. If this is non-small cell, we don’t do anything, right. We don’t offer adjuvant therapy for these very early stage patients. For small cell though I would. We don’t really have clear data here. There haven’t been randomized clinical trials, but this tumor is so frequently metastatic at the time of diagnosis that in my practice I would offer this patient 4 cycles of adjuvant cisplatin/etoposide therapy to try to minimize their risk of recurrent disease.

Of course, as I just pointed out, this is a little bit of a data-free zone, but I think in this context I would err on side of giving the chemotherapy. But prospective studies in this space have really suggested that the addition of adjuvant platinum/etoposide can dramatically alter the fate for these patients. So we would certainly offer it here.

And, Neil, I’ll stop there.

Clinical care of patients with combined SCLC; lineage plasticity and development of resistance

DR LOVE: A couple of follow-up questions to what you already presented.

Can you talk a little bit more about this entity, the second case scenario had a combined non-small and small cell and how you think through treatment?

DR RUDIN: So, sometimes we see combined histology tumors, small cell lung cancer, with one of the other non-small cell subtypes, and it can be any of them. You can have small cell with adeno. Small cell with squamous. Small cell with large cell neuroendocrine. All of these occur.

Our approach to that is really to treat for the more aggressive histology. So we treat with a small cell regimen in this context. And in this case we happen to have a patient who has a combined histology tumor. And if this were the third case scenario, that is a resected early stage, Stage I tumor, if this were combined, I would still give the small cell treatment. So combined histology we treat for the more aggressive histology, which is small cell.

DR LOVE: And just in terms of your vision, I guess nobody really knows, but do you envision that they’re 2 simultaneous tumors or some kind of mixed process? What do you think is going on?

DR RUDIN: That’s a great question. We’ve actually looked at this genetically and this is ongoing analysis, but we think these are 1 tumor that has multiple histologies. And this is what’s called lineage plasticity, where a tumor can adopt a neuroendocrine fate but also maybe an adenocarcinoma fate.

When we look at the genetics of those 2 tumors, they’re usually –– those 2 histologies –– they’re usually linked. They share mutational spectra. And so they’re really derivative from the same original tumor, just differentiating in two different ways.

It’s a little bit similar to the EGFR mutant adenocarcinomas that actually adopt a small cell histology as a mechanism of acquired resistance to EGFR TKI therapy.

DR LOVE: Oh, that’s interesting. Interesting analogy, yeah. I saw a bunch of papers that you did and all kinds of really interesting things. You mentioned lineage plasticity and all these other concepts I never heard about. I’m just kind of curious how you explain what it is that you’ve been trying to look at in terms of the biology? And what is this plasticity?

DR RUDIN: I think from the clinician’s perspective, the key thing here is how do tumors become resistant to the therapy that we’re trying to give them. We have a lot of therapies where we get great response initially, but then the tumor escapes. And how does the tumor escape?

In some cases, we know there are second mutations that occur that drive that escape. Again, EGFR, we’ll see the classic T790M resistance mutation to a first-generation EGFR TKI or C797S that’s a resistance mutation to osimertinib. Those are mechanisms that are mutational. But there’s also ways that tumors can evolve to become resistant. And this lineage plasticity, the shape shifting of tumors, is one way that we’re seeing a lot. Not only in lung cancer. We’re seeing this in prostate cancer where prostate adenocarcinomas are escaping, with neuroendocrine prostate cancer histology that’s really a lot like small cell lung cancer. So I think we’re going to be seeing a lot of this.

And in the more recent studies of tumors where we’re able to do sort of single cell analysis, we’re seeing that there’s a lot of heterogeneity in these tumors. And I think that allows these tumors to escape by a subclone that really has a very different appearance and different sensitivities to escape. That’s really what we mean by lineage plasticity.