Small Cell Lung Cancer: It’s a Time to Be Hopeful

It’s a time for patients with small cell lung cancer (SCLC) to be hopeful, as Amy C. Moore, vice president of global engagement and patient partnerships for the LUNGevity Foundation said. “There have been various reasons why we haven’t seen as many gains in this space,” Moore said. “I think it’s just a much different beast than non-small cell lung cancer (NSCLC) for a variety of reasons. But we’re more hopeful now than we’ve been in quite some time.”

For example, data from the phase 3 IMpower133 trial showed a five-year overall survival (how long patients lived following treatment, regardless of disease status) rate of 12% among patients treated with the immunotherapy Tecentriq (atezolizumab) plus chemotherapy.

“While that doesn’t sound like a very high number, for comparison, in patients receiving only chemotherapy, the overall survival is only 2%,” Moore noted.

The Food and Drug Administration (FDA) approved Tecentriq plus chemotherapy as a treatment for patients with extensive-stage SCLC in 2019 based on the results of IMpower133, which was followed by the FDA’s approval of the immunotherapy Imfinzi (durvalumab) plus chemotherapy for extensive-stage SCLC in 2020 based on findings of the phase 3 CASPIAN trial.

The research continues. The first patients were recently dosed in a phase 1/2 trial of the immunotherapy HPN328 and Tecentriq, while the FDA has also granted a priority review to a biologics license application for the immunotherapy tarlatamab for patients with advanced SCLC.

Moore discussed the science behind these treatments and explained why they represent a sea change for patients with SCLC as part of CURE’s “Speaking Out” series.

Q:What should patients with SCLC know about the current advancements in research for treatments?

A: Small cell lung cancer is one of the two main types of lung cancer, accounting for about 15% of all lung cancer diagnoses. And historically, it’s been more difficult to treat. For decades, we didn’t have a lot of options to offer patients with lung cancer. Chemotherapy was kind of the standard approach to managing that diagnosis. But we’ve seen a lot of recent progress that offers hope for patients who are diagnosed with small cell lung cancer.

Q: What are some trials that patients should be providing particular attention to and why?

A: There’s one called IMpower133, which [was] a study looking at the use of an immunotherapy drug called [Tecentriq] in combination with the platinum-based chemotherapy carboplatin or cisplatin that’s typically been used for treating small cell lung cancer along with a [chemotherapy] drug called etoposide. ... So, we’re starting to see some gains in survival, a durable survival benefit in some patients with small cell who are receiving that combination of immunotherapy and chemotherapy. One of the challenges with that study is that we can’t yet predict who those patients are who are going to derive that benefit.

That’s an area of ongoing investigation by researchers: Are there specific biomarkers that may predict who will get the most benefit from the addition of immunotherapy to their treatment regimen?

Another similar study is the CASPIAN study, which evaluated the use of a drug called [Imfinzi] in combination again with platinum-based chemotherapy, compared to patients receiving chemotherapy only. What they found in that study is that there were three times more survivors at three years in the [group of] patients receiving immunotherapy in combination with chemotherapy compared to the patients receiving chemotherapy alone.

In both these studies, IMpower133 and the CASPIAN study, they’re looking at the combination of immunotherapy added to traditional chemotherapy. And in both cases, you’re seeing a survival benefit and long-term survival in patients.

Going forward, we need to understand and be able to predict who those patients are that may derive that biggest benefit from the addition of immunotherapy, but [it’s] still very exciting and a sign of encouragement and, again, it validates the use of immunotherapy combined with chemotherapy in the first-line setting for patients diagnosed with extensive-stage small cell lung cancer.

Q: How does immunotherapy work to help the patient’s body deal with cancer?

A: Basically, immunotherapy harnesses the patient’s own immune system to go after and target the cancer. People hear about the brakes of the immune system and PD-L1 and PD-1 inhibitors, so there are these checkpoint inhibitors that scientists have learned how to manipulate, and they can basically activate the patient’s own immune system to try to go after and target the cancer. And that’s the goal here, to tap into the patient’s own ability to go after and treat the cancer.

Q: What are some roadblocks to treatment advancements that might exist due to factors such as the relative rarity of SCLC compared to NSCLC?

A: Of the two main types of lung cancer, we have non-small cell lung cancer and we have small cell lung cancer where small cell contributes about 15% of all diagnoses. It has typically been categorized as what we call recalcitrant cancer — that means it’s refractory or resistant to treatment.

Despite all the advances we’ve made in the treatment of non-small cell lung cancer, where we have several actionable biomarkers and targeted therapies and immunotherapy that have really opened up the survival and quality of life for those patients, we haven’t seen the same gains in patients diagnosed with small cell.

We’re trying to understand biologically what’s different about small cell.

Patients tend to be diagnosed at late stages [and] it’s a more aggressive form of lung cancer. So, it often responds well initially to chemotherapy, but then the tumor does what it does and patients can find that the chemotherapy [eventually] stops working.

And so, we just don’t have as many options available for small cell as we do for non-small cell, but it’s an area of intense investigation.

There are some other classes of drugs that are being evaluated to treat it. Another study ... is the DeLLphi-301 study, which looked at a drug called tarlatamab, which belongs to a new class of [immunotherapy] drugs called bispecific T-cell engagers. Back to this idea of harnessing the patient’s own immune system to go after and attack cancer, what bispecific T-cell engagers do is they allow us to bridge the small cell lung cancer cell with a T cell so they can bind to a molecule that is expressed by the small cell lung cancer tumor itself, a molecule in this case called DLL3, as well as a molecule expressed on the surface of the T cell called CD3. By linking those cells together, the T cell can then go in and lance or burst the small cell lung cancer cell.

It’s a novel class of drugs harnessing the patient’s own T cells to go in and attack and kill the small cell lung cancer. ... This was based on a phase 2 study where the objective response rate (patients who responded partially or completely to treatment) was roughly 40% and we saw median overall survival at 14.3 months.

Some [of the] safety considerations are that in some patients, because you’re stimulating the immune system, their immune systems go into overdrive, and [as a result] you can have something called cytokine release syndrome, where your body starts producing too many [proteins known as] cytokines, and you can have some complications from that. Another is that you can get some immune-associated neurotoxicity.

But again, it’s a novel class of drug that’s using the immune system, and it’s something that I think is very promising and that we’ll continue to evaluate.

A second class of drugs is antibody-drug conjugates [ADCs]. That’s another space where you’re using an antibody molecule to … bind a certain molecule, again, expressed on the small cell lung cancer surface. In this case, investigators looked at ADCs that bound to that DLL3 marker on the small cell cancer, and then the antibody brings in a payload of a drug that can go in and selectively, specifically treat the cancer.

We’re seeing mixed results on the use of [ADCs], both in the non-small cell lung cancer space as well as the small cell space, but it’s an area that’s the subject of a lot of research right now, and shows a lot of potential.

It’s a time for patients with small cell to be hopeful. There have been various reasons why we haven’t seen as many gains in this space. It’s just a much different beast than non-small cell lung cancer for a variety of reasons. But we’re more hopeful now than we’ve been in quite some time.

Transcript edited for clarity and conciseness.

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