Exploring Facets of Both the SCLC and NSCLC Therapeutic Landscapes

Eric Kumar Singhi, MD

Treatment for patients with limited-stage small cell lung cancer (LS-SCLC) has historically been limited in its activity, but findings from the first planned interim analysis of the phase 3 ADRIATIC study (NCT03703297), which evaluated durvalumab (Imfinzi) as consolidation treatment following chemoradiation in this population, generated encouraging results that has many hopeful for the future.

Treatment with the investigative regimen (n = 264) resulted in a median overall survival (OS) of 55.9 months (95% CI, 37.3-not evaluable) compared with 33.4 months (95% CI, 25.5-39.9) for placebo (n = 266; HR, 0.73; 95% CI, 0.57-0.93; P = .0104). Median follow-up was 37.2 months (range, 0.1-60.9) in censored patients.

“Thinking about new drugs that are going to be developed in [SCLC] is always very exciting. Trying to move beyond just combination strategies that we have tacking onto platinum [and] etoposide and trying to bring new drugs in is encouraging. That’s where tarlatamab-dlle [Imdelltra] comes in,” Eric Kumar Singhi, MD, stated in an interview with OncLive^®.

In the interview, Singhi gave an expansive overview on the current therapeutic landscape of treatment across both SCLC and non–small cell lung cancer (NSCLC); highlighted gaps and unmet needs that remain to be addressed across early-stage, locally advanced, and metastatic disease spaces; and expanded on ongoing research aiming to combat both SCLC and non-mutation driven NSCLC.

Singhi is an assistant professor in the departments of general oncology and thoracic/head and neck medical oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

OncLive: What is the prognosis of patients with limited-stage SCLC?

Singhi: There have been a lot of exciting updates with SCLC [that have led to] big changes for our patients. SCLC can be very aggressive; two thirds of patients, when we first meet them have extensive-stage disease, and one third of patients will have limited-stage disease where the disease is confined to 1 side of the chest.

Thinking about limited-stage SCLC, our standard of care [SOC] has not changed much in almost 4 decades. We’re using platinum-based chemotherapy concurrently with radiation therapy. It’s not an easy treatment for our patients. Therapy can take several weeks, and even after going through it, 5 years out, OS rates are still between 15% and 25%. We know that most patients are not being cured. The question we’ve asked ourselves is: How can we do better? How can we improve clinical outcomes for patients with limited-stage SCLC?

What caught your attention from the presentation of the ADRIATIC trial data at the 2024 ASCO Annual Meeting?

At the 2024 ASCO Annual Meeting we saw the results of the ADRIATIC study, which evaluated, in a phase 3 setting, the benefit of adding up to 2 years of immune checkpoint blockade following chemoradiation. We saw that [durvalumab led to] a significant OS benefit, with an improvement of almost 2 years.

The median OS for these patients was 55.9 months with durvalumab vs 33.4 months with placebo, which is quite impressive. Progression-free survival [PFS] was also improved [with durvalumab]. One of the things we think about when we’re trying to improve outcomes for our patients with lung cancer is the toxicity. One of the toxicities we worry about when sequencing radiation and immunotherapy is pneumonitis or inflammation of the lungs.

What we saw in the ASCO presentation was that overall grade 3/4 rates of pneumonitis following durvalumab consolidation was only slightly higher than with placebo; this was quite reassuring at just 3.1%. Those results are absolutely practice changing. It’s exciting to see that there are advancements for our patients with limited-stage disease after such a long time, and it’s a conversation I’m having in clinic with my patients.

Shifting to extensive-stage SCLC, what trials stand out in this disease setting?

Extensive-stage SCLC is the more common disease setting that we see in clinic at about two-thirds of patients. Just a few years ago, we learned that adding immunotherapy to platinum-based chemotherapy, platinum [and] etoposide, in the first-line setting improved OS and PFS, [although] not nearly [to the same extent] as what we saw from the [ADRIATIC trial] in the limited-stage setting. Improvement in OS is only about 2 months with the addition of immunotherapy, so we still need better strategies and better treatment regimens for our patients with extensive-stage disease. What we saw this year, with regard to improvements in the extensive-stage setting, was more so in subsequent lines of therapy.

[This was seen] in the phase 2 DeLLphi-301 trial [NCT05060016], [data from which] led to the May 2024 FDA approval of tarlatamab. Tarlatamab is a bispecific T-cell engager [BiTE]. The way it works is it latches on to DLL3 which is typically overexpressed on SCLC cells, and then it latches onto CD3 T cells, and it enhances the effectiveness of the T cells to go and kill the SCLC. [However], in the National Comprehensive Cancer Network [NCCN] guidelines, clinical trial enrollment is a category 1 preferred recommendation for our patients if they’re [developing progressive] disease after first-line chemoimmunotherapy. Clinical trials are important. However, the reason tarlatamab got approved was because the objective response rate was 40%; these patients had 2 or more lines of prior therapy. It is exciting to see this approval.

Many solid tumor oncologists are not used to some of the unique adverse effects [AEs] that tarlatamab can have. The one that’s unique is cytokine release syndrome [CRS]. Up to 50% of patients in the DeLLphi-301 study [who received the agent at the dose that’s now approved] had CRS. These events were mostly grade 1/2, so you could supportively manage these toxicities with fluids, steroids, or acetaminophen, which was reassuring. It was also very predictable and tended to happen on cycle 1, day 1, with a median onset of approximately 13 hours after infusion.

However, because of the unique AEs and the close monitoring that’s needed, it’s hard to roll this drug out to all patients nationwide and internationally. Patients have to be admitted into the hospital for the first 2 doses, so working that into your oncology workflow at your institution is challenging, but given the response rates, it’s practice changing. The drug is currently being studied, and there are plans to study it in patients who have limited-stage disease. What’s the benefit of bringing that drug into the earlier stage setting? We don’t have those results, but I’m looking forward to it. I am excited to see new drugs that are developing for our patients with SCLC.

How do you approach patients with NSCLC who present without driver alterations?

For patients with NSCLC that’s metastatic, we first want to make sure that they do not have a driver alteration. As a community, we’re doing better with making sure that all patients, regardless of what they look like or where they’re coming from, are receiving comprehensive molecular profiling. This discussion is limited to those patients for whom we’ve done a thorough job making sure there’s no driver alteration. In the first-line setting, for these patients there are a lot of options, especially listed in the NCCN guidelines, which is fantastic, but it’s also confusing. If a patient has no contraindications to immune checkpoint blockade the options that we have currently in the first-line setting can include chemotherapy plus single-agent immunotherapy, chemotherapy plus dual immunotherapy, and dual immunotherapy alone. The question is: How do we know which regimen is best for which patient? That is a very important question. Also, where does CTLA-4 inhibition fit into the treatment paradigm for our patients?

One study I’m excited about that is starting to accrue patients is the phase 3 TRITON study [NCT06008093]. The reason for the study is that retrospective reviews of trial data have shown that there is this unmet need for a subset of patients with metastatic NSCLC who harbor a KRAS mutation, or other co-mutations that we don’t right now consider actionable. This includes STK11 and KEAP1. When patients have these mutations driving their disease, it tends to render the tumor microenvironment less responsive to immunotherapy. We’ve looked back through some of the data that we have from our therapeutic trials, and we have seen that these patients seem to have better outcomes when we add CTLA-4 inhibition.

The TRITON study is comparing durvalumab, which is an anti–PD-L1 agent plus chemotherapy and tremelimumab [Imjudo], which is an anti–CTLA-4 agent vs pembrolizumab [Keytruda] plus platinum chemotherapy. These patients must have nonsquamous histology and co-mutations or mutations in STK11 and KEAP1 [because] we’re looking to see prospectively for the first time what the benefit is of adding CTLA-4 inhibition for this specific subset of patients as compared with chemoimmunotherapy. This could help define a role in a prospective setting for how we use CTLA-4 inhibition for these patients.

Transitioning to the second-line setting, what data have caught your attention for patients with NSCLC?

Another important [question] for patients with lung cancer that’s metastatic is what to do after they progress on immunotherapy or what to do in the second-line setting. Currently, docetaxel is our SOC in the second-line setting, and it’s been really challenging to beat. Lately, there has been a lot of enthusiasm with emerging antibody-drug conjugates [ADCs] in this space. We heard data during the 2024 ASCO Annual Meeting from the phase 3 EVOKE-01 study [NCT05089734] that compared the TROP2-directed ADC, sacituzumab govitecan-hziy [Trodelvy], with docetaxel in patients who had progressed after chemoimmunotherapy.

Unfortunately, that trial did not meet its primary end point of OS, but it did show a numeric improvement if patients had no response to immunotherapy previously. Now, we have to ask: Are we not defining the best patient population for this strategy with an ADC? Do we need more biomarkers to guide us? That question is still [up for debate]. Overall, these emerging ADCs have not translated into a slam dunk response for our patients in the second-line setting and beyond after they progress on chemoimmunotherapy; we need to think about other strategies.

One trial that I’m looking forward to the results of is the phase 3 PRAGMATICA-LUNG trial [SWOG S2302; NCT05633602], which is comparing ramucirumab [Cyramza] plus pembrolizumab vs SOC after patients recur on immunotherapy. This is [being done on the heels] of the Lung-MAP study [NCT02154490], which looked promising. The primary end point for this [phase 3] study is going to be OS. We’ll have to see if there’s a way to salvage a patient’s response to immunotherapy with the addition of ramucirumab. It seems like a very promising study, and I am looking forward to those results.

How does treatment differ for patients with early-stage NSCLC without driver mutations?

This landscape has really evolved over the past few years, particularly if patients have resectable disease. Historically, for almost 2 decades, the only systemic therapy that we were offering our patients after surgery was platinum-based, particularly cisplatin-based chemotherapy, and that data really came from the LACE meta-analysis, which showed up to a 5% OS benefit with 4 cycles of cisplatin-based chemotherapy. The higher the stage, the greater the benefit. What we’ve seen over the past few years is the incorporation of immunotherapy and targeted therapy strategies into the early-stage, resectable disease space.

With the incorporation of immunotherapy we’ve seen strategies that are [used in the] neoadjuvant [setting] such as with the phase 3 CheckMate-816 trial [NCT02998528]. We see adjuvant strategies for immunotherapy after surgery with the phase 3 IMpower010 [NCT02486718] and the PEARLS [NCT02504372] trials. Of course, we have perioperative strategies too, like with the FDA-approved KEYNOTE-671 trial [NCT03425643] regimen. Of course, there are also emerging perioperative phase 3 trials that are underway.

An exciting aspect for patients with early-stage, resectable NSCLC is not only thinking about our traditional immunotherapies, like anti–PD-[L]1 [inhibitors] and [how we can] incorporate them into chemotherapy, but [how we can do with our] novel immunotherapies. The phase 2 NeoCOAST-2 study [NCT05061550] is comparing neoadjuvant durvalumab-based [regimens which include] other novel immunotherapies such as anti-CD73 [agents] and the monoclonal antibody oleclumab. Are there opportunities to fortify that strategy, add additional novel immunotherapies in the perioperative setting for our patients, and see if that’s better than what we’re using currently? That study read out [at the 2024 IASLC World Conference on Lung Cancer], and we are excited to see whether that can translate into potential clinical benefits for our patients in the early-stage setting.

Across the entirety of lung cancer how do you choose which treatment to recommend with so many options?

[This is] the biggest question. It’s difficult because we don’t have any head-to-head studies comparing each of these approaches with each other. So, what do I do in clinic? A staple is shared decision-making with your patients. Some patients want to be very aggressive about the treatment that they have, and some patients want to get to surgery more quickly and be done. Having that understanding of the goals of your patient and what they hope to achieve with treatment [is important, as is] thinking about disease characteristics and molecular characteristics. Regarding PD-L1 expression levels, how much does that factor in, or should it factor into your decision-making? Is it based on other characteristics, like treatment effect? What if your patient gets a pathologic complete response [pCR]? Should you be continuing immunotherapy or not?

Of course, there are emerging biomarkers that we’re hoping to utilize to guide strategies, and that includes circulating tumor DNA [ctDNA] dynamics. Strategies and studies are being developed to look at de-escalation and escalation strategies based on pCR and ctDNA dynamics. That’s the way of the future, and I’m really looking forward to it. This includes studies from SWOG that are going to be coming out. Hopefully we’ll better be able to define how to tailor the treatment strategy for our patients in the early-stage setting.

Out of everything we’ve discussed what data or regimens have affected your clinical practice?

What’s most practice-changing has been the data from the ADRIATIC study for patients with limited-stage SCLC. We have clear evidence that [the regimen] is improving OS on the span of close to 2 years, which is quite impressive and unprecedented in that space. I also believe that the FDA approval of tarlatamab is practice-changing for patients with extensive-stage SCLC. Any time we get a new drug for patients with SCLC it’s a celebration because we can add another strategy for these patients when there’s such an unmet need. Those are the two most [recently] practice-changing therapies that I have integrated into my practice already.

Reference

Spigel DR, Cheng Y, Cho BC, et al. ADRIATIC: durvalumab (D) as consolidation treatment (tx) for patients (pts) with limited-stage small-cell lung cancer (LS-SCLC). J Clin Oncol. 2024;42(suppl 17):LBA5. doi:10.1200/JCO.2024.42.17_suppl.LBA5