Exploring Innovative Targeted Therapies for Relapsed SCLC

Pharmacy Times interviewed Jordyn P. Higgins, PharmD, BCOP, a thoracic and head and neck clinical pharmacist at Duke University Medical Center, on the emerging treatment landscape for patients with small cell lung cancer (SCLC) at the 2024 Oncology Pharmacists Connect conference. Higgins shares the latest advancements and implications of new therapies for relapsed SCLC, which can offer patients with poor prognoses new opportunities for treatment.

Pharmacy Times: Can you provide an overview of the emerging targeted therapies for relapsed [SCLC] and how these new therapies compare with existing treatment options in terms of effectiveness and patient outcomes?

Jordyn P. Higgins, PharmD, BCOP: It's an exciting time right now for [SCLC]. As you may know, [SCLC] accounts for about 15% of all new lung cancer diagnoses. And it's associated with a pretty dismal overall survival rate. About 8.9% of patients are alive at 5 years. And there really hasn't been any updates in this space for about 20 years or so in the relapse setting of extensive stage [SCLC]. So, for the typical first line treatment of extensive stage [SCLC], we now treat with carboplatin [Paraplatin; Bristol-Myers Squibb] and etoposide [Toposar; Teva Pharmaceuticals] in combination with immunotherapy. The two that we utilize are atezolizumab [Tecentriq; Roche] and durvalumab [Imfinzi; MedImmune/AstraZeneca]. And we do this for about 4 to 6 cycles and then we switch patients to maintenance atezolizumab or durvalumab until their disease ultimately relapses. At that time, the treatment landscape was if patients were deemed to be platinum-sensitive, meaning that they relapsed in over 6 months since their last dose of the platinum, you could retrial with the platinum containing regimens or you had clinical trial. Other things that we would consider were lurbinectedin [Zepzelca; Pharma Mar SA] as well as topotecan [Hycamtin; GlaxoSmithKline] in later line settings. But now we have 1 newly approved agent that just came out last month. Tarlatamab [Imdelltra; Amgen] is a DLL3 [delta-like protein 3] bispecific BiTE [bispecific T cell engager] therapy, which means that it binds to DLL 3 on the cancer cells and forms a synapse with CD3 [cluster of differentiation 3] on the T cells, allowing for T cells to fight off the cancer cells. And this was just FDA approved. And the other option that we have with promising results is ifanatamab derutecan [I-DXd], that is still in the clinical trial space. This is a B7-H3 [immune regulatory protein] antibody drug conjugate with deruxtecan, which is a topoisomerase 1 [enzyme responsible for DNA processes] payload.

Pharmacy Times: How are these emerging targeted therapies expected to change the treatment paradigms for relapsed SCLC and what specific changes do you anticipate in clinical practice as these therapies become more widely available?

Higgins: Yeah, so with the newer treatments that I just described, they have a better overall response rate and better overall survival, which is really exciting. And sort of how they fit into the treatment paradigm is, for me, if I have a patient who progresses on first line therapy, so carboplatin, etoposide and immunotherapy with extensive stage [SCLC], I would move to tarlatamab in the second line—and this is how it was accelerated to FDA approval. For I-DXd, since this is still in clinical trials and we're only treating patients in the clinical trial space. It's looking very promising that I-DXd, as well as potentially other antibody drug conjugates, will be utilized in the third line and beyond. And something that we start to see a lot more of because these patients are heavily pretreated. Instead of just exposing them to more rounds of chemotherapy, we now have the option to specifically deliver the chemotherapy to the cancer cells limiting some of those toxicities.

Pharmacy Times: What strategies are being developed to overcome resistance to treatments and improve long-term outcomes for patients?

Higgins: So we've newly developed or understood the biomarkers DLL3, as well as the B7-H3 that I alluded to earlier that are utilized for tarlatamab and I-DXd, respectively. So DLL3 is actually overexpressed in about 80 to 90% of all [SCLC] patients, so much so that we don't even have to test to see if they are overexpressing DLL3, to know that they will most likely respond to tarlatamab. And so that's an exciting new biomarker that a lot of our BiTes are currently targeting in this space. Regarding B7-H3, this is also overexpressed in a variety of tumor types. And it's associated with worse duration of responses to therapies and a poor overall prognosis. We've seen that this is overexpressed in a lot of [SCLC] as well. So, for patients being treated with I-DXd, we don't have to specifically test for this biomarker either now that we know that it exists. Another really interesting biomarker that we've discovered is Schlafen 11 [a DNA/RNA helicase that sensitizes cancer cells to DNA-damaging agents], which actually helps to determine responses to PARP [poly ADP-ribose polymerase] inhibitors in some of the various subtypes of small cell lung cancer.

Pharmacy Times: What role do biomarkers play in identifying patients who are most likely to benefit from these emerging targeted therapies?

Higgins: So, for the longest time, we've treated all patients with [SCLC] the same, which is very different than what we currently do in non-small cell lung cancer; for example, where we have so many various biomarkers that we look at and really treat patients with a personalized medicine approach. And so, the reason why we typically used to do this for [SCLC] is just the disease is so rapidly progressing and it looks very similar under a microscope. But what we've come to uncover is that there's actually various subtypes of [SCLC] that I think we'll start to, to utilize in clinical trials, helping determine which patients will respond best to what treatments. Currently, there are about four subtypes of [SCLC] that are being studied. There is A subtype, N subtype, P subtype and I subtype. And these subtypes are determined by the overexpression of various genes. Particularly with the I subtype, this is an overexpression of a combination of amino genes. And we have seen that patients with the I subtype of [SCLC] respond really well to immunotherapy. In addition, patients with the P subtype respond really well to PARP inhibitors we are seeing and so I think this will be the future of the [SCLC] space to help to determine which patients will respond best to which treatments upfront and help prevent resistance down the road.

Pharmacy Times: What are some innovative research directions or novel approaches to targeted therapy in SCLC and how might these research findings influence future treatment protocols?

Higgins: I think something that we're seeing across multiple oncology disease states, but also very specifically in [SCLC], is that we need to be more inclusive so that more patients can participate in these clinical trials to help drive the future of treatment for [SCLC]. One of the things that we have seen in clinical practice is because this disease is so deadly, it's so quickly progressing, a lot of patients upon diagnosis are admitted to the hospital and have to receive their first round of platinum-based chemotherapy there. And so, for a lot of clinical trials, that could be considered an exclusion criteria. But we really need to include these patients, because these are the patients that we typically see, and so we can get the best results in future treatments for them. Another thing is these patients are usually older, heavy, lifelong smokers, a lot of times associated with poor socio-economic status, and maybe lack various resources. So having resources available to these patients who have to come in sometimes on a weekly basis to participate in clinical trials, stipends for food and lodging and things of that nature. Also potentially having telehealth options for these patients or allowing them to get labs at an outside institution to make it more accessible for all types of [SCLC] patients to participate in clinical trials, etc.

Pharmacy Times: What do you like about Oncology Pharmacists Connect?

Higgins: Yeah, so this is my first time at Oncology Pharmacists Connect. And it's been a great conference experience. So far, what I really like about it is that it's taking the data that was just presented at ASCO, a conference that a lot of times, pharmacists don't have the either privilege or time to attend. And it's really boiling it down to what the pharmacist needs to know, to immediately change their practice. And so, I really liked that we have pharmacist experts across solid tumor in hematologic malignancy disease states who are coming together to present this new data that you can immediately implement into your practice. I also like that it's a bit more of a smaller conference compared to HOPA or ASHP, for example. So great opportunities for networking and meeting other people.