Emerging Therapeutic Targets Shape Testing and Treatment Decisions in SCLC and NSCLC

Apar Kishor Ganti, MD

Developments in the management of lung cancer include novel targets that may continue to move the needle in the direction of increasingly targeted therapies for patients with small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC), according to Apar Kishor Ganti, MD. 

“Although SCLC is difficult to treat, there is hope on the horizon. We are identifying different subtypes and trying to understand more about the biology. A couple molecules are currently being tested that could change how we treat patients with SCLC in the next few years,” Ganti said in an interview with OncLive^® following a State of the Science Summit on lung cancer, which he chaired.

In the interview, Ganti discussed key points shared at the meeting, including molecular targets to test for in SCLC and NSCLC; treatment approaches for extensive-stage SCLC (ES-SCLC) and late-stage SCLC (LS-SCLC); and immunotherapy options for patients with metastatic NSCLC (mNSCLC) in the frontline setting and beyond.

Ganti is a professor in the Division of Oncology and Hematology in the College of Medicine at the University of Nebraska Medical Center (UNMC) in Omaha, as well as the associate director of Clinical Research at the UNMC Fred and Pamela Buffett Cancer Center.

OncLive: What newer targets in SCLC did you discuss in your presentation?

Ganti: SCLC has been difficult to treat for a long time and the primary reason for that was that we have not had a good handle on the biology of SCLC. We are slowly understanding that it is not 1 disease but has at least 4 different subtypes. The interesting feature about SCLC is these subtypes are not static—when you start treating 1 subtype, it can transform into another subtype. That’s what makes the treatment of SCLC so challenging. Now that we’re starting to understand the various subtypes, we will have more targets and [we can] improve outcomes for this disease.

My presentation focused on a couple different targets. The most exciting one seems to be DLL3. There was a drug that was used earlier called rovalpituzumab tesirine, but unfortunately, it [needed] to be abandoned.

Newer drugs target the same DLL3 molecule, which is seen in approximately 70% of all SCLC tumors. A bispecific antibody that binds to DLL3 and CD3-positive T cells, called tarlatamab [AMG 757], has been shown to be promising in initial studies in relapsed SCLC. In a phase 1 study [NCT03319940] of patients with refractory or relapsed SCLC, tarlatamab was shown to have an objective response rate of 23.4%, with a disease control rate of 51.4%.

The main adverse effects [AEs] observed with this agent included cytokine release syndrome, which was mostly grade 1 or 2 and well managed. Other AEs included pyrexia, fatigue, and nausea, but most of these were grade 1 and 2. Only 4% of patients discontinued tarlatamab [because of treatment-related AEs] in this phase 1 study.

Other drugs target DLL3 as well, but tarlatamab seems to be the most advanced in this stage. Soon, there will be ongoing phase 3 trials done using tarlatamab in SCLC.

The other [treatment strategy] I touched upon was using a combination of PARP inhibitors and temozolomide [Temodal]. PARP inhibitors are approved for [patients with] breast cancer. The biology and blockage of PARP leads to DNA strand damage and prevention of the repair of DNA strands that are already broken. If you combine a PARP inhibitor with an alkylating agent such as temozolomide, theoretically, you could get better cell kill and increased effectiveness in SCLC.

These combinations have been studied and there are 3 different PARP inhibitors that have been studied in combination with temozolomide, namely: talazoparib [Talzenna], olaparib [Lynparza], and veliparib [ABT-888]. All of them seem to have good response rates and a median overall survival [OS] in the second-line setting between 10 months to 12 months.

What unmet needs remain for patients with SCLC?

SCLC, despite all the recent advances with immunotherapy, remains a difficult disease to treat. Even with the approvals of durvalumab and atezolizumab for [patients with] metastatic or ES-SCLC, the median OS is only 1 year and almost all patients relapse. Once they relapse, we have no good treatment options available, so that is an area of huge unmet need for these patients. A lot needs to be done to improve outcomes for patients with SCLC. 

Alissa Marr, MD, of UNMC, further discussed the management of SCLC. What treatment options exist for patients with ES and LS disease?

We divide SCLC into two stages as far as treatment is concerned: LS and ES. LS patients are those whose disease can be encompassed within a single radiation field. The current standard of care [SOC] for those patients is a combination of chemotherapy and radiation. Ongoing studies are adding immunotherapy to chemotherapy and radiation. However, currently, we would recommend giving chemotherapy and radiation [for patients with LS-SCLC].

For patients whose disease is extensive and has spread beyond the lungs, the SOC is a combination of chemotherapy and immunotherapy. Two drugs are currently approved [for patients in this population]: durvalumab [Imfinzi] and atezolizumab [Tecentriq], both of which are PD-L1 inhibitors. All patients [with ES-SCLC], unless they have a specific contraindication to immunotherapy, should receive a combination of chemotherapy and immunotherapy.

There are a lot of controversial areas in the management of SCLC, the most prominent being the role of prophylactic cranial irradiation in this group of patients. Historical studies in the 1980s and 1990s have shown that patients with LS-SCLC who receive prophylactic brain irradiation after they’ve completed their initial chemotherapy and radiation seem to have an OS advantage. A study out of Europe evaluated the same question in patients with ES-SCLC and found a survival advantage. There were a lot of problems with this study. A subsequent study done in Japan showed that there was no benefit with prophylactic cranial irradiation. That raised a controversy. Why did we have 1 phase 3 study showing a benefit and another phase 3 study showing no benefit?

A study is underway in the US that is trying to answer that question in ES-SCLC and LS-SCLC. Because of changes in radiation techniques, a lot of people are concerned about the AEs of radiation. They do not necessarily believe that prophylactic brain irradiation helps. Hopefully, this ongoing study will answer that question once and for all.

Mary Wells, MD, of Nebraska Cancer Specialists, discussed first-line immunotherapies in mNSCLC. What disease characteristics help determine whether a patient with mNSCLC may benefit from immunotherapy?

Dr Wells focused mostly on immunotherapy in the first-line setting for patients with untreated mNSCLC. Immunotherapy has revolutionized the management of NSCLC, especially stage IV [disease]. Almost all patients, [besides] a few notable exceptions that we discussed during the conference, [are candidates] for immunotherapy.

If patients’ tumors have high PD-L1 expression, they can receive single-agent immunotherapy. If they have low PD-L1 expression, they could potentially receive chemotherapy with immunotherapy. Or, if they are not in a physical condition where they would be able to tolerate cytotoxic chemotherapy, you could use single-agent pembrolizumab [Keytruda] or a combination of ipilimumab [Yervoy] and nivolumab [Opdivo] and still get good responses. Most patients with NSCLC, especially patients with adenocarcinoma who do not have a driver mutation, are candidates for immunotherapy.

Kate-Lynn Muir, DO, of UNMC, spoke about immunotherapies in mNSCLC in the second line and beyond. What immunotherapies are available in later lines for this patient population?

Unfortunately, we don’t use a lot of immunotherapy agents in the second-line setting because as data have evolved, we’ve started using them in the first-line setting. Having said that, the second-line treatment of patients with NSCLC is an area of unmet need.

Upcoming studies are combining immunotherapy with a VEGF inhibitor. A study out of SWOG as part of the Lung-MAP trial [NCT02154490] investigated a combination of ramucirumab [Cyramza] and pembrolizumab in patients who have progressed on pembrolizumab. That study indicated that this combination may be effective. That [combination] is being tested in an ongoing phase 3 study.

However, other newer immunotherapy targets are being studied in the second line because at this point, that is an area of unmet need. For patients who progress on immunotherapy, the only approved option is chemotherapy alone or with ramucirumab. Trials are underway evaluating other immunotherapy targets to see if we can make a difference for this group of patients.

Omar Abughanimeh, MBBS, of UNMC, discussed EGFR-positive NSCLC in the adjuvant and metastatic settings. How do you approach genetic testing for this patient population?

My practice has evolved since the presentation of the [phase 3] ADAURA trial [NCT02511106] results at the 2023 ASCO Annual Meeting. I now tend to test all patients with ES lung adenocarcinoma for EGFR mutations. My practice always has been to test all patients with metastatic adenocarcinoma and most patients with metastatic squamous cell carcinoma with next-generation sequencing [NGS]. That has not necessarily changed. However, with the results of the ADAURA trial showing an OS advantage with osimertinib [Tagrisso], it’s important that patients with earlier-stage lung cancer also get tested to see if they are candidates for adjuvant osimertinib.

What NSCLC targets are emerging in the field, as discussed by Peter Silberstein, MD, of CHI Health Henry Lynch Cancer Center at Bergan Mercy in Omaha, Nebraska?

When we talk about targets for NSCLC, we mostly focus on targets such as EGFR, ALK, ROS, and BRAF. However, Dr Silberstein discussed multiple other targets that may be relevant for this patient population, targets that are not as frequent as the ones I mentioned but are nonetheless important. [These include] RET, MET, TRK, and KRAS.

These targets should be tested for because if a patient has 1 of these targets, even though [RET, MET, and TRK mutations] make up less than 2% of all NSCLCs, just by sheer volume, they still would be [present in] a lot of patients. KRAS is the most common target in adenocarcinoma of the lung—it makes up approximately 30% to 35% of adenocarcinomas. Additionally, KRAS G12C mutations, the most common of the KRAS mutations for which we have a drug available, make up about approximately 12% to 13% of adenocarcinomas. Those targets are all important to test for. All patients should undergo a comprehensive NGS panel evaluation rather than evaluations of individual targets.

What lung cancer research is ongoing at UNMC?

We have several trials in lung cancer. The trial I’d like to highlight is [investigating] cellular therapy in lung cancer and it is an ongoing [phase 2] trial [NCT04614103] of tumor-infiltrating lymphocytes [TILs], which are being tested as second-line treatment for patients with NSCLC. When patients progress on chemotherapy and immunotherapy, we take their tumor, send it to the laboratory, extract the TILs, train them against the tumor antigens, and re-administer those trained TILs into the patient and observe them.

We have a similar study investigating a CAR T-cell product against MUC1, which is mucin that’s present on all epithelial cancers. We have an off-the-shelf CAR T-cell product that targets MUC1 and that [trial is] for all patients with lung cancer or any epithelial tumor because most epithelial tumors express MUC1.