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Fawzi F Abu Rous, MD Advances in treatment strategies for squamous cell carcinoma of the lung—including dual-targeting agents like ivonescimab (SMT112) and ongoing research on predictive biomarkers for immunotherapy response, and efforts to bolster the efficacy of first-line therapies—are offering new hope for improved treatment outcomes in this difficult-to-treat cancer subtype, according to Fawzi F Abu Rous, MD. “A key area of unmet need is improving and refining first-line treatment strategies for squamous cell carcinoma,” Abu Rous stated in an interview with OncLive ®. “[Ivonescimab is] one of the promising drugs currently in development.
Subgroup [analyses of the phase 3 HARMONi-2 trial (NCT05499390) showed that] patients with squamous cell carcinoma benefited significantly [from treatment with ivonescimab vs pembrolizumab (Keytruda)]. The same [was true] for [those with] adenocarcinoma. Based on [those data], there are now 2 [phase 3] spin-off trials [further evaluating ivonescimab in lung cancer subgroups].
” In the interview, Abu Rous, who is a thoracic medical oncologist at Henry Ford Health in Detroit, Michigan, expanded on several unmet needs in squamous cell carcinoma of the lung; shared previously reported data and ongoing trials clarifying the role of ivonescimab across patient subgroups with varying PD-L1 expression levels and histologies; and addressed historical concerns about bleeding risks with anti-VEGF therapies in this subtype. Abu Rous :Squamous cell carcinoma of the lung accounts for approximately 25% to 30% of lung cancer cases and is the second most common type of non–small cell lung cancer [NSCLC]. It is typically a difficult-to-treat subtype and is often resistant to treatment.
One of the major areas of unmet need is improving outcomes for patients with [this disease]. [In contrast], patients with adenocarcinoma tend to have a higher likelihood of harboring targetable alterations, such as mutations in EGFR , ALK fusions, or other actionable genomic changes. They also tend to have higher rates of elevated PD-L1 expression, which can predict response to immunotherapy.
Generally speaking, because of these factors, patients with adenocarcinoma tend to have better outcomes than those with squamous cell carcinoma. The standard-of-care [SOC] first-line treatment for patients with squamous cell carcinoma is a combination of immunotherapy [with or without] chemotherapy. This approach depends on the level of PD-L1, which I often explain to patients as the ‘immune score.
’ The higher the score, the more likely the patient is to benefit from immunotherapy. Based [on PD-L1 expression], treatment may be either single-agent or doublet immunotherapy, or immunotherapy [with or without] chemotherapy. The response rate [associated with] this type of treatment is approximately 50% to 60%, and the overall survival [duration] is typically in the range of 1.
5 to 2 years. [Despite these improvements], a significant number of patients do not respond and unfortunately succumb to the disease. This is an ongoing area of unmet need.
[On the] bright side, [these numbers are] a huge and remarkable improvement from the numbers we had in the past, which tells us that some patients clearly benefit from this treatment [approach]. One [promising] treatment we’re all keeping an eye on right now is ivonescimab. Ivonescimab is a unique immunotherapy.
It’s an antibody, but we can think about it as having 2 heads. One head [targets] PD-1, which is an immune checkpoint—so [the agent is] an immunotherapy in that regard. The other head [targets] the VEGF receptor, which is involved in the development of new blood vessels.
[The presence of] these 2 heads can [result in] synergy between the 2 components of the antibody, [leading to] better responses and outcomes. [The data] we know so far about this drug were reported at the [ 2024 World Conference on Lung Cancer ]. [The HARMONi-2 trial] from China compared patients with stage IV NSCLC receiving pembrolizumab [with those receiving] ivonescimab.
It was a large patient population. The trial did not [limit enrollment to] a certain subset of PD-L1 patients; [it allowed] patients with all levels of PD-L1 expression. Despite some critiques of the trial, the results were promising.
Ivonescimab almost doubled the progression-free survival that pembrolizumab [produced] in those patients. Even when investigators divided the patients based on PD-L1 expression level, all the subsets still benefited significantly from ivonescimab compared with pembrolizumab. Based on [those data], there are now 2 [phase 3] spin-off trials.
One is called HARMONi-3 [NCT05899608]. [This trial is enrolling] patients regardless of PD-L1 status or histology—so [patients with either] squamous cell carcinoma or adenocarcinoma [will be included]—and is comparing SOC chemotherapy plus pembrolizumab vs chemotherapy plus ivonescimab. It’s a global trial enrolling patients in the United States, Europe, China, and Japan.
This trial will give us important information and could be practice changing. The other trial in a different subset of patients is called HARMONi-7 [NCT06767514]. This trial’s goal is to compare ivonescimab with pembrolizumab in patients with a PD-L1 [TPS of] 50% or greater.
In this patient population, single-agent pembrolizumab is typically the SOC. [This trial] is similar to [HARMONi-2] but in a more specific—and, in my opinion, more appropriate—patient population. There has been a historical fear about using anti-VEGF or anti-angiogenesis therapies in this population.
This fear is based on older studies with bevacizumab [Avastin] in patients with squamous cell carcinoma of the lung, which showed significant bleeding events and even led to early trial termination. We now have better anti-VEGF agents, such as ivonescimab, and we’re learning more about what makes a patient at a high risk of bleeding. This is what Aliyah Pabani, MD, MPH, of Johns Hopkins School of Medicine in Baltimore, Maryland; Jack West, MD, FASCO, of Summit Therapeutics; and I discussed in a paper [we published in JCO Oncology Advances in December 2024].
1 We tried to [highlight] the key features that make a patient at a high risk for bleeding. Having a large tumor or squamous cell carcinoma itself is a risk for bleeding. However, not all tumors are equally high risk.
Tumors that are large, cavitary, very close to a blood vessel, or pushing on critical structures like airways or vessels are more likely to bleed. Patients may also be receiving blood thinners, aspirin, or clopidogrel [Plavix], which increase their risk of bleeding. Another key area of unmet need is the [identification and use] of biomarkers.
Biomarkers are characteristics of the patient or their disease that can help predict which patients will or will not respond to a specific treatment. Knowing that early on can help us plan for the future and either intensify or de-intensify treatment based on these biomarkers. Other than PD-L1, tumor mutational burden, and some other [less-established] biomarkers, we don’t have an accurate biomarker for squamous cell carcinoma of the lung.
During my fellowship, I worked on a project on cancer genetics in squamous cell carcinoma to try to develop a biomarker. We focused on an area on chromosome 3, specifically the long arm of chromosome 3, [which is] referred to as 3q. [This region is] commonly amplified in many patients with squamous cell carcinoma of the lung.
We worked with our genomic scientists and bioinformaticians and [identified] a specific area on 3q that appeared to predict outcomes and even [mediate] responses to immunotherapy. We’re still working on this project, but it looks promising. In the future, [this area on 3q might] become a biomarker that can help predict outcomes and response to immunotherapy in patients with squamous cell carcinoma.
Pabani A, West H, Abu Rous F, et al. Safety and efficacy of antiangiogenesis agents in patients with squamous cell carcinoma of the lung: time to revise outdated constraints. JCO Oncol Adv.
2024;1. doi:10.1200/OA-24-00089.
