Intentional Treatment Sequencing Strategies Optimize SCLC and NSCLC Management

Miguel Gonzalez-Velez, MD

Emerging lung cancer data presented at the 2025 ASCO Annual Meeting signal a paradigm shift toward more targeted, synergistic treatment strategies, with trials such as the phase 3 DeLLphi-304 (NCT05740566) and CheckMate 816 (NCT02998528) studies demonstrating that strategically sequenced immunotherapy regimens may significantly improve survival outcomes, according to Miguel Gonzalez-Velez, MD.

“We will keep doing research, and we will keep adding on the progress that we [present] every year at meetings like ASCO,” Gonzalez-Velez said in an interview with OncLive® during the 2025 ASCO Annual Meeting.

In the interview, Gonzalez-Velez discussed the clinical implications of several lung cancer trials that were presented at ASCO 2025; as well as and future directions for improving the synergistic effects of chemotherapy, immunotherapy, and emerging targeted therapies in development.

He highlighted the impetus for conducting small cell lung cancer (SCLC) studies like the DeLLphi-304 trial in which, at a median follow-up of 11.2 months, the median overall survival (OS) was 13.6 months with second-line tarlatamab-dlle (Imdelltra; n = 254) in patients with SCLC; at a median follow-up of 11.7 months, the median OS was 8.3 months with chemotherapy (n = 255; HR, 0.60; 95% CI, 0.47-0.77; 2-sided P < .001).1

He also noted clinical considerations for the use of neoadjuvant chemoimmunotherapy in non–small cell lung cancer (NSCLC), as seen in the CheckMate 816 study. At a median follow-up of 68.4 months, neoadjuvant nivolumab plus chemotherapy (n = 179) generated a statistically significant and clinically meaningful OS benefit vs chemotherapy alone (n = 179) in patients with resectable NSCLC, with a median OS that was not reached vs 73.7 months (HR, 0.72; 95% CI, 0.523-0.998; P = .0479).2

Gonzalez-Velez is a thoracic oncologist at Hackensack Meridian Health’s John Theurer Cancer Center in New Jersey.

OncLive: What unmet needs for patients with SCLC was the DeLLphi-304 trial designed to address?

Gonzalez-Velez: At this time, SCLC is an aggressive disease, and we need to improve OS, which hasn't changed much in the past 2 decades. Finally, we are getting new mechanisms of action with newer medications that are more targeted to improve the OS [for an] aggressive disease that has a median OS of approximately 12 months.

How might tarlatamab be unique compared with other bispecific T-cell engagers in lung cancer?

This is new agent that activates parts of the immune system. It engages the immune system directly, instead of just doing cytotoxic damage like traditional chemotherapies that kill the cancer directly. [In DeLLphi-304], we are adding a mechanism of action that boosts or activates the immune system, which hopefully creates a synergistic effect that accumulates [on top of] the effects of traditional treatments like chemotherapies or immunotherapies [that patients may have previously received].

How might the DeLLphi-304 influence SCLC management in the future?

In the oncology world, there is a common saying that cancer management should be a marathon, not a sprint. At this time, SCLC management is only a sprint. Patients progress rapidly. Patients [develop] complications rapidly.

The general idea [in SCLC management] is to increase outcomes [like] progression-free survival and OS and make it a bit more of a marathon. In that way, we can give patients more options. We can hopefully get the patients to the second-line setting, to the third-line setting, and to clinical trials. We hope that in the future, this will improve long-term outcomes and allow us to get the right medications to the right patients and improve clinical outcomes and survival.

What was the impetus for conducting the phase 3 IMforte trial (NCT05091567)?

[Patients with] SCLC [typically] have a good response to treatments, but [this disease] recurs quickly. One key [goal of SCLC treatment development] is extending the maintenance [phase] and improving the maintenance treatments. We are trying to boost the synergistic effects of treatments. [In IMforte], we added [lurbinectedin to] immunotherapy [in the hopes of extending] maintenance outcomes to get patients to future treatments.

How might the IMforte data affect clinical practice moving forward?

One of the ways [these data are] going to play out clinically is that [they will motivate us to investigate] more combinations. We are going to be using more immunotherapy sooner, and we are going to do longer maintenance periods of hopefully more than 1 to 2 years. This is going to be good for patients, but it's going to be challenging, because many of the patients will be pre-exposed to immunotherapy, which can [complicate] future treatments.

Turning to NSCLC research, what was the rationale for conducting the CheckMate 816 trial?

The rationale for CheckMate 816 was to try to engage the immune system prior to patients receiving other treatments like surgery and chemotherapies, [after which they may] have a weaker immune system. Hot tumors, which are active inflammatory tumors, respond better to immunotherapy. A pathologic response [to immunotherapy] can improve surgical outcomes; it can hopefully make the surgeries and recoveries easier [because] the immune system is already primed to attack the cancer. The idea is to move [immunotherapy into] the neoadjuvant setting, and then hopefully after the surgery, we can reintegrate the immune system in a more comprehensive way.

What is your advice for colleagues about the use of neoadjuvant chemoimmunotherapy in NSCLC clinical practice?

[To use] neoadjuvant approaches, you have to have good communication with your teams. We all work in different teams and different settings, but in the ideal world, you should have good communication and relationships with your surgeons and pulmonary teams. You need to make sure you meet with them. You [need to] explain with them the rationale [for administering neoadjuvant therapy], the duration, the possible complications, and the possible timing for surgeries, so they understand and you work hand by hand [with them] to give patients immunotherapy and surgery at the right time.

What might be the future clinical implications of the phase 2 InTRist trial of toripalimab plus chemotherapy followed by concurrent chemoradiotherapy and consolidation toripalimab in NSCLC?

The InTRist trial is a chemoimmunotherapy and radiation study [similar to the phase 3] PACIFIC trial [NCT02125461]. In oncology, we want synergistic effects [between therapies]. We want the chemotherapy, immunotherapy, and radiation to work together to add on and multiply the effects [of each other]. That will boost the immune system and the effects of the chemotherapy to improve patients’ outcomes. [Many investigational] combinations are trying to work with that mechanism. We just need to find the right order and the right time.

How might the phase 3 HERTHENA-Lung02 trial (NCT05338970)help clarify the role of patritumab deruxtecan (HER3-DXd) in EGFR-mutated NSCLC?

The HERTHENA-Lung02 trial is solidifying the use of antibody-drug conjugates [(ADCs) in lung cancer]. We talk about ADCs as a single family, but in reality, we need to build them using different pieces: targets, payloads, receptors, microenvironments, and timing. At some point, we need to find the right combination, target, and payload to improve the efficacy [of this class of agents]. ADCs in general, slowly, are going to phase out traditional cytotoxic chemotherapies, and we are going to be designing more precise chemotherapies with the payloads and drug conjugates to [achieve] better efficacy, better targeting, and less toxicity. HERTHENA-01 is one of these [trials] that is at the forefront [of this research], and hopefully [its regimen of HER3-DXd] will be available in the regular thoracic clinic for our use.

References

1. Rudin C, Mountzios G, Sun L, et al. Tarlatamab versus chemotherapy (CTx) as second-line (2L) treatment for small cell lung cancer (SCLC): primary analysis of Ph3 DeLLphi-304. J Clin Oncol. 2025;43(suppl 17):LBA8008. doi:10.1200/JCO.2025.43.17_suppl.LBA8008
2. Forde PM, Spicer JD, Provencio M, et al. Overall survival with neoadjuvant nivolumab + chemotherapy in patients with resectable NSCLC in CheckMate 816. J Clin Oncol. 2025;43(suppl 17):LBA8000. doi:10.1200/JCO.2025.43.17_suppl.LBA8000