CCR4 Antagonists May Bolster Immune Responses With Checkpoint Inhibitors in PD-L1+ NSCLC

The addition of tivumecirnon to pembrolizumab was safe, well-tolerated, and clinically active vs the historical activity of pembrolizumab monotherapy in patients with checkpoint inhibitor–naive non–small cell lung cancer.

Robert A. Anders, MD, PhD

Robert A. Anders, MD, PhD

Adding the oral, selective CCR4 antagonist tivumecirnon (FLX475) to pembrolizumab (Keytruda) may help overcome immune resistance and enhance antitumor responses with standard immunotherapy in patients with advanced non–small cell lung cancer (NSCLC) who are naive to checkpoint inhibitors, supporting the continued development of this approach for PD-L1–positive patients, according to Robert A. Anders, MD, PhD.

Interim data from the dose-expansion portion of the phase 1/2 FLX475-02 trial (NCT03674567) of tivumecirnon in combination with pembrolizumab were presented during the 2023 SITC Annual Meeting. Results showed that the combination was safe, well-tolerated, and clinically active vs the historical activity of pembrolizumab monotherapy in patients with checkpoint inhibitor–naive NSCLC.

At the data cut-off of October 6, 2023, all evaluable patients (n = 36) experienced a confirmed overall response rate (ORR) of 28% (95% CI, 16%-44%) and an unconfirmed ORR of 36% (95% CI, 22%-52%). All responders experienced a partial response, and the confirmed stable disease and progressive disease rates were 39% and 33%, respectively.

In patients with a PD-L1 tumor proportion score (TPS) of 1% or greater (n = 20), the confirmed ORR was 40% (95% CI, 22%-61%). Those with a TPS of 1% to 49% (n = 16) experienced a confirmed ORR of 38% (95% CI, 18%-61%), and those with a TPS of at least 50% (n = 4) had a confirmed ORR of 50% (95% CI, 15%-85%). The confirmed median progression-free survival with the combination in the overall cohort was 3.5 months (95% CI, 2.1-8.9) and 6.3 months (95% CI, 3.4–not reached) in patients with a TPS of at least 1%. The confirmed median duration of response was 10.2 months (95% CI, 2-20.6+) for both groups.1

Moreover, a concurrent presentation of biomarker data showed that FLX475 alone or in combination with pembrolizumab significantly increased the levels of regulatory T cells in the blood in a dose-dependent manner. Overall, results suggested that a higher level of intratumor regulatory T cells vs non-responders at baseline, and a low level of regulatory T cells in peripheral blood, correlating with more favorable responses and survival outcomes with the combination.2

“Up to this point, [tivumecirnon] has shown encouraging results [indicating that] that it may increase responses [in patients with NSCLC],” said Anders, who is an associate professor of pathology at the Johns Hopkins University School of Medicine and a member of the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland. “[The agent’s] limited toxicity and results in combination with an immuno-oncology [agent] are both encouraging signs.”

In an interview with OncLive®, Anders discussed the how unique mechanism of CCR4 antagonists such as tivumecirnon could improve immune responses when administered alongside checkpoint inhibitors; early results with tivumecirnon in patients with NSCLC, particularly those with PD-L1–high status; and the potential use of tumor-driven biomarkers for patient stratification and prediction of benefit with this approach for this patient population.

OncLive: What is the rationale for investigating CCR4 antagonists as possible therapeutic options across various malignancies?

Anders: The CCR4 receptor is postulated to recruit inhibitory cells into the tumor and work locally within the tumor. [Accordingly], using agents that target CCR4 [could allow] us to inhibit the immunosuppressive function that's associated with this receptor [through 2 different mechanisms].

What is unique about the mechanism of action of the CCR4 antagonist tivumecirnon? How does this support its investigation in combination with checkpoint inhibitors in patients with NSCLC?

[Tivumecirnon] is a small molecule and it's orally available, which makes it [an] attractive [option]. Because it's not antibody based, tivumecirnon is not necessarily depleting these inhibitory cells, [which] is postulated to [produce] fewer adverse effects [AEs]. Depleting inhibitory cells throughout the body could lead to immune-mediated AEs.

The main rationale for adding a CCR4 antagonist [to pembrolizumab] would be that tivumecirnon monotherapy has been shown to be so well tolerated. There have been no additional immune-associated AEs.

Could you provide an overview of initial responses seen with the combination in the phase 2 study of patients with NSCLC?

Anti–PD-1 treatment is a standard therapy in NSCLC. One of the encouraging results [seen with] pembrolizumab plus tivumecirnon is that [the combination is producing] good responses not only in patients with a high TPS [score], but also in patients with a TPS score that's below 50%.

From a pathologist’s perspective, what strategies can be used to identify patients who might benefit from this type of therapy?

Patient biomarkers are useful. Now, they may not be useful for an individual patient, but they're certainly useful in populations. [We tend to] exclude patients we know won't benefit [from a given therapy], thereby enriching for patients who may derive a response. With [tivumecirnon], we know that there is a decrease in regulatory T cells and an increase in CD8 cells. That could function as a tissue-based biomarker. There's also some modulation of regulatory T cells in the patients’ peripheral blood, so there's opportunity for developing both tissue-based and peripheral blood–based biomarkers.

Looking ahead, what do these early data indicate about the potential role for tivumecirnon plus pembrolizumab in this patient population?

The take-home message here is twofold. First, tivumecirnon [has appeared] to be safe. The AE profile is limited to QTc prolongation, which is reversible by decreasing the dose of the drug. Over 300 patients have received the agent, and it has been very well tolerated. Second, the data up to this point have been encouraging [and signal] that there may be some additional benefit derived from adding this agent [to checkpoint inhibitors]. That needs to be tested [further], but these are encouraging signs.


  1. Kim T, Ngamphaiboon N, Lee K, et al. Phase 2 safety and efficacy of oral CCR4 antagonist FLX475 (tivumecirnon) plus pembrolizumab in subjects with non–small cell lung cancer not previously treated with checkpoint inhibitor. Presented at: 2023 SITC Annual Meeting; November 1-5, 2023; San Diego, CA. Abstract 629-C.
  2. Adamki J, Grant A, Trujillo D, et al. Biological activity of FLX475, an oral CCR4 antagonist, as monotherapy and in combination with pembrolizumab in advanced cancer. Presented at: 2023 SITC Annual Meeting; November 1-5, 2023; San Diego, CA. Abstract 704.
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