Durvalumab, Tremelimumab, and Chemotherapy Elicit Promising Long-Term OS Rates in NSCLC

Melissa L. Johnson, MD

Adding tremelimumab to durvalumab (Imfinzi) plus 4 cycles of chemotherapy resulted in durable long-term overall survival (OS) for patients with metastatic non­–small cell lung cancer (NSCLC), according to data from long-term follow-up of the phase 3 POSEIDON trial (NCT03164616).

In findings presented at the 2022 ESMO Congress, investigators found at a median follow-up of 46.5 months (range, 0.0-56.5) that the tremelimumab-based combination induced a median OS of 14.0 months (95% CI, 11.7-16.1) compared with 11.7 months (95% CI, 10.5-13.1) with chemotherapy alone (HR, 0.75; 95% CI, 0.63-0.88). That translates into a 25% reduced risk for death. The 36-month OS rates were 25% vs 13.6%, respectively.

Furthermore, investigators observed OS benefits with the combination therapy in a subgroup analysis of patients with difficult-to-treat mutations, including KRAS and STK11 mutations and KEAP1 alterations, according to Melissa L. Johnson, MD.

“The potential option of utilizing durvalumab, tremelimumab, and chemotherapy [in patients with metastatic NSCLC] adds another tool to the toolbox in terms of helping take a more personalized approach to the care of patients,” Johnson explained.

In an interview with OncLive^®, Johnson, a program director of the Lung Cancer Research, lead of the Solid Tumor Immune Effector Cellular Therapy Program, Sarah Cannon Research Institute, and chair of the Cancer Committee at Tristar Health, expanded on the updated data from the POSEIDEN trial, the rationale for investigating the combination, and what these results mean for the treatment of metastatic NSCLC.

OncLive^®: What was the rationale of investigating the combination in patients with metastatic NSCLC?

Johnson: At the 2022 ESMO Congress, the 4-year follow-up data on the clinical trial, POSEIDEN, were presented. The rationale behind POSEIDEN was [to determine] if we can add an anti–CTLA-4 [agent], tremelimumab, to the PD-L1 inhibitor durvalumab in combination with chemotherapy.

It was a limited amount of tremelimumab. That is in contrast with other randomized clinical efforts that have investigated PD-L1 and tremelimumab until progression with a limited amount of chemotherapy. However, in POSEIDEN all patients got at least 4 and as many as 6 cycles of chemotherapy. [We explored] the idea of adding anti–CTLA-4 and anti–PD-L1 to chemotherapy early, complete 4 cycles of chemotherapy [rather than just 2]. Then [we gave] with 1 more dose of tremelimumab once the chemotherapy has finished and patients’ immune systems were not being suppressed. Then, we would see the long-term effects of these immunotherapy agents.

Can you expand on the methodologies used during the trial?

Patients in the trial were [randomly assigned] to 1 of 3 treatment arms. Chemotherapy once every 3 weeks for up to 6 cycles was the control arm. In the first experimental arm, [patients received] durvalumab and chemotherapy once every 3 weeks for 4 cycles, followed by durvalumab maintenance once every 4 weeks until progression. The second experimental arm was durvalumab, tremelimumab, and chemotherapy once every 3 weeks for 4 cycles, followed by a fifth dose of tremelimumab at week 16, then durvalumab maintenance once every 4 weeks until progression.

The primary end points of the trial were progression-free survival [PFS] and OS in patients treated with durvalumab and chemotherapy. Alpha-controlled secondary endpoints included PFS and OS for patients treated with durvalumab plus tremelimumab and chemotherapy vs chemotherapy [alone].

What updated data were reported at the 2022 ESMO Congress?

In the primary report of the analysis a year ago, investigators reported that the addition of durvalumab improved PFS with a trend [toward] improvement in OS for patients treated with durvalumab/chemotherapy vs chemotherapy. Because the PFS end point was positive, we could share the alpha with the primary end points. Both PFS and OS were positive. They were prolonged for patients who received durvalumab/tremelimumab/chemotherapy vs chemotherapy.

[The durvalumab/tremelimumab/chemotherapy] regimen has emerged as perhaps a better [option] in some patients than the durvalumab plus chemotherapy standard of care for all others.

A median follow-up of 46.5 months was reported at the 2022 ESMO Congress, with a preservation of the OS benefit for patients treated with durvalumab and tremelimumab plus chemotherapy vs chemotherapy alone. The hazard ratio was 0.75, and 25% of patients [in the combination arm] were alive at 3 years.

We’ve seen over time with additional follow-up is that there are a group of patients at the tail end of the curve that are benefiting from the addition of tremelimumab [vs durvalumab/chemotherapy alone].

Were there any other additional insights gleaned from these updated data?

In this analysis, we also looked at subgroups, particularly for patients with nonsquamous NSCLC and those with PD-L1 levels of less than 1%. We saw an extended OS benefit for the durvalumab/tremelimumab/chemotherapy vs chemotherapy alone.

However, the most interesting analysis that was presented was an ad hoc analysis that looked at patients with difficult-to-treat mutations, including KRAS mutations, STK11 mutations, and KEAP1 alterations.

These are mutations that have been identified as difficult to treat with chemotherapy, as well as immunotherapy, in prior datasets. It doesn’t appear that the addition of immunotherapy to chemotherapy makes these patients do as well as other patients with NSCLC.

However, in the POSEIDEN dataset, what has emerged is that subgroups [of patients with KRAS mutations, STK11 mutations, and KEAP1 alterations] also did better with durvalumab, tremelimumab, and chemotherapy vs chemotherapy alone.

Although this dataset wasn’t powered to look at those subsets, it is interesting and thought provoking, as we await the decision from the FDA regarding durvalumab, tremelimumab, and chemotherapy. Will these mutation types be a place where we could use this quadruplet regimen?

What is the importance of testing for these potentially actionable targets?

With several different chemo-immunotherapy regimens to choose from, the question that is emerging is as you’re looking at a patient in the clinic is, what is best for that patient? We currently have only PD-L1 as biomarker to help guide us. However, these other potentially negative prognostic factors, or perhaps predictive factors, could help guide treatment decisions.

If I were a patient, I would want my doctor to know absolutely everything they could about my cancer before prescribing a frontline regimen, and this is valuable in terms of information that might be helpful.

What could these data mean for the treatment paradigm in metastatic NSCLC?

The frontline NSCLC cancer space couldn’t be more complicated than it is these days. We have several different mixtures of chemotherapy and immunotherapy to choose from. The general community oncologist has a big challenge trying to figure out when to use what.

Within my own practice, we are trying to assist doctors decide when to use immunotherapy alone, when to use chemotherapy plus immunotherapy, and when to add an anti–CTLA-4 therapy.

The good news is that the more complex that the frontline armamentarium becomes, the better the prospects are for our patients. We’ll be able to treat everyone differently, and we’ve never thought that all NSCLC should be treated equally.

Reference

Johnson M, Cho BC, Luft A, et al. Durvalumab (D) ± tremelimumab (T) + chemotherapy (CT) in 1L metastatic (m) NSCLC: Overall survival (OS) update from POSEIDON after median follow-up (mFU) of approximately 4 years (y). Ann Oncol. 2022;33(suppl 7):S1424-S1425. doi:10.1016/j.annonc.2022.08.061