Data With TTFields Raise Questions Around the Future of Immunotherapy in Metastatic NSCLC

The utilization of tumor treating fields (TTFields) holds promise for patients with advanced in non–small cell lung cancer (NSCLC) who progress on frontline therapy. However, questions about this and other immune-modulating approaches remain, according to Tony S.K. Mok, MD, BMSc, FRCPC, FASCO.¹

Notably, data from the phase 3 LUNAR trial (NCT02973789), which evaluated TTFields in patients with metastatic NSCLC whose disease had progressed on or after platinum-based chemotherapy, were presented at the 2023 ASCO Annual Meeting. Eligible patients were randomly assigned to receive TTFields in combination with standard of care treatment: docetaxel or an immune checkpoint inhibitor, or standard of care treatment alone. Results demonstrated that the addition of TTFields led to a median overall survival (OS) of 13.2 months (95% CI, 10.3-15.5) vs 9.9 months (95% CI, 8.1-11.5) with standard of care treatment alone (HR, 0.74; 95% CI, 0.56-0.98; P = .035).²

“TTFields use a magnetic treatment field to affect the mitotic process of cancer cells, or its surrounding cells. Although early data obtained with this approach involve brain tumors, [its use in] lung cancer is different because [we] are using chemotherapy and immunotherapy,” Mok said in an interview with OncLive^® during the 24th Annual International Lung Cancer Congress^®. “Overall, there has been a positive outcome, but we have to be very cautious in interpretation.”

In the interview, Mok provided his perspective on the use of TTFields in lung cancer, the use of anti–PD-L1 inhibitors approved in China, and the potential impact of the microbiome on response with immunotherapy.

Mok is the Li Shu Fan Medical Foundation Professor of Clinical Oncology and the chairman of the Department of Clinical Oncology at The Chinese University of Hong Kong in China.

OncLive: What are some of the most promising areas with regard to improving response to immunotherapy in lung cancer?

Mok: A lot is coming with immunotherapy. Firstly, I discussed TTFields, as well as potential combination [strategies], including TIGIT or LAG3 [inhibitors] in combination with PD-L1 inhibitors. I also discussed bispecific molecules that may be coming.

Since I come from Asia, I [also highlighted] the potential of Chinese anti–PD-L1 treatment coming [to the] United States. Additionally, I [pointed out] new approaches. Of course, apart from checkpoint inhibitors, there's other ways to moderate the immune system, including cancer vaccines, cell therapy, as well as fecal transplant.

What makes TTFields a potentially novel approach in lung cancer? What stood out to you about the data from the phase 3 LUNAR trial?²

[In this trial], investigators compared TTFields with standard of care treatment, which included treatment with single-agent docetaxel or single-agent immunotherapy. The outcome has been positive. However, if you look at a subgroup analysis, there's no benefit [with the] combination with docetaxel. Rather, the benefit is with the immunotherapy. That’s interesting because, in theory, the chemotherapy may work better with this kind of therapy. However, if you look carefully into the data on PD-L1 status, approximately 49% of the patients have unknown PD-L1 status in the [investigational] arm and 38% [have unknown status] in the control arm.

Because of these [factors], it is unknown where the [benefit] is coming from, making this the number 1 query that we have. Secondly, stage IV lung cancer is a systemic disease. How can a local treatment change the paradigm of a systemic disease? Therefore, I would like to look at the data of the tumor response outside the treatment field, but those data are lacking [in] this presentation. Therefore, at this point, I don't think the data are convincing enough for me to change my practice.

What are some of the most promising targets for immunotherapy? What remains to be seen with this research?

One headline in my presentation is: Will the skyscraper crumble? A lot is riding on the phase 3 SKYSCRAPER-01 trial [NCT04294810] because it's 1 of the biggest studies [in the space] based on randomized phase 2 data. We already know that progression-free survival is negative, and we are waiting for the overall survival [data] to come out. Therefore, if that turns out to be negative as well, the question mark will be even bigger. A lot will be riding on [the SKYSCRAPER] studies.³

In terms of cellular therapy, we haven't seen huge success in solid tumors. Therefore, what is the rationale for its investigation in lung cancer?

The rationale is the fact that [there is still a big] proportion of patients who need [an effective] therapy. However, there are major roadblocks. One roadblock is whether the epitope is specific enough for the cancer. Another one is that the tumor microenvironment may be hostile, and it is unclear whether the CAR T cells can penetrate the microtumor environment of a solid tumor. Those are the major things that we have to look into.

However, this [therapy] is not without success. There is an ongoing study looking at CAR T-cell therapy, and early data look interesting. The study is ongoing and I think that we should wait and see [more data]. In lung cancer, there are a lot of discussions, but there's no good data so far that I can see.

In your presentation, you discussed the potential role of toripalimab in the United States. Why should the FDA consider approving a PD-1 inhibitor for which a trial has not been performed in a United States population?

It's not a matter of we need another one, it is rather whether we need a cheaper one. Right now, an anti–PD-1 [inhibitor can be] available in China for only a fraction of the price [of an equivalent agent] in the United States. [Toripalimab] is good, as demonstrated by multiple randomized studies, but the only issue is that [investigators] do not have the resources to do a study in the United States. This doesn't mean that it's not applicable to patients in the United States. There is a lot of regulatory issues, but what should be the case? Should it be the biology we look at more, or should we investigate the regulatory issues barrier?

What further research would you like to see conducted for patients with oncogene-driven disease?

It would be very interesting to look into a subgroup of patients with the KRAS G12C [mutation] in association with KEAP1 and STK11. It is interesting that each [alteration] could be an independent predictor [of response]. However, that patient subgroup in most clinical trials is very small, making it [difficult] to make an interpretation of the data. We face this clinical situation [in our practice] and have to [extrapolate] from the subgroup analysis of this major clinical trial, which can be very challenging.

How would you approach treatment for such a patient in your practice?

In these situations, we may have to look at what the most dominant predictor is. To me, mutation status may have implications on immunotherapy, but they're not sufficient [enough] to exclude me from using them as a single agent. I still look at the PD-L1 status as the optimal [predictor of response] and if they are above 50%, I may still be very interested to use single-agent immunotherapy.

How does a patient’s microbiome influence response with immunotherapy? What can be done to trigger response with checkpoint inhibition?

The interaction between the microbiome and the immune system has been well established. But, [we have yet to establish] how changing the microbiome may affect [responses with] immune checkpoint inhibitor therapy. That is still a big question mark and we're still learning. At the 2023 ASCO Annual Meeting, an interesting study was presented using fecal microbiota transplant combined with PD-1 inhibition. Out of the 13 patients on study, 1 patient [had a partial response]. That gives an interesting signal because there's no other reason to believe why this patient may have had a response.

There's a lot to learn. The fecal transplant is probably just speculative [at this point], dependent on a good microbiome from the patient. This is then hypothesized to affect responses. This is too new in the way of management, but trying to identify which bacteria may have an impact [on response to treatment] may be helpful in the future.

References

1. Mok T. What is coming in immunotherapy? Presented at: 24th Annual International Lung Cancer Congress; July 27-29, 2023; Huntington Beach, CA.
2. Leal T, Kotecha R, Ramlau R, et al. Tumor Treating Field (TTFields) therapy with standard of care (SOC) in metastatic non-small cell lung cancer (mNSCLC) following platinum failure: randomized, phase 3 LUNAR study. J Clin Oncol. 2023;41(suppl 17):LBA9005. doi:10.1200/JCO.2023.41.17_suppl.LBA9005
3. Roche reports interim results for phase III SKYSCRAPER-01 study in PD-L1–high metastatic non-small cell lung cancer. News release. Roche. May 11, 2022. Accessed August 2, 2023. https://www.roche.com/media/releases/med-cor-2022-05-11