Borghaei Breaks Down Choices in Immunotherapy Approaches in Lung Cancer

Hossein Borghaei, DO, MS

multiple immunotherapy approaches in recent years, the decision of whether to use a single-agent checkpoint inhibitor, to pair it with chemotherapy, or to pair it with another immunotherapy agent has come to the forefront of treatment, according to Hossein Borghaei, DO, MS. The luxury of having so many options is “progress—a [win] for our patients, and for what we can offer them,” said Borghaei. “At the end of the day, you consider the patient’s best interest, and what you, as a physician, think they can or cannot tolerate. With appropriate discussion and patient engagement, you come up with the best treatment option for each patient.”

In an interview with OncLive^® during the 18th Annual Winter Lung Cancer Conference®, a program hosted by Physicians Education Resource®, LLC, Borghaei discussed different immunotherapy strategies in the treatment arsenal, potential biomarkers of response to this approach, and ways to make the right decision for each patient with lung cancer. He is chief of thoracic medical oncology, professor in the Department of Hematology/ Oncology, and the Gloria and Edmund M. Dunn Chair in Thoracic Malignancies at Fox Chase Cancer Center.

OncLive®: Broadly speaking, singleagent immunotherapy, combination chemoimmunotherapy, and dual immunotherapy strategies are all available. What factors do you consider when choosing one approach over another?

Borghaei: [When making this decision,] we want to tailor the treatment to what each patient needs, and we also need to take into consideration their preferences. In general, for more simplified treatment, if I can get adequate control of the disease with 1 drug, that will be my preference— especially if that approach is supported by clinical data. On the other hand, we do know that the chemotherapy combinations, or even the dual immunotherapy combinations, that have been approved are fairly well tolerated and they have a toxicity profile that’s manageable.

As such, if it’s an appropriate patient, then I don’t hesitate to use combinations. I believe that this is an area where additional biomarkers can be helpful. However, at this point, PD-L1 and level of PD-L1 are quite helpful in deciding who might be a good candidate for single-agent treatment vs someone who might benefit more from a combination approach.

What ongoing research is being done to identify biomarkers of response to immunotherapy?

We have largely concentrated on PD-L1 [expression] and tumor mutational burden [TMB]. Obviously, a lot of data exist to support the use of PD-L1. Even though we still don’t think it’s that great of a biomarker, it is still pretty good at helping us figure out who should get a single-agent immunotherapy and do reasonably well with it. To date, many of the TMB studies that have been discussed or presented have utilized different methodologies; [for example,] there’s blood-based TMB and there’s tissue-based TMB. It has been difficult to put the data into perspective; however, it does appear, at least based on some of the retrospective data that have been presented so far, that TMB can be a useful biomarker.

I don’t consider myself a biomarker investigator, but my colleagues who are heavily involved in this area seem to believe that we’re heading toward more of a composite biomarker, perhaps PD-L1, TMB, and maybe a couple of other things coming together and sort of helping us figure out what the best way to treat a patient is.

[To that end,] there have been several discussions about these molecular determinants of response to immunotherapy. [Are] genes like STK11, AKT1, ARID1A associated with a lack of response or clinical efficacy, or do they indicate a lower benefit? A lot of work is ongoing in this area, and [I hope] we’ll come up with a composite score of some sort that will be a better determinant of efficacy than what we’re using right now.

You mentioned patient preference. Given the pandemic, patients may be concerned with spending extended periods of time in the clinic and potentially contracting coronavirus disease 2019. Are any specific regimens preferred for these patients?

Clearly, combination [regimens] require more time [to administer]. [A regimen of] chemotherapy with immunotherapy needs a little bit more time, and [a regimen of] 2 immunotherapy drugs given together obviously requires more time. Some single-agent immunotherapy drugs, or checkpoint inhibitors, can be given on an alternate schedule, where the patient doesn’t need to come in quite as often. From those perspectives, you can modify treatment for patients who are being treated with a single drug.

Many of the chemotherapy protocols have developed this once-every-3-weeks type of a dosing schedule; if your patient is getting a combination of chemotherapy and immunotherapy, it’s kind of hard to separate the 2. The patient still has to come in every 3 weeks for chemotherapy.

[That being said,] I don’t find that to be a major barrier with all the screening and other processes that most cancer centers and offices have put in place. I don’t believe this is a major issue to the extent that I would choose a treatment strictly because patients [may be able] come [into the clinic] less frequently.

We saw a benefit with atezolizumab and chemotherapy in patients with pretreated EGFR-mutant disease in the IMpower150 trial (NCT02366143), with the caveat that this was a small subgroup analysis. Is there a rationale to suggest that maybe those patients who receive osimertinib in the adjuvant setting and then progress could potentially receive immunotherapy in the metastatic setting?

IMpower150 tells us that there is a potential path forward for patients who have an EGFR-positive tumor post osimertinib, for instance. [It also showed us that] at least hypothetically and theoretically, the combination of a checkpoint inhibitor plus VEGF inhibition can be more effective in treating these tumors. I still believe that immunotherapy alone does not have a role in the treatment of patients with these molecularly driven tumors. Whether the combination of a chemotherapy and a VEGF inhibitor is definitely better than chemotherapy alone is [a question that requires] additional data. An ongoing randomized study [is evaluating this further].

If access to a clinical trial [is not an option], am I OK with a combination of chemotherapy plus immunotherapy? Yes, I’m fine with it, but I would also tell the patient that I don’t believe there are a lot of data right now to tell us whether that combination is necessarily going to be a lot better than chemotherapy alone; however, it’s a reasonable option to consider.

I definitely do not believe that patients who have these molecularly driven tumors, especially EGFR or ALK, should receive single-agent immunotherapy. IMpower150 really provided at least a hypothesis that can be tested in subsequent studies, and [I hope] we’ll have answers [to these questions] sooner rather than later.

Would you like to relay anything else to your colleagues who are currently deciding among all these regimens in the clinic?

I know it appears to be a little confusing, [deciding among] single-agent immunotherapy, chemoimmunotherapy, and dual immunotherapy. However, we now have a lot of choices for our patients, and that’s a good thing. If we have a patient who wants to avoid chemotherapy, a dual immunotherapy combination might be reasonable, or a short course of chemotherapy with immunotherapy, as in CheckMate 9LA [NCT03215706], might be appropriate for some patients who are truly unhappy about receiving chemotherapy for whatever reason. If a patient comes in with a really high PD-L1 expression, it is very reasonable to consider single-agent immunotherapy, but it’s also very reasonable to consider chemotherapy plus immunotherapy.

It just gives us these additional options that we didn’t have. In the world of lung cancer, we have to get used to the fact that we now have all these options, whereas 10 to 15 years ago, our options were very, very limited.