Borghaei Stresses Importance of Immunotherapy Biomarkers in Frontline Advanced NSCLC Treatment

Hossein Borghaei, DO, MS, further discusses the benefit of immunotherapy combinations, the potential of tiragolumab, and the need for better biomarkers to guide treatment in NSCLC.

The availability of immunotherapy combinations, some of which feature the addition of chemotherapy, presents a beneficial frontline treatment option for patients without molecularly driven non–small cell lung cancer (NSCLC), but patient selection for these regimens needs to be improved, according to Hossein Borghaei, DO, MS.

“Being familiar with the regimens, knowing the [adverse event] profile, and having that open discussion with the patient about what their regimen can or cannot do is the bottom-line message,” said Borghaei.

One of the recent immunotherapy combination approvals in the space comprises nivolumab (Opdivo) plus ipilimumab (Yervoy) for use in patients who do not have EGFR or ALK genomic tumor aberrations, as well as a PD-L1 level ≥1%. The May 2020 approval is based on findings from the phase 3 CheckMate-227 trial, in which the combination improved overall survival (OS) independent of PD-L1 expression, compared with chemotherapy. However, PD-L1 expression and tumor mutational burden (TMB) should not be used as biomarkers to predict clinical efficacy, explained Borghaei.

Later in May 2020, the FDA approved nivolumab plus ipilimumab and 2 cycles of platinum-doublet chemotherapy s a first-line treatment of patients with metastatic or recurrent non—NSCLC with no EGFR or ALK genomic tumor aberrations.

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on lung cancer, Borghaei, chief of Thoracic Medical Oncology, professor in the Department of Hematology/Oncology, co-director of the Immune Monitoring Facility, and Gloria and Edmund M. Dunn chair in Thoracic Oncology at Fox Chase Cancer Center, further discussed the benefit of immunotherapy combinations, the potential of tiragolumab, and the need for better biomarkers to guide treatment in NSCLC.

OncLive®: What excites you the most regarding recent advances in frontline NSCLC treatment?

Borghaei: There are a lot of developments in the frontline treatment of NSCLC. We have several targeted therapies and a couple of different immunotherapy-based regimens that have been approved. It has been quite fascinating and is a very active area of approval, drug development, and regimen improvement. Targeted therapies, such as the approval of MET and RET inhibitors, have been quite exciting, as well.

For patients who do not have molecularly driven tumors, what we're seeing now is the use of an immunotherapies alone or in combination. This is regarding the combination of nivolumab plus ipilimumab for patients with PD-L1 expression of at least 1%, or the use of an abbreviated course of chemotherapy with just 2 cycles of chemotherapy plus nivolumab plus ipilimumab—a quadruple therapy. This seems to be regardless of the level of PD-L1 expression.

What are the barriers or challenges surrounding genetic testing in this patient population?

From personal experiences here and there, getting adequate tissue has always been a problem. The introduction of liquid biopsy panels has been quite effective and helpful in alleviating some of the need for tissue for patients who require molecular testing. I'm hoping that with improvement in the sensitivity and specificity of liquid biopsies, and the spread of really good data that we have now, we'll be able to cover more patients than we are now. 

The other big challenge has been turnaround time. Some of us are fortunate enough to have in-house panels where the testing can be done relatively quickly. Some of us live in areas where we have relatively easy access to other entities that can do molecular testing. But, waiting anything beyond 2 weeks for a patient with metastatic lung cancer, to get molecular data to decide what treatment they should get, becomes a little bit of a difficult proposition for both patients and clinicians. Again, this is an area where, based on the available data, liquid biopsy panels seem to be quite effective and limits the time that is required. Nonetheless, that is a problem. 

Patient characteristics [are another important factor]. In patients with advanced or symptomatic lung cancer, there's a need to start treatment as early as possible. We know that once they deteriorate in terms of performance status, then it becomes difficult to take patients through aggressive treatment. It's a combination of different issues that include reimbursements and copays, at least for some patients.

Recently, we have been introduced to the idea that perhaps interpretation of some of the molecular data has been a bit more difficult. Additional discussions [are taking place] around what the data mean when you get the molecular testing and how to use it. This is definitely a multifactorial reason for why molecular testing is not as adequate as we want it to be and what we need to concentrate on in order to make it better.

In turning the focus to immunotherapy/chemotherapy combinations, what are the clinical implications of the KEYNOTE-407 and KEYNOTE-189 trials?

The bottom-line message is that the combination of chemotherapy plus a checkpoint inhibitor is more effective than chemotherapy alone. The IMpower150 trial is a little bit different in that a quadruplet therapy [was used]. Nonetheless, there is at least an additive effect when you combine a checkpoint inhibitor with chemotherapy. If someone has NSCLC, regardless of histology and [without] a driver mutation, the combination of standard platinum-based doublet chemotherapy with a checkpoint inhibitor can be quite effective. 

In this case, KEYNOTE-189 and KEYNOTE-407 used pembrolizumab [Keytruda], but there are other examples of combinations that could be helpful. The clinical efficacy does seem to cross all PD-L1 levels. This means that if you look at KEYNOTE-189, patients with PD-L1 expression of 50% or higher who benefit from single-agent immunotherapy also benefit quite a lot from chemotherapy plus immunotherapy. Patients with lower or zero levels of PD-L1 expression still seem to benefit from a combination of chemotherapy plus immunotherapy over chemotherapy alone. 

Moreover, the immune-related AEs did not seem to worsen with the combination. There is definitely a bit more toxicity [overall] when you combine chemotherapy with a checkpoint inhibitor, but that sort of makes sense. Overall, at least from the clinical efficacy point of view, it does seem that efficacy outweighs some of the increased risks that we see. 

In some studies, such as KEYNOTE-189, there was an increase in renal toxicity, so paying attention to these [immune-related] AEs is important. Nonetheless, given the efficacy that we see with the combination suggests that the combination [regimen] should be the standard of care. 

The CheckMate-227 trial evaluated a chemotherapy-free regimen. How does this change an optimal sequence of therapies for an individual patient?

[I have presented on some of the data from] CheckMate-227 [and am on the steering committee]. I have to admit, and I've said this several times at meetings, I'm biased towards a checkpoint inhibitor–only approach. This is not because I don’t like chemotherapy but because I think chemotherapy comes with added AEs. If we can avoid it, or if we can use it down the road, it might be a little bit more beneficial. Nonetheless, chemotherapy plus immunotherapy, clearly in a number of studies, has shown to be quite effective. 

CheckMate-227 is a study that basically investigated the role of a chemotherapy-free regimen with nivolumab and ipilimumab in the management of patients with advanced lung cancer. Patients were randomized based on if they had PD-L1 expression 1% or higher versus PD-L1 [expression] less than 1%. The goal was to see the [efficacy] of ipilimumab/nivolumab compared with chemotherapy, regardless of the level of PD-L1 [expression].

The bottom line is that a couple of different biomarkers were looked at, including TMB, and at the end of the day TMB, at least the way it was measured and used in this particular study, did not seem to predict clinical efficacy. However, in PD-L1–positive patients, which is where the FDA approval is, the combination of ipilimumab/nivolumab was superior to standard platinum-based doublet chemotherapy. That represents another option.

CheckMate-227 also does show that perhaps ipilimumab/nivolumab in PD-L1–negative tumors can be efficacious. That was not [included in] the FDA approval process because that subgroup wasn't necessarily statistically accounted for in the analysis. As it stands now, for patients with PD-L1–positive tumors, the combination of ipilimumab/nivolumab without any chemotherapy can represent a reasonable treatment option. 

There are patients who don't want chemotherapy or might not be good candidates for chemotherapy for a variety of different reasons—if a patient has significant preexisting neuropathy and squamous cell histology, for example, using a taxane-based regimen might exacerbate that. Patients who have renal insufficiency and nonsquamous histology might not be candidates for a pemetrexed-based regimen.

Therefore, having the option of ipilimumab/nivolumab and a patient with PD-L1 [expression] over 1% is attractive. From a personal point of view, I like the data on the PD-L1–negative [patients], but that requires additional studies and investigation. Perhaps, additional trials in terms of comparing that regimen to chemotherapy will be conducted in the future.  

How do these findings compare with those of the CheckMate-9LA study?

In CheckMate-9LA, [the investigators utilized] ipilimumab/nivolumab with a slightly different dosing. However, it has only 2 cycles of chemotherapy [used in combination]. From my point of view, if I can use only 2 cycles of chemotherapy and limit the cytotoxic effect of chemotherapy, that might be better. I can always come back to chemotherapy if ipilimumab/nivolumab by itself doesn't control the disease. 

In a way, that allows us to personalize the care a bit more. I wish there were better biomarkers to really tell us who would really benefit from an ipilimumab/nivolumab combination and who would really benefit from a chemotherapy/immunotherapy combination. Right now, we don't have that and that is a deficiency that hopefully will be corrected.

The novel immunotherapy agent tiragolumab was heavily discussed this year. How does this agent differ from other available checkpoint inhibitors?  

CITYSCAPE was a little bit of a surprise. All of a sudden we have another immunotherapy/immunotherapy combination here using an antigen with a PD-L1 inhibitor in a smaller study in the frontline setting. In patients with high PD-L1 [expression, tiragolumab] shows good clinical efficacy in terms of improvements in PFS and response rates.

It's interesting because it could represent yet another chemotherapy-free option. This has led to the discussion, rightfully so, that perhaps TIGIT expression and PD-L1 sort of co-travel together. It’s a really interesting phenomena. Again, it could be another immunotherapy/immunotherapy combination for high PD-L1–expressing tumors.

The AE profile seems to be reasonable. Obviously, a patient’s perspective is a lot more important than a clinician’s perceived clinical benefit and toxicity. You're going to ask a patient how they feel on regimens. Nonetheless, having some information about patient-reported outcomes and how patients feel on these studies becomes very important; [we need to] make sure that we're not missing something from a clinician point of view that can be overlooked. 

Based on everything that I have seen, the data that have been presented, and talking to colleagues who review some of these regimens over the years, tiragolumab in combination with atezolizumab (Tecentriq) does seem to be very promising. 

What do these combination studies tell us about the future of advanced NSCLC treatment?

There are a ton of data out there and there are a number of different options. Having an understanding of what the patient's priorities are and what the regimen can or cannot do is important. You can now potentially offer a patient a regimen that fits with their lifestyle. [Additionally,] trying to predict what AEs could get a patient into trouble matters, such as neuropathy in somebody who might need to get a paclitaxel-based regimen. Having an understanding of some of these basic ideas and preferences all becomes an important factor [in treatment decision making].

We have a lot of options now in lung cancer and it might look overwhelming or confusing, but we've always liked options. For patients who do not have a molecular-driven tumor, we have chemotherapy/immunotherapy, immunotherapy/immunotherapy, and abbreviated chemotherapy plus immunotherapy doublets. We potentially have a CITYSCAPE[-type regimen] if we can confirm those data in larger studies. These are good for our patients because it gives us more options.


  1. Hellmann MD, Paz-Ares L, Caro RB, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Eng J Med. 2019;381:2020-2031. doi:10.1056.NEJMoa1910231