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Lung IO: Considerations From Experts
Considerations From Experts on Optimal Use of Immunotherapy for Patients With Lung Cancer

Released: January 23, 2023

Julie R. Brahmer
Julie R. Brahmer, MD, MSc, FASCO
Jarushka Naidoo
Jarushka Naidoo, MB BCH BAO, MHS
Zofia Piotrowska
Zofia Piotrowska, MD, MHS
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Key Takeaways

  • Both PD-L1 expression level testing and broad-based molecular testing are critical for all patients with NSCLC.
  • Patients with early-stage NSCLC should receive multimodality therapy including surgery, radiation therapy, chemotherapy, and/or immunotherapy (or targeted therapy) based on disease stage, tumor resectability, and multidisciplinary care team discussions.
  • For patients with advanced NSCLC and no driver mutations, chemotherapy plus an ICI can be considered regardless of PD-L1 expression, whereas single-agent ICI therapy should be considered for patients with high PD-L1 expression or those not considered candidates for chemotherapy.

In this commentary, Julie R. Brahmer, MD; Zofia Piotrowska, MD, MHS; and Jarushka Naidoo, MB, BCH, MHS, answer audience questions regarding challenges and strategies for the use of immune checkpoint inhibitors (ICIs) from a recent live symposium at the 2022 Society for Immunotherapy of Cancer Annual Meeting.

In your current clinical practice, when do you use an ICI as part of therapy for early-stage non-small-cell lung cancer (NSCLC)? How do you decide on neoadjuvant therapy? When do you consider initial surgery followed by adjuvant chemotherapy and atezolizumab? When would you consider definitive chemoradiation followed by maintenance durvalumab?

Zofia Piotrowska, MD, MHS:
For newly diagnosed patients with early-stage NSCLC, the key question is whether the patient is resectable or unresectable. That is a decision that should be made as a team with input from our thoracic surgery colleagues. This decision will guide us as to whether these patients should receive multimodality therapy including surgery or a nonsurgical multimodality approach.

When we talk about stage III disease, it is always important to remember that this is a very heterogeneous group of patients. Stage III disease includes either those with a large or centrally invasive T3 or T4 tumor with any nodal status or, by virtue of mediastinal lymph node involvement, either ipsilateral or N2 or contralateral or N3.

I practice at an institution where even for potentially resectable patients, we favored trimodality therapy with chemoradiation followed by surgery. There has been quite a lot of discussion among surgeons, radiation oncologists, and medical oncologists on our team, as these are not easy decisions. However, we have been impressed by the recent neoadjuvant data with the addition of an ICI to chemotherapy, and in patients for whom surgery is an option, we are leaning more and more toward a neoadjuvant chemotherapy/ICI approach, based primarily on the CheckMate 816 study. For patients with bulky disease or when the surgeon considers it not resectable, we would consider definitive chemoradiation followed by maintenance durvalumab based on the data from the PACIFIC trial in patients with unresectable stage III disease.

Jarushka Naidoo, MB, BCH, MHS:
The phase III Lung ART study recently demonstrated that the use of postoperative radiation in patients with stage III N2 disease after complete resection (with previous neoadjuvant or adjuvant chemotherapy allowed) was not associated with a disease-free survival benefit compared with no radiation. Based on these data, our radiation oncology colleagues in Europe have embraced the fact that the role of radiation in this setting might be declining, aside from those who are bona fide candidates for the regimen from the PACIFIC trial. 

However, choosing between the PACIFIC approach and a neoadjuvant approach is a nuanced area and does rely on our surgical colleagues to define what is resectable. One concern that we often see in our multidisciplinary team discussions is for patients who are borderline resectable, and I think it would be useful to have dedicated trials for this subset of patients, for whom there is not currently a consensus definition.

Julie R. Brahmer, MD:
I agree that it can be difficult to decide which approach is best for some of our borderline patients. In my practice, radiation oncologists are consistently still recommending chemoradiation for too bulky N2 disease or even in some patients with difficult N1 disease. For example, we recently had a patient with N1 disease that wrapped around the pulmonary artery and ultimately decided to manage their disease with chemoradiation. 

What would you recommend for a patient who received neoadjuvant therapy with chemotherapy plus ICI therapy but did not achieve a pathologic complete response? 

Zofia Piotrowska, MD, MHS:
In my current clinical practice, I feel compelled to give these patients additional therapy, but I struggle with the fact that the adjuvant therapy we have to offer is the same chemotherapy and ICI therapy that the tumor did not respond to previously. 

What I hope to do is put these patients on clinical trials with novel adjuvant treatment approaches, and this is certainly an area where I would love to see more work done. However, today we will offer these patients additional therapy with chemotherapy and/or ICI therapy.

Julie R. Brahmer, MD:
The CheckMate 816 study did allow optional adjuvant chemotherapy with or without radiation therapy. I am interested to see additional analyses of these patients who did receive additional therapy from this study and how well they did long term.

What is your pathway for making treatment decisions for patients diagnosed with advanced NSCLC? When do you recommend ICI-based therapy?

Julie R. Brahmer, MD:
Certainly, our understanding of advanced NSCLC and the treatment modalities available has greatly changed over the past couple of years and continues to change, even on a weekly basis. Overall, we base management decisions on disease histology (squamous vs nonsquamous) and any targetable mutations present, and then we assess PD-L1 expression for those patients who do not have a targetable mutation. Of course, patient-related factors are always important to consider and include preference and goals of therapy, overall health, and any history of autoimmune diseases or transplant if considering ICI-based therapy. 

Treatment options for advanced NSCLC without driver mutations depend on the disease histology, as well as PD-L1 status. Generally, chemotherapy plus an ICI can be considered regardless of PD-L1 expression, whereas single-agent ICI therapy should be considered for patients with high PD-L1 expression, based on the KEYNOTE-024 trial with pembrolizumab, the EMPOWER-Lung 1 trial with cemiplimab, and the IMpower110 trial with atezolizumab. ICI/ICI combinations nivolumab and ipilimumab with or without chemotherapy also can be considered for some patients based on CheckMate 9LA and CheckMate 227. For patients who may not need chemotherapy or may not tolerate chemotherapy, single-agent ICI therapy can be a good option.

What do you do for patients who received an ICI as part of neoadjuvant or adjuvant treatment and progressed to advanced-stage disease? Do you still consider an ICI for advanced-stage disease?

Zofia Piotrowska, MD, MHS:
We have very little data to guide us for this question, as many of the studies with ICI therapy in the advanced setting were designed before ICI therapy had been approved in early-stage disease. My answer depends on various patient factors, including the interval of time from last ICI therapy and the patient’s PD-L1 expression.

For a patient who has relapsed during or soon after ICI therapy, I might feel less inclined to continue with additional ICI treatment for advanced disease, whereas if they had a durable response and later relapsed, I would feel more compelled to reintroduce an ICI because it did have some benefit in the past. This decision also depends on a patient’s PD-L1 status, in that I would be more likely to recommend additional treatment with an ICI for patients with high PD-L1 expression. For patients who have previously received ICI monotherapy, I would mostly likely consider a chemotherapy plus ICI combination.

Julie R. Brahmer, MD:
In the EMPOWER-Lung 1 trial with first-line cemiplimab, there was an option to continue cemiplimab and add 4 cycles of chemotherapy after progression of their disease. Of interest, a response rate of 31.3% was reported in those patients who continued the ICI and added chemotherapy, with a median overall survival of 15.1 months after progression (27.4 months overall).

It is hard to say how much this differs from going directly to chemotherapy instead of the combination, but we have a few ongoing trials that may help answer this question. The phase III INSIGNA trial from ECOG-ACRIN/SWOG is exploring how best to sequence therapies for patients with PD-L1 expression ≥1%. In this trial, patients will be randomized to receive either first-line pembrolizumab and second-line chemotherapy at the time of progression or first-line pembrolizumab and adding chemotherapy to the ICI at progression (as in the cemiplimab trial) or first-line therapy with pembrolizumab plus chemotherapy.

Jarushka Naidoo, MB, BCH, MHS:
I agree, and I currently also think about the treatment-free interval and extrapolate from other disease settings. In these data-free zones, it is important for us to revisit the first principles; in effect, we need to keep the tumor guessing. If a patient experiences progression within 6 months or a short timeframe, there is an argument for not continuing ICI therapy and switching to chemotherapy alone.

Final Thoughts on the Use of ICIs for NSCLC

Jarushka Naidoo, MB, BCH, MHS:
Immunotherapy is considered a standard of care for patients with NSCLC without oncogenic driver mutations, particularly in patients with PD-L1-positive disease, and these agents have transformed our care. One of the features that makes us so excited about immunotherapy is that a proportion of our patients achieve long-term benefit, particularly in the earliest-stage setting. So, it is important to remember that patients with lung cancer all have different journeys and different comorbidities and are in very different clinical situations, and we have to tailor our approach toward that.

Zofia Piotrowska, MD, MHS:
Yes, it is critical for all patients with NSCLC, even in the early-stage setting, to have biomarker testing performed so that we can select the right treatment. Immunotherapy is a wonderful option for many patients, but there are some patients for whom targeted therapies are more appropriate. I hope that we will begin seeing broader molecular testing in early-stage disease moving more and more to the forefront of our clinical practice recommendations. 

Jarushka Naidoo, MB, BCH, MHS:
When we think about tailoring our treatment approach for individual patients, it is also important to think about potential disparities in care, including access to treatment options for our patients with NSCLC. Data presented at the 2022 American Society of Clinical Oncology Annual Meeting suggested that in earlier-stage lung cancer, even in the United States, there remain significant disparities in terms of timeliness to surgery, quality of anatomic resection, use of minimally invasive approaches, and adequacy of nodal staging and negative margins. Differences in some of these surgical techniques result in differences in both recurrence-free and overall survival and can have a major effect on the outcomes for our patients. Of course, no topic on disparities would be complete without mentioning recommended molecular testing, which Dr Piotrowska did. In many retrospective reports, patients continued to have inadequate molecular testing in some settings, resulting in many racial and ethnic and socioeconomic disparities in care.

As the treatment landscape for NSCLC continues to evolve, we need to make sure that all of our patients are able to access equitable diagnostic testing; treatment in terms of standard surgical and other techniques, as well as ICIs and novel agents; and clinical trials.

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