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Expert Answers to FAQs on Immune Checkpoint Inhibitors for NSCLC

Julie Brahmer, MD, MSc

Professor of Oncology
Thoracic Oncology
Co-Director, Upper Aerodigestive Cancer Program
Bloomberg-Kimmel Institute for Cancer Immunology
Sidney Kimmel Comprehensive Cancer Center
Johns Hopkins Medicine
Baltimore, Maryland

Julie Brahmer, MD, MSc, FASCO: consultant/advisor/speaker: Amgen, Blueprint, Bristol-Myers Squibb, Genentech/Roche, Lilly, Janssen, Johnson & Johnson, Merck; researcher: Bristol-Myers Squibb.

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Natasha Leighl, MD, MMSC, FRCPC, FASCO

Department of Medicine
University of Toronto
Lung Site Lead
Department of Medical Oncology and Hematology
Princess Margaret Cancer Centre
Toronto, Ontario, Canada

Natasha Leighl, MD, MMsc, FRCPC, FASCO: researcher: Amgen, Array, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, EMD Serono, Guardant Health, Inivata, MSD, Novartis, Pfizer, Roche, Takeda; consultant/advisor/ speaker: Amgen, Bristol Myers Squibb, GlaxoSmithKline, MSD, Novartis, Puma Biotechnology, Sanofi Genzyme, Takeda.

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Jarushka Naidoo, MB BCH BAO, MHS

Consultant Medical Oncologist
Beaumont Hospital/RCSI University of Health Sciences
Dublin, Ireland
Adjunct Assistant Professor
Department of Oncology
Johns Hopkins University
Baltimore, Maryland

Jarushka Naidoo, MB BCH BAO, MHS: advisor: Amgen, AstraZeneca, Bristol-Myers Squibb, Merck, NGM Pharmaceuticals, Pfizer, Roche/Genentech, Takeda; data and safety monitoring board: Daiichi Sankyo.

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Released: August 26, 2022

Key Takeaways:

  • Testing for EGFR/ALK alterations and PD-L1 status up front in patients with early-stage non-small-cell lung cancer (NSCLC) can help inform whether to recommend immunotherapy.
  • Immunotherapy rechallenge may be beneficial in patients experiencing disease recurrence ≥12 months after completing immunotherapy for early-stage
  • Single-agent immunotherapy may be considered for a patient with advanced NSCLC and an Eastern Cooperative Oncology Group performance status of 2 based on supportive data from the PePS2 study.

In this commentary adapted from a live satellite symposium at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, expert faculty Julie Brahmer, MD, MSc; Natasha Leighl, MD, MMSC, FRCPC, FASCO; and Jarushka Naidoo, MB BCH BAO, MHS, answer audience questions on leveraging immune checkpoint inhibitors (ICIs) for the management of early-stage and advanced non-small-cell lung cancer (NSCLC). 

How would you treat a patient with stage IIIA NSCLC, a single tumor in the right upper lobe, and a single involved right-side mediastinal node that is 2 cm?

Jarushka Naidoo, MB BCH BAO, MHS:
I recently saw such a patient—a 63-year-old man who was a former smoker with no comorbidities and an excellent performance status (PS). In my practice, this type of patient with a small primary tumor and single-station N2 disease would be a strong candidate for neoadjuvant therapy followed by surgery, which we would recommend over definitive chemoradiotherapy. However, it is important to understand the patient’s preferences regarding systemic therapy before or after surgery.

In my opinion, a patient like this would benefit from neoadjuvant chemoimmunotherapy given the results of the phase II NADIM II trial. This study observed a significantly higher pathologic complete response rate of 36.8% with the addition of nivolumab to neoadjuvant chemotherapy followed by adjuvant nivolumab vs 6.9% with chemotherapy alone followed by postsurgery observation in resectable NSCLC. 

Natasha Leighl, MD, MMSC, FRCPC, FASCO:
I agree. As recently as 2 years ago, immunotherapy was used only as consolidation therapy following chemoradiation in this setting based on data from the phase III PACIFIC study, which led to the FDA’s approval of durvalumab after chemoradiation for unresectable stage III NSCLC. In some clinics, patients with N2 disease may have delayed surgery to follow the PACIFIC approach.

Now, data from NADIM II and the phase III CheckMate 816 trial have expanded eligibility for neoadjuvant chemoimmunotherapy. CheckMate 816 demonstrated significant improvements in event-free survival and pathologic complete response rates with neoadjuvant nivolumab plus platinum chemotherapy vs chemotherapy alone in patients with resectable stage IB-IIIA NSCLC. These supportive results led to the FDA approval of neoadjuvant nivolumab in combination with platinum-doublet chemotherapy for patients with resectable NSCLC (tumors ≥4 cm or node positive). 

In our clinic, the tumor board debates whether patients like this should receive the PACIFIC approach or neoadjuvant chemoimmunotherapy. In my experience, neoadjuvant chemoimmunotherapy is particularly beneficial for younger, fit patients who can undergo a lobectomy.

Jarushka Naidoo, MB BCH BAO, MHS:
We have further supportive data for the use of neoadjuvant anti–PD-1 therapy from a long-term follow-up analysis of patients with stage IA-IIIB NSCLC who received neoadjuvant therapy with the investigational PD-1 inhibitor sintilimab followed by adjuvant therapy with or without sintilimab on an early-phase trial. Among the 36 patients who underwent R0 resection, the 3-year overall survival (OS) rate was 88.5%, and the 3-year disease-free survival (DFS) rate was 75.0%. These results are consistent with the significant OS benefits reported for the first-line combination of sintilimab plus chemotherapy vs placebo plus chemotherapy in patients with advanced nonsquamous and squamous NSCLC.

Do you test for PD-L1 status and actionable mutations in patients with early-stage NSCLC who are candidates for perioperative therapy?

Julie Brahmer, MD, MSc:
We just discussed neoadjuvant and consolidation options for a patient with stage IIIA NSCLC, and we also should discuss adjuvant therapy options. The first of 2 notable examples comes from the phase III IMpower010 study, which demonstrated a significant DFS benefit in patients with completely resected stage IB-IIIA NSCLC who received atezolizumab vs best supportive care after adjuvant chemotherapy. The greatest benefit was seen in patients with PD-L1 ≥1%. Our second example is the phase III PEARLS/KEYNOTE-091 trial, which showed significant DFS improvement with pembrolizumab vs placebo following complete resection in patients with stage IB-IIIA NSCLC and a PD-L1 tumor proportion score ≥50%. Unlike IMpower010, PEARLS/KEYNOTE-091 did not require adjuvant chemotherapy before immunotherapy. 

The question is, how do these findings affect testing in patients with NSCLC?

Jarushka Naidoo, MB BCH BAO, MHS:
The testing paradigm in lung cancer evolved with these results, along with the findings from CheckMate 816 showing benefit with neoadjuvant chemoimmunotherapy in patients with no known sensitizing EGFR or ALK alterations. Because we know that patients with EGFR or ALK alterations are unlikely to respond to immunotherapy, I believe we should perform both PD-L1 and genetic mutation testing when assessing patients with early-stage disease. However, there are important considerations related to delaying treatment to allow time to obtain the biopsy and testing results.

Dr Leighl, how do you approach testing in your practice?

Natasha Leighl, MD, MMSC, FRCPC, FASCO:
This is a genuine challenge. A study conducted in our institution evaluated small-needle biopsies taken for diagnosis of early-stage NSCLC, as well as the subsequent surgical resection samples. We found that the surgical samples were more likely to be PD-L1 positive than the needle biopsies, even in the absence of intervening therapy. This means that in the neoadjuvant setting, needle biopsies may miss patients who have PD-L1–positive disease.

Dr Brahmer, how do you approach treating patients with early-stage NSCLC harboring EGFR mutations?

Julie Brahmer, MD, MSc:
I often treat such patients with definitive chemoradiotherapy, but that is challenging. I am unenthusiastic about chemoimmunotherapy in this population, and more data are needed.

How do you proceed with patients with stage III NSCLC who have both PD-L1–positive disease and an EGFR mutation and have undergone chemoradiotherapy?

Jarushka Naidoo, MB BCH BAO, MHS:
At ASCO 2022, I presented results from a post hoc subgroup analysis of the phase III PACIFIC study, which compared consolidation with durvalumab vs placebo in the EGFR-mutated subgroup of the overall patient population who had unresectable stage III NSCLC without progression on platinum-based chemoradiotherapy. In this exploratory analysis of 35 patients, progression-free survival (PFS) and OS outcomes were similar with durvalumab vs placebo.

The caveats are that this was a small population with imbalances in the baseline characteristics, and the study was not designed to evaluate outcomes by EGFR mutation status. Of note, the adverse events (AEs) seen with both treatment approaches (eg, pneumonitis) were similar regardless of whether patients had an EGFR mutation. I do not currently use durvalumab in patients with stage III/IV NSCLC, in part due to concern for synergistic toxicity with sequential tyrosine kinase inhibitor (TKI) therapy.

Dr Leighl, what is your approach in this setting?

Natasha Leighl, MD, MMSC, FRCPC, FASCO:
Most oncologists and tumor boards will not recommend durvalumab as consolidation in EGFR-mutated disease due to the high risk of relapse. When talking to patients, I explain these issues, but some still elect to try durvalumab if there is any chance of benefit. In our clinic, we have not had many issues with TKI-associated pneumonitis, but caution is always needed.

Jarushka Naidoo, MB BCH BAO, MHS:
At Johns Hopkins, we have given neoadjuvant immunotherapy for NSCLC in clinical trials, but usually not as standard of care. Dr Leighl, are you using neoadjuvant immunotherapy in your clinic?

Natasha Leighl, MD, MMSC, FRCPC, FASCO:
We do not currently use neoadjuvant immunotherapy as a standard of care in Canada, but I anticipate adopting this approach later this year.

Julie Brahmer, MD, MSc:
I have used neoadjuvant immunotherapy as standard of care in our clinic.

How do you treat a patient who experiences disease recurrence after receiving immunotherapy in the perioperative setting or as consolidation therapy?

Natasha Leighl, MD, MMSC, FRCPC, FASCO:
This question hinges on the duration of PFS. If PFS has lasted ≥12 months, an immunotherapy rechallenge may be beneficial. If PFS has lasted only several months, I would look for a different approach. Clinical trials are an important option in this setting.

How is this clinical scenario being approached in the United States?

Jarushka Naidoo, MB BCH BAO, MHS:
At Johns Hopkins, we take the same approach regarding duration of PFS, and I also factor in PS and any toxicities the patient experienced with immunotherapy. For those deemed ineligible for immunotherapy rechallenge, we would consider treatment with a taxane, docetaxel with or without ramucirumab, or a clinical trial.

Julie Brahmer, MD, MSc:
Would you consider the combination of an anti–CTLA-4 agent plus an anti–PD-1/PD-L1 agent for this scenario?

Natasha Leighl, MD, MMSC, FRCPC, FASCO:
In results from a substudy of the phase II/III Lung-MAP trial published in 2021, fewer than 10% of patients with metastatic squamous cell lung cancer who failed single-agent anti–PD-1/PD-L1 therapy responded to rechallenge with durvalumab plus tremelimumab. Adding CTLA-4 inhibition does not seem to benefit patients who already failed PD-1/PD-L1 inhibition. There may be a subgroup who benefit, but I would not use this approach for an unselected population.

Jarushka Naidoo, MB BCH BAO, MHS:
Looking at melanoma, a rechallenge study reported a response rate of 29% with pembrolizumab plus ipilimumab in patients with melanoma who had progressed on anti–PD-1/PD-L1 therapy. However, I do not think this would lead me to use this approach in my patients with lung cancer.

Julie Brahmer, MD, MSc:
I agree. If a patient with lung cancer progressed on immunotherapy, I would be more inclined to use a chemoimmunotherapy regimen rather than rechallenge per se, but there are many nuances to such a patient with no clear consensus on optimal treatment. This is a substantial unmet clinical need.

What is the best course of action for a patient with advanced NSCLC who does not achieve an objective response to an ICI? Should they switch to chemotherapy?

Natasha Leighl, MD, MMSC, FRCPC, FASCO:
This is a great question currently under investigation in the phase III INSIGNA trial (NCT03793179), which is comparing first-line treatment with single-agent pembrolizumab followed by chemotherapy with or without pembrolizumab after progressive disease vs pembrolizumab plus chemotherapy followed by maintenance with pembrolizumab and pemetrexed. In other words, the study is seeking to determine the optimal timing of pembrolizumab in stage IV nonsquamous NSCLC.

My current clinical practice is to continue the ICI if the patient is stable, with the hope that they will develop a response that deepens over time.

Julie Brahmer, MD, MSc:
I do the same. This is a marathon, not a sprint. I would not switch a patient who is not responding to immunotherapy to chemotherapy unless they were obviously progressing.

How long should a patient stay on an ICI once they have started to progress? What factors determine when to stop treatment with an ICI?

Julie Brahmer, MD, MSc:
This is a difficult question to answer, as I sometimes will add chemotherapy to single-agent immunotherapy when patients experience progression. Another tactic is to use radiotherapy if only a single site is progressing, which can help keep patients on immunotherapy if they are doing well otherwise.

Jarushka Naidoo, MB BCH BAO, MHS:
With ICIs, I would note that patients can experience pseudoprogression—a temporary increase in tumor size due to immune cell infiltration followed by regression. If the patient is overall asymptomatic and improving, it makes sense to continue the ICI.

Natasha Leighl, MD, MMSC, FRCPC, FASCO:
I am also suspicious of “progression” on ICIs, which can sometimes be a nodal immune flare (a type of pseudoprogression). I had a patient with what appeared to be progression several years ago, but instead of going with my colleagues’ recommendation to stop therapy, I biopsied the nodule and found that the involvement was due to lymphocytes, with the nodule disappearing after the biopsy.

When would you consider single-agent immunotherapy for a patient with advanced NSCLC, an Eastern Cooperative Oncology Group (ECOG) PS of 2, and intermediate PD-L1 expression?

Jarushka Naidoo, MB BCH BAO, MHS:
There is debate surrounding treatment for patients with an ECOG PS of 2. In the phase II PePS2 study, durable clinical benefit was seen with pembrolizumab monotherapy in approximately one half of patients with an ECOG PS of 2 and PD-L1 ≥1%. Of importance, both efficacy and the rate of immune-related AEs were comparable to those observed in patients with an ECOG PS of 0/1. There is an ongoing discussion about whether patients with poor PS should receive anti–PD-1/PD-L1 monotherapy or even chemotherapy alone if they cannot tolerate a 3-drug combination regimen. 

Currently, National Comprehensive Cancer Network guidelines recommend single-agent immunotherapy with pembrolizumab, atezolizumab, or cemiplimab for first-line treatment of patients with advanced NSCLC, an ECOG PS of 0-2, and PD-L1 ≥50%. Cemiplimab is newer to US practice, having been approved by the FDA in 2021 based on significant improvements in OS and PFS vs first-line platinum chemotherapy in patients with advanced NSCLC and high PD-L1 expression enrolled on the phase III EMPOWER-Lung 1 trial. 

Natasha Leighl, MD, MMSC, FRCPC, FASCO
In Canada, single-agent immunotherapy is difficult to access, so we would likely try to stop treatment early or offer them a short course of chemotherapy, possibly with switching quickly to immunotherapy. Patients have a low likelihood of responding to monotherapy.

As a specific example, would you consider single-agent immunotherapy for a patient with stage IV squamous NSCLC, multiple comorbidities, low PD-L1 expression, and an ECOG PS of 2?

Jarushka Naidoo, MB BCH BAO, MHS:
We have prospective data suggesting poor efficacy with single-agent immunotherapy in patients with squamous NSCLC and an ECOG PS of 2. In the phase II CheckMate 171 trial, patients with previously treated squamous NSCLC received single-agent nivolumab. The subgroup of 103 patients with an ECOG PS of 2 experienced treatment-related AEs at rates comparable to the overall population. However, this subgroup had a median OS of only 5.2 months—markedly shorter than the median OS of 10 months in the overall population.

Your Thoughts?
What challenges do you face in using ICIs to manage patients with NSCLC? Please answer the polling question and join the conversation by posting a comment in the discussion section.

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