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Corticosteroids and Immunotherapy: Guilty or Guilt By Association?


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Thomas E. Stinchcombe, MD

Thomas E. Stinchcombe, MD

FIRST-LINE TREATMENT options for advanced non–small cell lung cancer (NSCLC) include single- agent immunotherapy for patients with a programmed cell death ligand 1 (PD-L1) tumor proportion score of at least 50% or in combination with chemotherapy in unselected patients.1-3 Single immunotherapy is the standard second-line therapy for patients with disease progression after platinum-based therapy who have not received immunotherapy as part of first-line therapy.4-7 Recently, a phase III trial revealed superior overall survival with the combination of chemotherapy and immunotherapy compared with chemotherapy alone in extensive-stage small cell lung cancer.8 Thus, most patients with lung cancer will receive immunotherapy at some point in their care.

“Clinicians should minimize the use, duration, and dose [of corticosteroids] if they are contemplating the use of immunotherapy.”
— Thomas E. Stinchcombe, MD

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These trials excluded patients receiving corticosteroids at the time of starting the study due to the concern that immunosuppressive doses of corticosteroids would compromise the efficacy of immunotherapy. The frequently used exclusion criterion was use of prednisone at 10 mg daily (or equivalent) or higher. However, corticosteroids are frequently used to treat immune-related adverse events, and the use of on-treatment corticosteroids does not appear to compromise outcomes. The emerging data on the use of corticosteroids after the start of immunotherapy, the concern about excluding an effective therapy from a significant number of patients, and the common clinical need to start immunotherapy before tapering corticosteroids below the threshold of prednisone < 10 mg daily have raised questions about the use of this exclusion criterion.

Corticosteroid Use and Treatment Efficacy

AS IMMUNOTHERAPY has transitioned from clinical trials to routine clinical care, inevitably patients who were receiving corticosteroids at the time of initiation were treated with immunotherapy. A study by Arbour and colleagues, reviewed in this issue of The ASCO Post, retrospectively investigated the outcome of patients who received single-agent immunotherapy at two centers—Memorial Sloan Kettering Cancer Center and Gustave Roussy Cancer Center—to evaluate the outcomes of patients who did and did not receive steroids at the start of therapy.9 Of the 640 patients, 90 (14%) received prednisone at ≥ 10 mg (or equivalent) at the start of single-agent immunotherapy. The most common indications were dyspnea (33%), fatigue (21%), and brain metastases (19%). Patients receiving corticosteroids were more likely to have a performance status of at least 2 and presence of brain metastases (P < .01 for both). In the pooled cohort, patients receiving compared with patients not receiving corticosteroids experienced a lower objective response rate (overall response rate, 7% vs 18%) and worse progression-free (P < .001) and overall survival (P < .001).

The authors performed a multivariable analysis including smoking history, performance status, history of brain metastases, and corticosteroid use (≥ 10 mg vs < 10 mg at the start of immunotherapy), and corticosteroid use continued to be associated with worse progression-free and overall survival. In the Memorial Sloan Kettering Center cohort (data not available for the Gustave Roussy Cancer Center cohort), patients who discontinued corticosteroids 1 to 30 days before starting immunotherapy had intermediate progression-free and overall survival compared with patients receiving and not receiving corticosteroids at the start of therapy.

Proceed With Caution

PRIOR TO THIS study, many clinicians may have been lenient about the use of corticosteroids at the time of starting immunotherapy. The reduced efficacy is concerning enough that the use of concurrent corticosteroids should be discouraged. Clinicians should minimize the use, duration, and dose if they are contemplating the use of immunotherapy. Importantly, some patients taking corticosteroids at the start of therapy did respond to immunotherapy, and these retrospective data are not definitive enough to exclude patients receiving corticosteroids from receiving immunotherapy. The patients studied included all lines of therapy, with a significant percentage of patients receiving immunotherapy as third-line treatment or later, and the prevalence of corticosteroid use observed in this study may be higher than in a first-line patient population. We also do not know if the association between corticosteroid use and efficacy observed exists with chemotherapy and immunotherapy combinations.

Next Step: Large Retrospective Study

THE MOST DIFFICULT question is whether the use of corticosteroids compromises the efficacy of immunotherapy or identifies a group of patients with a poor prognosis or more aggressive disease who would be unlikely to benefit from immunotherapy. The multivariable analysis in the study assessed known prognostic factors, but additional prognostic factors (eg, weight loss), or unrecognized prognostic factors, were not included in the analysis. Data related to disease characteristics (PD-L1 status, tumor mutational burden) associated with benefit from immunotherapy were not available for this analysis. The patients seen at these two referral centers may vary from the broader patient population.

The next step is to perform a retrospective study of baseline corticosteroid use in a database with a larger number of patients and a variety of practice locations. To adequately assess the impact of baseline corticosteroids and to account for all the potential confounding factors, the inclusion of a separate cohort of patients receiving corticosteroids at baseline in clinical trials, similar to previous chemotherapy trials in patients with organ dysfunction, is necessary.

Dr. Stinchcombe is Professor of Medicine, Duke Cancer Institute, Duke University School of Medicine, Durham, North Carolina. ■

DISCLOSURE: Dr. Stinchcombe is a consultant or advisor for Regeneron, Takeda, AstraZeneca, Novartis, and Genentech/Roche; and has received institutional research funding from Genentech/Roche, Blueprint Medicines, Merck, AstraZeneca, and Takeda.

REFERENCES

1. Reck M, Rodriguez-Abreu D, Robinson AG, et al: Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375:1823-1833, 2016.

2. Paz-Ares L, Luft A, Vicente D, et al: Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer. N Engl J Med. September 25, 2018 (early release online).

3. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al: Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med 378:2078- 2092, 2018.

4. Borghaei H, Paz-Ares L, Horn L, et al: Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373:1627- 1639, 2015.

5. Brahmer J, Reckamp KL, Baas P, et al: Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N Engl J Med 373:123-135, 2015.

6. Herbst RS, Baas P, Kim DW, et al: Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet 387:1540-1550, 2016.

7. Rittmeyer A, Barlesi F, Waterkamp D, et al: Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): A phase 3, open-label, multicentre randomised controlled trial. Lancet 389:255-265, 2017.

8. Horn L, Mansfield AS, Szczęsna A, et al: First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. September 25, 2018 (early release online).

9. Arbour KC, Mezquita L, Long N, et al: Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non–small-cell lung cancer. J Clin Oncol 36:2872-2878, 2018.


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