Chemotherapy and Immune Checkpoint Inhibitor Combination Regimens: How do we manage corticosteroid use to prevent adverse effects from chemotherapy?

Sara Moran Smith, PharmD BCOP
Hematology/Oncology Clinical Pharmacist
M Health Fairview
Minneapolis, MN

Up until about three years ago, it seemed counterintuitive to combine immune checkpoint inhibitors (ICI) and chemotherapy, given the immunosuppressive properties of chemotherapy and the theoretical potential to decrease the efficacy of ICI. Today, we have a number of FDA-approved regimens that combine ICI and chemotherapy in the front-line setting. Major advances were made in lung cancer with multiple regimens approved for metastatic non-small-cell lung cancer and extensive-stage small-cell lung cancer.^1,2 In addition, pembrolizumab was recently studied in combination with chemotherapy for early stage triple-negative breast cancer in previously untreated patients.³

With the use of ICI, medication management question arise. Specifically, how are corticosteroids best managed to ensure minimal impact on efficacy while preventing adverse effects of chemotherapy, such as nausea, vomiting, skin rash, and hypersensitivity reactions? Corticosteroids have long been known for their immunosuppressive properties; however, their anti-inflammatory action is quite complex and not fully understood. Corticosteroids suppress effector T-cells and increase regulatory T-cells, which results in decreased inflammation, immune activity, lymphopenia and impaired T-cell response to antigen. Corticosteroids likely bring a balance between costimulatory and coinhibitory signals rather than overall direct suppression of the immune system.^4,5 The effects on the immune system from the con-current administration of corticosteroids and ICI remain unknown.

Data in Non-Small-Cell Lung Cancer
The trials supporting front-line use of chemo-immunotherapy maintained corticosteroid use for prevention of nausea and vomiting or skin rash.

In the IMpower130 trial, metastatic non-small-cell lung cancer patients were randomized to receive nab-paclitaxel and platinum agents plus or minus atezolizumab. Nab-paclitaxel is considered to have low emetogenicity and many institutions will give dexamethasone only prior to nab-paclitaxel to prevent nausea. In this trial, it was left to provider discretion but noted that about 80% of patients were given corticosteroids prior to their chemotherapy in both groups. Despite the corticosteroid premedication, patients still benefited from the addition of atezolizumab in progression-free survival (PFS) (7 months vs 5.5 months, p<0.0001) and overall survival (OS) (18.6 months vs 13.9 months, p=0.033).⁶

In the IMpower150 trial, treatment-naïve metastatic non-small-cell lung cancer patients were randomized to receive paclitaxel, bevacizumab and platinum plus or minus atezolizumab. Corticoste-roids are commonly used to prevent hypersensitivity reactions with paclitaxel, and this study left the management of corticosteroids to institution standard. Outcomes were favorable in the atezolizumab plus chemotherapy arm with improvement in PFS (8.3 months vs 6.8 months, p<0.001) and OS (19.2 months vs 14.7 months, p=0.02).⁷ In Keynote-021 and Keynote-189, non-small-cell lung cancer patients were randomized to receive pemetrexed plus platinum agents plus or minus pembrolizumab. Corticosteroids are commonly used to prevent rash from pemetrexed. As in the IMpower130 trial, the management of corticosteroids was left to institution standard. PFS and OS were favorable with the addition of pembrolizumab.

In Keynote-021G, PFS was improved at 24 months compared to 9.3 months in the chemotherapy alone arm (p=0.0049). OS was improved at 21.1 months in the chemotherapy alone arm and the median OS not yet reached in the pembrolizumab plus chemotherapy arm (p=0.0151).⁸ PFS was significantly better at 8.8 months versus 4.9 months (p<0.001) with addition of pembrolizumab in the Keynote-189 trial. OS also significantly improved at 11.3 months in the chemotherapy alone arm and median OS not yet reached (p<0.001) with the addition of pembrolizumab.⁹

In Keynote-407, non-small-cell lung cancer patients were randomized to receive a platinum agent, paclitaxel or nab-paclitaxel plus or minus pembrolizumab. It’s typical that nearly all patients on paclitaxel will get corticosteroids prior to their chemotherapy, at least for the first two doses. On the other hand, nab-paclitaxel, given its low emetogenicity and other options for anti-nausea, the corticosteroid may be omitted.

Unfortunately, the authors did not disclose the percentage of patients on corticosteroids with paclitaxel and nab-paclitaxel and this information was not able to be obtained. However, this study still showed that the treatment benefit of pembrolizumab was seen in PFS and OS. PFS was improved at 6.4 months versus 4.8 months (p<0.001) in the chemotherapy alone arm. OS was significantly better at 15.9 months versus 11.3 months (p<0.001) in the chemotherapy alone arm. Sixty percent of patients were on paclitaxel and it was found there was no difference in the treatment effect between the paclitaxel group and the nab-paclitaxel group.¹⁰

Data in Small-Cell Lung Cancer
In extensive-stage small-cell lung cancer, there are two trials supporting front-line indications. In the IMpower133 study, treatment-naïve patients were randomized to four cycles of carboplatin and etoposide with or without atezolizumab, followed by atezolizumab or placebo maintenance therapy. Premedications prior to chemotherapy were left to institution standard with a statement of caution to minimize corticosteroid use as much as possible given the theoretical effects of corticosteroids on ICI efficacy. The median OS was significantly improved in the atezolizumab group at 12.3 months vs 10.3 months (p=0.007). Furthermore, PFS was favorable in the atezolizumab group at 5.2 months versus 4.3 months (p=0.02).¹¹

In the CASPIAN trial, durvalumab was evaluated in combination with the then standard of care chemotherapy regimen, a platinum (carboplatin or cisplatin) and etoposide. The addition of durvalumab provided a significant improvement in OS of 13 months versus 10.3 months (p=0.0047). In this study, premedications with corticosteroids was permitted prior to chemotherapy for prevention of nausea and vomiting.¹²

Data in Triple-Negative Breast Cancer
Keynote-522 evaluated pembrolizumab in combination with paclitaxel and carboplatin in previously untreated stage II or III triple-negative breast cancer patients. Patients received neoadjuvant therapy with four cycles of the pembrolizumab plus chemotherapy followed by four additional cycles of pembrolizumab or placebo alone. Both groups received four cycles of either doxorubicin and cyclophosphamide or epirubicin and cyclophosphamide every three weeks. After definitive surgery, patients received pembrolizumab or placebo alone for up to nine cycles.

Their first interim analysis was positive with a pathological complete response of 64.8% in the pembrolizumab plus chemotherapy group versus 51.2% in the chemotherapy alone group (p<0.001). The protocol left the premedications to institution standard, allowing corticosteroids prior to chemotherapy administration for prevention of nausea, vomiting, and hypersensitivity reactions.³

Guidelines
Prior to an update made this year, National Cancer Comprehensive Network (NCCN) guidelines contained a caveat when it comes to antiemetic use. In part, the guidelines said, “When ICI are administered concurrently with emetogenic chemotherapy, inconclusive data suggest concurrent corticosteroid administration may negatively impact cancer outcomes. Until more evidence is available, the panel recommends employment of a corticosteroid-sparing approach to antiemetic prophylaxis on a case-by-case and regimen basis.” This has been removed with the most recent 2020 update based on the multiple previous trials, which included concurrent corticosteroid use to prevent adverse effects from chemotherapy when combined with ICI13.

American Society of Clinical Oncology (ASCO) cites the two pembrolizumab trials (Keynote-021G and Keynote 189) completed in non-small-cell lung cancer patients as evidence that dexamethasone should not be removed from guideline-compliant antiemetic prophylaxis regimens used in chemotherapy plus ICI regimens.¹⁴Thus, the two leading oncology guidelines for antiemetic use supports the use of corticosteroids when appropriate prior to chemotherapy in combination with ICI.

Treatment Doses of Corticosteroids for Immune-related Adverse Effects
There has been the question of whether treatment of immune-related adverse events with corticosteroids impacts the efficacy of ICI. A retrospective review at Memorial Sloan Kettering Cancer Center looked at treatment of 103 patients that required systemic corticosteroids for their immune-related adverse events out of 254 patients who experienced immune-related adverse events. These doses of corticosteroids are usually as high as 1mg/kg of prednisone or equivalent but can vary widely between prescribing physicians.

Median time to treatment failure was 5.7 months and median OS was 16.5 months, which compared favorably with other ipilimumab studies. The time to treatment failure curve plateaued at 88%, leaving 12% who experienced long-term disease control despite the use of corticosteroids to treat immune-related adverse events. When patients were stratified by the presence or absence of immune-related adverse events of any grade, there was no difference in OS or time to treatment failure.

In addition, no difference in OS or time to treatment failure was observed when patients were stratified by administration of corticosteroids.¹⁵ Thus, high doses of corticosteroids used to treat immune-related adverse events do not appear to impact efficacy of immune-checkpoint inhibitors.

Baseline Corticosteroid Use
A physiologic dose of corticosteroids is approximately 7.5 mg of prednisone; therefore, doses less than or equal to 10 mg of prednisone have been deemed acceptable.^{16,17,18,19,20} Patients receiving more than 10 mg of prednisone or equivalent prior to and concurrently with immune-checkpoint inhibitors for longer durations than a few days have been excluded from trials thus far. There is some evidence that corticosteroid use prior to and within 30 days of initiation of immune-checkpoint inhibitors could impact efficacy.

A retrospective review of two cancer centers, Memorial Sloan Kettering and Gustrave Roussy reviewed 640 patients treated with single agent ICI. Ninety of these patients were on at least 10 mg of prednisone for various indications, including dyspnea, fatigue and brain metastasis. The overall response rates, PFS, and OS were significantly decreased in the corticosteroid group compared to the control group who had no steroids or less than 10 mg of prednisone on board. There was a similar detriment in efficacy with prednisone amounts greater than 20 mg versus 10-19 mg of prednisone.

They did find that the timing of discontinuation of the steroids had a varying impact on PFS and OS. When patients discontinued their corticosteroids at least one day prior to initiation of the ICI, they had intermediate PFS and OS. The best PFS and OS was seen in patients who had no corticosteroids within 30 days of therapy. Of note, authors adjusted for confounding factors, such as smoking history, performance status, and history of brain metastasis, and use of corticosteroids remained associated with decreased efficacy.²¹

Another retrospective review evaluated early use of corticosteroids in non-small-cell lung cancer patients treated with nivolumab monotherapy. The median daily dose of prednisone was 35 mg and went as high as 180 mg per day. Authors found that OS was significantly decreased at 11 months versus 4.3 months (p=0.017).²² These studies do have limitations and the design does not differentiate between correlation versus causation with baseline corticosteroids.

To answer this question, the Dana-Farber Cancer Institute com-pleted a retrospective review of 650 patients with non-small-cell lung cancer treated with single agent ICI. They categorized the indication for the corticosteroids as either palliative (cancer-related) or nonpalliative. Out of 650 patients, 93 were on at least 10 mg of prednisone to as high as 150 mg per day. Palliative indications included brain metastasis, cancer-related dyspnea, pain from bone metastasis, and cancer-related anorexia. Nonpalliative indications included, pneumo-nitis from prior treatment, chronic obstructive pulmonary disease, autoimmune disease and iodinated contrast prophylaxis.

There were significant differences in the baseline characteristics between the two groups. The performance status was poorer and the number of patients with brain metastasis prior to starting ICI was significantly higher. In those patients receiving corticosteroids for nonpalliative indications, the ICI was typically in the second-line or later. This could be significant as patients treated in the first line with ICI are expected to have better outcomes compared to patients being treated in subsequent lines of therapy.

After analysis, this review confirmed that baseline use of less than 10 mg of prednisone at the time of ICI initiation was associated with significantly lower overall response rates, PFS, and OS. However, when the indication for the corticosteroids was teased out, those patients on corticosteroids for nonpalliative indications had a similar PFS and OS compared to patients who were not on corticosteroids. Patients on corticosteroids for palliation still had significantly lower outcomes than patients not on corticosteroids. From this data, those patients on corticosteroids for cancer-related palliation had decreased efficacy likely due to an already poorer prognosis and not necessarily from the use of corticosteroids being concurrently administered with ICI.²³

Although the mechanisms of corticosteroids are not fully elucidated, there is a theory regarding the potential mechanism of corticosteroids early administration in ICI treatment. In cancer, there is a state of CD8+ T-cell dysfunction that is associated with the expression of PD-1 inhibitory receptors. In a study in labs rats, it was found these PD-1 positive CD-8+ T-cells underwent self-renewal but mainly differentiated into terminally exhausted CD-8+ T-cells. When these mice were treated with PD-1 blockade, there was a proliferative burst almost exclusively of CD-8+ T-cells, resulting in restoration of their function. It is likely the benefit from ICI is largely derived from this initial burst in CD-8+ T-cells upon initiation of therapy. Therefore, the concern with corticosteroid use at baseline would blunt this T-cell burst and decrease the benefit.²⁴ If true, the administration of cortico-steroids after this CD-8+ T-cell burst would not impact ICI efficacy.

Conclusion
Several trials have studied ICI in combination with chemotherapy and have allowed the use of corticosteroids to prevent adverse effects from chemotherapy. Outcomes have been favorable with the addition of ICI despite the use of corticosteroids. These trials are not conclusive that corticosteroids used to prevent adverse effects from chemotherapy do not have any impact on the efficacy of ICI, but they do show that the benefit of the addition of an ICI to chemotherapy is still appreciated despite the concurrent use of corticosteroids. It is appropriate for patients on these regimens to continue to receive corticosteroids to prevent adverse effects from chemotherapy.

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