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The arrival of immune checkpoint inhibitors (ICIs) turned the diagnosis of advanced non-small-cell lung cancer (NSCLC) from one of imminent and certain death to one that is, in some cases, neither.

However, the use of these same agents in real-world patients is still challenging as the clinical trials leading up to their approval in advanced NSCLC largely excluded problematic patients and have not reported on longer-term issues.

In short, questions remain about usage, flagyl for bv dosage including how well will patients with poor performance status (PS) respond and how long should maintenance therapy last?

Two separate sets of authors recently took a careful look at the evidence related to a set of especially pressing questions and arrived at tentative conclusions for some.

As published in the August issue of the JCO Oncology Practice, here are their answers.

What Are the Benefits Among Poor PS Patients?

A number of immunotherapy studies have involved patients with advanced NSCLC with poor PS. In one such study, investigators of the PePS2 phase III trial found that 36% of patients achieved durable clinical benefit when treated with pembrolizumab (Keytruda) in terms their overall response rate (ORR) at 31%, median progression-free survival (PFS) of 4.4 months, and overall survival (OS) of 10.4 months.

“These results are comparable with data from KEYNOTE-001, which included patients with PS 0-1,” Sophie Stock-Martineau, MD, University of Ottawa in Ottawa, Ontario, Canada, and colleagues observe in the new clinical review.

Another study, CheckMate 817, had 2 cohorts — cohort A with a good PS and cohort A1, which largely comprised patients with a PS of 2. Following treatment with nivolumab (Opdivo) and ipilimumab (Yervoy), there was an ORR of 20% in cohort A1 and median PFS of 3.6 months, which were not as good as those in cohort A at 35% and 6 months, respectively, as reported in the Journal of Thoracic Oncology.

On the other hand, rates of grade 3 and 4 treatment-related adverse events were not higher among those with the poorer PS, irrespective of comorbidities.

Another trial, CheckMate 171, included 13% of patients with a PS of 2. Again following treatment with nivolumab, it was reported that median OS was approximately half that at 5.2 months in patients with a PS of 2 compared to 10 months for all treated patients.

Furthermore, in a large review of patients with metastatic NSCLC receiving nivolumab, median OS at 6.8 months in the small group of patients with a PS of 2 was again about half compared to a median of 12.9 months for patients with a PS of 0-1.

“This [review] and [another trial] CheckMate 817 suggest that although PS2 patients have poorer survival outcomes on ICI therapy, they are not more susceptible to additional toxicities compared with more fit patients,” Stock-Martineau and team concludes.

Should You Use ICIs in Patients on Corticosteroids?

As Stock-Martineau and colleagues explain, the concurrent use of corticosteroids likely decreases antitumor responses to either programmed cell death receptor-1 (PD-1) or programmed cell death-ligand-1 (PD-L1) inhibitor therapy. However, the reality is that lung cancer patients often need treatment with a corticosteroid because of cancer-related issues or for common pre-existing medical conditions such as chronic obstructive pulmonary disease.

“The core question is whether the use of steroids is antagonistic to the efficacy of immunotherapy,” the authors note.

Retrospective data suggest that oncologists should, in general, try to avoid using the two together, even though steroid use is not an absolute contraindication to ICI use, they also state.

In one study of advanced NSCLC patients on nivolumab, almost one third of whom received concurrent steroids at a dose in excess of 10 mg of prednisone or its equivalent, median OS was shorter at 4.3 months for patients on steroids vs a median of 11 months for those not on steroids, at least not during the first 30 days of treatment.

Others have also reported that patients on 10 mg of prednisone or more for cancer-related issues had a worse median PFS and OS compared with those on less than 10 mg of prednisone for cancer-unrelated indications. “When used for cancer-related issues, corticosteroid use is associated with a poorer prognosis,” the JCO Oncology Practice review authors affirm.

“Most experts still agree on avoiding concurrent use of supraphysiological doses of steroids at baseline and early on after ICI initiation,” they conclude.

Use in Patients With Pre-existing Autoimmune Disorders?

Roughly one quarter of patients receiving an ICI have a concomitant autoimmune disease, according to data from the American Society of Clinical Oncology. In a review of close to 4500 patients, those with a pre-existing autoimmune disease were more likely to be hospitalized for an immune-related adverse event (irAE) as were those on corticosteroids, but they were not more likely to be hospitalized for any cause.

The US Food and Drug Administration also reviewed 22 ICI trials involving NSCLC patients with an autoimmune disorder. Their post-hoc analysis revealed that flares of pre-existing autoimmune disorders were found in between 6% to 16% of patients, depending on the autoimmune disorder present.

Thus, Stock-Martineau and colleagues conclude that using an ICI in patients with a pre-existing autoimmune disorder is “probably reasonable,” especially when that disorder does not require high-dose steroids.

Is it Wise to Rechallenge With an ICI After an irAE?

Even though most irAEs are mild to moderate and resolve after the ICI is stopped, patients are at risk of developing an irAE when exposed to an ICI. In one study, a small group of 38 patients with NSCLC were retreated with an ICI after discontinuing treatment because of a previous irAE. In this cohort, almost half did not experience a recurrence of any irAE, although about one quarter of patients did experience the same irAE on being rechallenged.

Similar findings were found in a retrospective study of irAEs in patients undergoing rechallenge where approximately 29% of patients had a recurrence of the same irAE that led to their first treatment discontinuation.

Another study looked at the incidence of a second irAE in patients who were rechallenged with an anti-PD-1 or an anti-PD-L1 inhibitor after experiencing an initial grade 2 or higher irAE. In this group of 40 patients, some 42% experienced a recurrence of the same type of irAE and 12% experienced a different irAE. “Notably, the second irAEs were not more severe than the first event that had led to the initial treatment discontinuation,” the review authors observe.

“And in summary, in those who discontinue treatment with ICIs because of irAEs, treatment rechallenge can be safe and appropriate,” they conclude.

What is the Duration of Maintenance ICI?

In a separate commentary also published in the August JCO Oncology Practice, Nikhil Shukla, MD, of Indiana University Bloomington in Bloomington, Indiana, and colleagues, whose analysis was sponsored by Eli Lilly, note that unlike maintenance chemotherapy, ICIs have the potential to achieve a durable response and even cure for some patients with stage IV NSCLC and no targetable mutations.

In fact, two trials in which patients with advanced NSCLC were treated with nivolumab showed that between 10% to 20% achieved long-term freedom from progression.

Indeed, some patients who discontinue ICI therapy due to early development of irAEs maintain long-term disease control despite discontinuance — which raises the question of whether patients who respond to the ICIs can be spared unnecessary maintenance therapy, Shukla observes.

The best evidence in which the optimal duration of ICI therapy was explored in patients with advanced NSCLC comes from CheckMate 153’s results. A recently published exploratory analysis of this study compared outcomes between patients with advanced NSCLC who received a fixed duration of nivolumab treatment for 1 year and those who received continuous treatment beyond 1 year. Median PFS was longer at 24.7 months in the continuous treatment group compared with 9.4 months for the 1-year fixed duration treatment group.

The study provides an “unprecedented look at an unanswered and clinically important issue,” Shukla observes. This study among others provides some clues as to which patients may have prolonged PFS with minimal exposure to ICIs, he adds.

For example, a number of studies have shown that some patients who experience early irAEs still maintain long-term disease control with minimal exposure to immunotherapeutic drugs, he writes, citing two trials: one from 2018 and another from 2019.

Another study involving patients with stage III NSCLC showed that despite early discontinuation of pembrolizumab, patients exposed to a median of five cycles had no significant reduction in median OS at 30.7 months compared with those exposed to a median of 15 cycles. As Shukla suggests, “emerging biomarkers of minimal residual disease (MRD) hold the promise of identifying which patients with advanced NSCLC can safely stop therapy without future disease progression.”

For example, almost all members of a small group of NSCLC patients without detectable circulating tumor DNA (ctDNA) after treatment had no evidence of disease progression up to 3 years post-treatment.

“Biomarker-based approaches using ctDNA to assess for MRD have the potential for delineating patients who may achieve long-term disease control with limited CPI [checkpoint inhibitor] therapy,” Shukla affirms.

“[Although] the optimal duration of CPI therapy remains an open question,” he cautions.

Stock-Martineau has disclosed no relevant financial relationships. Shukla is now an employee of Eli Lilly.

JCO Oncol Prac. 2021;17:465-71, 472-74. Full text, Editorial

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