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Expert Critique

FROM THE ASCO Reading Room

Amit Reddy, MBBS Postdoctoral Fellow Mitchell Cancer Institute, University of South Alabama

The PACIFIC clinical trial involving the drug durvalumab had very robust and promising results in patients with stage III unresectable non-small cell lung cancer (NSCLC) that had not progressed following platinum therapy and radiotherapy. The trial revealed that the median progression-free survival (PFS) for patients treated with durvalumab was 16.8 months versus only 5.6 months for the patients given placebo, which was significant both statistically and clinically. There was also a reduced amount of new lesions with the drug (20.4%) compared with placebo (32.1%), but the treatment side effects were seen in 67.8% of patients given durvalumab versus 53.4% for the placebo group. These results then led the FDA to grant approval for durvalumab in February 2018 for use in NSCLC patients. Some studies have focused on the toxic effects of durvalumab and the best way to maximize the treatment regimen in a "real-world" setting. For example, a group in China performed a meta-analysis of 22 trials evaluating the side effects of durvalumab, PD-L1 inhibitors, and PD-1 inhibitors. A significant discovery was that the incidence of all-grade pneumonitis in PD-L1 and PD-1 inhibitor therapy was higher compared with chemotherapy. As a precaution, ASCO and NCCN worked together to develop new guidelines for immunotherapy toxicity profiles. As a result, this course of action will help provide the maximum quality of care to cancer patients as this type of immunotherapy is becoming more routine in clinical practice.

Full Critique

Strong, highly encouraging, reassuring, a game changer -- that was just some the praise lavished on the results of the PACIFIC trial after it was presented at not one but two meetings in late 2017 (the European Society for Medical Oncology and the American Society for Radiation Oncology).

The phase III trial tested durvalumab (Imfinzi) as sequential treatment in patients with stage III unresectable non-small cell lung cancer (NSCLC) that had not progressed following platinum-based chemotherapy concurrent with radiation therapy.

The median progression-free survival (PFS) was 16.8 months in the durvalumab arm versus 5.6 months in the placebo arm, according to trial results. Also, patients in the durvalumab arm showed fewer new lesions (20.4%) than those in the placebo arm (32.1%). Finally, treatment-related adverse events occurred in 67.8% of patients in the durvalumab group compared with 53.4% in the placebo group.

"The main results of the trial are that PFS is and at a very significant level -- not only statistically, but also clinically," noted PACIFIC trial investigator Luis Paz-Ares, MD, PhD, of Hospital Universitario Doce de Octubre in Madrid, in an interview with VJOncology.

Thanks to these successful results, durvalumab gained in February 2018 for NSCLC patients whose cancer has not progressed after chemotherapy and radiation treatment.

results from PACIFIC are still pending, but as with any new-on-the-scene treatment regimen, answers often lead to more questions. While some focus on the toxicity profiles of durvalumab (and other checkpoint inhibitors), others are asking questions that may shed light on the best way to maximize durvalumab therapy in a real-world setting.

Rare but Life-Threatening

Ping Zhan, MD, of Medical School of Southeast University in Nanjing, China, and colleagues pointed out that "immune-related adverse effects [with checkpoint inhibitors] can on occasion be life-threatening even though usually rare."

The team conducted a assessing adverse effects from 22 trials -- 14 with data about pneumonitis, 19 with other severe immune-related adverse events or treatment-related deaths, and five with control groups. The incidence of all-grade pneumonitis was found to be 2.9% (95% CI 2.0%-4.8%) and grade 3 or higher pneumonitis was 2% (95% CI 1.0%-2.0%). The agents used in the trials were durvalumab, among other PD-L1 inhibitors, and two PD-1 inhibitors.

A noteworthy finding was that the incidence of all-grade pneumonitis in PD-1 and PD-L1 inhibitor therapy was significantly higher than that in chemotherapy (OR=2.35, 95% CI 1.32-4.20, P=0.004), but had no significance in grade 3-5 pneumonitis.

Cardiac events (cardiorespiratory arrest, cardiac failure, myocardial infarction, and stroke) had an incidence of 1% to 2%, pancreatitis was 1%, and severe skin reactions was 2%. The incidence of treatment related deaths was 0.7%.

While Zhan's group acknowledged that the analysis was impacted by limitations -- open-label trials, results that were not final, highly selected trial populations -- the incidence of pneumonitis in NSCLC treated with PD-1 and PD-L1 inhibitor therapy was still shown to be significantly higher than that with chemotherapy.

"Further meta-analysis should be conducted to deeply investigate the incidence of other rare and potentially unrecognized life-threatening [immune-related adverse events]."

'Take the Brakes Off the Immune System'

ASCO and the National Comprehensive Cancer Network (NCCN) collaborated on .

"With rapidly increasing use of immune checkpoint inhibitors, it is imperative that clinicians are knowledgeable about the unique toxicity profiles," said ASCO CEO Clifford Hudis, MD, in a statement. "These new guidelines from ASCO and NCCN will help our community continue to provide the highest quality of care to all patients as they incorporate these agents into routine care."

According to the guidelines, immunotherapy-related side effects can occur at any time and can affect any organ. The most common side effects are rash, diarrhea, low thyroid hormone, and fatigue, but can also include inflammation of the lung, intestines, or liver, hormonal abnormalities, and kidney, heart, or neurologic problems.

"If you take the brakes off the immune system and allow it to attack cancer, it may also attack the healthy tissue in a patient's body," John Thompson, MD, of Fred Hutchinson Cancer Research Center in Seattle and co-chair of the panel that developed the NCCN/ASCO guidelines. "Fortunately, most of the side effects are reversible, but early recognition and proper treatment are critical."

The panel recommends that clinicians keep four key recommendations in mind when administering immunotherapy:

1. In general, checkpoint inhibitors can be continued with close monitoring for mild (grade 1) toxicities, with the exception of neurologic and some hematologic toxicities
2. For moderate (grade 2) toxicities, checkpoint inhibitors should be held until symptoms and/or lab values revert to grade 1 levels or lower; corticosteroids may be offered
3. For severe (grade 3) toxicity, patients should receive high-dose corticosteroids for at least 6 weeks; extreme caution when restarting immunotherapy after a grade 3 toxicity is recommended, if restarted at all
4. In general, very severe (grade 4) toxicity necessitates stopping checkpoint inhibitor therapy permanently

The authors emphasized that clinicians should consult the guidelines directly for specific recommendations, depending on which organ is affected.

PACIFIC Queries

Results from the PACIFIC trial were published in November 2017 in the . Subsequently, clinicians followed up with questions in letters to the editor.

First, Mehmet S. Copur, MD, of CHI Health St. Francis Cancer Treatment Center Grand Island, NE, and colleagues pointed out that "one big challenge in stage III NSCLC is the lack of standard definitions for 'locally advanced' and 'unresectable.'" The team inquired if the PACIFIC patients underwent brain evaluations with bronchoscopy, mediastinoscopy, PET, pathology or MRI.

"Given the clinical and prognostic heterogeneity of this group of patients and local variations in approaches to staging, multidisciplinary evaluation, and treatment, we wonder whether the trial included patients with ," Copur et al wrote.

Scott J. Antonia, MD, PhD, and the PACIFIC investigators responded that according to the trial inclusion criteria, patients must have had stage III disease based on the International Association for the Study of Lung Cancer (version 7).

"Global patterns do indeed vary regarding screening procedures to ascertain stage III disease," the researchers acknowledged. "However, even if patients with occult stage IV disease were included, the randomized, double-blind, placebo-controlled design of our trial provided a robust platform for controlled analysis in which the characteristics of the patients were well balanced between the groups at baseline, and efficacy differences remain valid."

In a second letter, Matteo Santoni, MD, of Macerata Hospital in Italy, and colleagues noted that in PACIFIC, the was shifted from 1-14 days to 1-42 days, and patients were stratified according to this interval. As a result, PFS was longer among patients who had been enrolled within the shorter time period than the longer one (hazard ratio [HR] 0.39 for durvalumab versus HR 0.63 for placebo for disease progression or death).

Santoni et al also called attention to the fact that PFS was longer among patients in the durvalumab group with a level of PD-L1 expression in the tumor sample before radiotherapy versus those with a lower expression.

"Is it conceivable to reassess the PD-L1 expression level within 14 to 21 days after chemoradiotherapy to identify patients who may benefit from durvalumab?"

In other words, the Italian clinicians highlighted the numerical differences in the HRs in the PFS analyses in the subgroups, "defined according to the time from last radiation therapy to randomization or PD-L1 tumor expression, which favored a shorter duration and higher expression, respectively."

However, "the 95% confidence intervals overlapped, and a benefit with durvalumab was observed across all the prespecified subgroups," Santoni et al added.

The theory that chemoradiotherapy may increase PD-L1 expression and that its assessment after chemoradiotherapy may have clinical benefit is worth exploring, Antonia and co-authors concurred.

"New studies may shed further light on potential mechanisms driving the interaction between chemoradiotherapy and immunotherapy. However, our trial was limited because the PD-L1 expression level was assessed only at diagnosis, not after concurrent chemoradiotherapy."