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NSCLC Treatment Paradigm
Expert View on the Evolving Treatment Paradigm in Advanced NSCLC

Released: June 23, 2020

Expiration: June 22, 2021

Matthew Gubens
Matthew Gubens, MD, MS
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PACIFIC: Study Design

We have discussed treatment of stage IV NSCLC in great detail, but immunotherapy is also entering earlier stage treatment, specifically stage III disease. Unresectable stage III NSCLC is an area where there had not been improvement in the standard of care for decades. The PACIFIC trial led to the first major change in therapy in years.

PACIFIC was a randomized, double-blind, placebo-controlled, phase III trial for patients with unresectable stage III NSCLC who did not have progressive disease after at least 2 cycles of definitive platinum-based chemoradiation (N = 713). Patients were randomized 2:1 to receive either durvalumab 10 mg/kg every 2 weeks for up to 12 months or placebo on the same schedule. Of note, these patients had to start therapy within 42 days of completing chemoradiation. The coprimary endpoints were PFS and OS. Secondary endpoints included responses, time to distant metastases, and patient-reported outcomes.93,94

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PACIFIC: PFS and OS (ITT)

The results were striking. There was an 11-month median PFS benefit with durvalumab, with an HR of 0.52 (P < .001) over placebo after the long-established standard of chemoradiation. The PFS data were strong enough to secure FDA approval of durvalumab in the setting.

The subsequently reported OS results corroborated the strong PFS results: The median OS was not reached with durvalumab at a median follow-up of more than 2 years vs 28.7 months in the placebo arm (HR: 0.68; P = .0025). This demonstrates a clear benefit for consolidation immunotherapy, which in this study was given for up to a year.93,94

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PACIFIC: PFS and OS by Subgroup (ITT)

The benefit from durvalumab was seen across almost all prespecified subgroups.93-95  One important point is that PD-L1 status was assessed in patients using a threshold of 25%, which aligns with the durvalumab development program (patients with < 25% PD-L1 expression had a nonsignificant OS benefit).

A post hoc analysis was done, at the request of regulatory authorities, which looked with more granularity at patients whose tumors had less than 1% PD-L1 expression, and those with 1% to 24% expression.

Patients whose tumors were below the 1% threshold (a small population) did not gain a significant PFS benefit from durvalumab, and in this group the OS was actually superior with placebo. Of note, in Europe durvalumab is not approved for patients whose tumors have PD-L1 expression of less than 1%, although in the United States, these patients are part of the approved indication.

Most notably, a small number of patients with EGFR mutations were allowed on the study, and the point estimate for PFS favored durvalumab consolidation in this group as well. There were not enough patients to establish an estimate for OS, but this will hopefully receive further study.

 

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PACIFIC: OS with Durvalumab at 3 Years

At ASCO 2019, Gray and colleagues96 presented longer term follow-up results from PACIFIC showing that the OS benefit for durvalumab remains very strong at 3 years on this study: 57% of patients receiving durvalumab consolidation remained alive vs 44% of placebo-treated patients. The median OS was still not reached with durvalumab vs 29.1 months with placebo.

Of course, this is a curative treatment regimen, so even longer-term follow-up, particularly the traditional 5-year cutoff, is going to be very important. We are very optimistic about durvalumab in unresectable stage III NSCLC given these 3-year data.

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PACIFIC: Updated Safety

One of the concerns with giving immune therapy after radiation is increasing the risk of pneumonitis. Radiation pneumonitis is a known risk, as is immunotherapy-induced pneumonitis. Early studies of immunotherapies did not allow the use of immune-modifying therapy within months of radiation. Therefore, in PACIFIC, administering an immune checkpoint inhibitor as soon as 1 day after finishing radiotherapy was a concern.

Fortunately, the safety profile in this large, international trial was very reassuring.94,95,97 Grade 3/4 AEs were reported in 30.5% of patients on the durvalumab arm vs 26.1% on the placebo arm. Likewise, serious AEs were seen in similar incidences, at 29.1% and 23.1%, respectively.

The rate of any-grade pneumonitis was somewhat higher in the durvalumab arm, at 33.9% vs 24.8% with placebo—an approximate 9% difference. Of more importance, the rates of grade 3/4 pneumonitis—which requires oxygen, steroids, and hospital admission—were very similar between arms: 3.6% with durvalumab and 3.0% with placebo. Only 5 deaths from pneumonitis were seen on the durvalumab arm, which was the same as the placebo arm. Pneumonitis led to discontinuation in only 6% of patients on the durvalumab arm.

In addition, there were no clinically important differences in the key patient-reported outcomes identified between the 2 arms; this is very reassuring for the use of immunotherapy directly after chemoradiation.

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