Findings from the PACIFIC trial have made a significant impact on the treatment of patients with unresectable stage III non–small cell lung cancer, especially in light of the history of treatment options in this setting.
Edward B. Garon, MD
Findings from the PACIFIC trial have made a significant impact on the treatment of patients with unresectable stage III non—small cell lung cancer (NSCLC), especially in light of the history of treatment options in this setting, according to Edward B. Garon, MD.
Garon, director of thoracic oncology at the Jonsson Comprehensive Cancer at the University of California, Los Angeles, discussed the newer role of immunotherapy in the treatment of patients with unresectable stage III NSCLC with the approval of durvalumab (Imfinzi) in this setting for patients whose disease has not progressed following concurrent chemoradiation.
“Because we have robust both efficacy and safety data it’s clearly what I would use in this setting,” Garon said in a presentation at the 16th Annual Winter Lung Cancer Conference. “From my perspective, the tolerability of durvalumab in this setting was much better than I would have anticipated…and has led it to be for most of us the therapy that we look to in this group of patients.”
He explained that there is a degree of controversy regarding the resectability of stage III NSCLC. “I would say that this is the area that leads to the greatest degree of debate at our tumor boards, as to whether it is resectable or not resectable.”
“What is unresectable stage III I still feel is not completely defined and I think there’s even the potential [for the definition] to shift,” he said.
Garon took the audience through a brief history of treatment options for patients with stage III disease that are the foundation for the argument between surgery and systemic therapy for this setting.
The phase III INT 0139 study looked at the possibility for surgery after chemotherapy and radiation treatment in patients with resectable stage IIIa (pN2) NSCLC. Patients were randomized to chemotherapy with concurrent cisplatin and etoposide with radiation with or without surgery thereafter. Progression-free survival (PFS) showed a benefit for the arm that received surgery (HR, 0.77; 95% CI, 0.62-0.96; P = .017), but overall survival (OS) was more similar between the 2 arms (HR, 0.87; 95% CI, 0.70-1.10; P = .24).1
Garon mentioned that thoracic surgeons focus as well on subset findings that while patients undergoing pneumonectomy did not significantly benefit from added surgery (5-year OS, 22% with surgery vs 24% without), patients who underwent lobectomy did have improved survival rates (5-year OS, 36% vs 18%, respectively; P = .002).
“When surgeons talk about this they will say that based on the subgroup analysis, anyone who would get lobectomy in this setting should go to lobectomy,” Garon said. “A little source of caution to go to the subset analysis, but it’s a reasonable course in a case where it’s not entirely clear which course to go to.”
Studies have also explored sequential versus concurrent chemotherapy with radiation therapy. A meta-analysis found that there was a 4.5% absolute OS benefit at 5 years with concomitant chemotherapy rather than sequential (HR, 0.84; 95% CI, 0.74-0.95; P = .004).2
Several years ago, the standard of care for stage III NSCLC was docetaxel after concurrent chemoradiation based on the results of the SWOG 9504 trial. Patients received cisplatin and etoposide with radiotherapy followed by consolidation with docetaxel. The regimen led to an OS of 26 months and a 5-year OS rate of 29%.3
“The toxicity was quite substantial, particularly during the consolidation with docetaxel. We did it because of the 5-year survival of 29% in a nonrandomized study, which was far greater than we had ever seen before in this subgroup,” Garon commented.
A phase III trial of concurrent chemoradiation with or without consolidation docetaxel in patients with inoperable stage III NSCLC later demonstrated that there was no difference in survival with added docetaxel (median OS, 21.5 months with docetaxel versus 24.1 months with observation; P = .940).4
Not all potential treatment options added to chemoradiation have been beneficial, however, which was part of why the results of the PACIFIC trial were so significant.
The randomized phase III SWOG 0023 trial explored the potential to add gefitinib (Iressa) as maintenance therapy after chemoradiation followed by consolidation docetaxel. The placebo arm of the trial significantly outperformed the gefitinib arm with a 2-year OS rate of 46% with gefitinib versus 59% with placebo (P = .01).5
“I think [this underscores] the point that you can’t just anticipate that because you’re adding a therapy that is a good lung cancer therapy that you are actually going to improve outcomes after chemoradiotherapy,” Garon stated.
“There are great rationales for why PACIFIC would be different, but of course, there were also rationales for why gefitinib would be different,” he said, which is why the findings were so significant.
PACIFIC was a phase III randomized, double-blind, placebo-controlled, multicenter trial exploring durvalumab versus placebo in patients with stage III locally advanced unresectable NSCLC who received concurrent chemoradiation.
Originally, 983 patients were enrolled in the study but only 713 underwent randomization as more than 200 did not meet the eligibility criteria. “One of the things that I think is important to realize is that this is a study that enrolled patients after chemoradiotherapy. If you had enrolled people before chemoradiotherapy, the drop off almost certainly, if your clinic looks anything like mine, would be more significant. There are of course patients who either progress on chemoradiotherapy or often just look pretty beat up after chemoradiotherapy.”
The median PFS in the PACIFIC trial was 16.8 months (95% CI, 13.0-18.1) with durvalumab compared with 5.6 months (95% CI, 4.6-7.8) with placebo with a stratified hazard ratio of 0.52 (95% CI, 0.42-0.65; 2-sided P <.001). Of note, Garon said, the PFS for the placebo arm was less than what is typically seen in other studies, but it was a randomized population.
At 12 months, the PFS rate was 55.9% (95% CI, 51.0%-60.4%) with the PD-L1 inhibitor versus 35.3% (95% CI, 29.0%-41.7%) with placebo and the rates were 44.2% (95% CI, 37.7%-50.5%) and 27.0% (95% CI, 19.9-34.5%), respectively, at 18 months.6
The PFS benefit was also seen across subgroups. In a subgroup analysis by PD-L1 status, the benefit was greater in patients who had PD-L1 expression levels ≥25% versus <25%. Also, patients with EGFR mutations still benefited from therapy, even though it was a small proportion of patients, although the hazard ratio was better in patients who had EGFR-negative disease.
By the time of the updated data with OS results in 2018, the median OS had still not yet been reached in patients receiving the immunotherapy (95% CI, 34.7-not reached [NR]) compared with 28.7 months (95% CI, 22.9-NR) with placebo with a stratified hazard ratio of 0.68 (99.73% CI, 0.47-0.997; 2-sided P = .0025).7
At 12 months, the OS rate was 83.1% (95% CI, 79.4%-86.2%) with durvalumab compared with 75.3% (95% CI, 69.2%-80.4%) with placebo, and at 24 months, the OS rates were 66.3% (95% CI, 61.7%-70.4%) and 55.6% (95% CI, 48.9%-61.8%), respectively.
Garon also noted that the toxicity profile was better than expected with durvalumab. The rate of any-grade pneumonitis was 24.8% with placebo and 33.9% with durvalumab, and grade 3/4 pneumonitis was seen in 3.0% of patients receiving placebo and 3.6% receiving the anti—PD-L1 therapy. “From my perspective, the toxicity…was much less than what I would have anticipated going into the trial,” he said. The range of pneumonitis was in the range of what is seen with other immune checkpoint agents.