Looking at the PACIFIC Trial

Stephen Liu, MD:The PACIFIC trial is a landmark study that showed the role of immunotherapy after concurrent chemoradiation for stage III non—small cell lung cancer. In this study, patients completed chemoradiation using a platinum doublet chemotherapy. They received at least 2 doses of chemotherapy during the course of treatment. No consolidation was performed, though. Induction chemotherapy was permitted. After completion of chemoradiation within 14 to 42 days, patients started treatment and were randomized to either placebo or durvalumab, a PD-L1 [programmed death-ligand 1] inhibitor given at the dosage of 10 mg/kg every 2 weeks for 26 doses, or 1 year.

The study showed that the addition of durvalumab to the chemoradiation setting in patients with unresectable non—small cell lung cancer improved progression-free survival, a substantial improvement in progression-free survival. With more follow-up, we saw that this improvement in progression-free survival translated to an improvement in overall survival. It’s really the first intervention in quite a long time to show an impact on survival in this setting. We’ve been using chemoradiation, delivering cure to some patients but not improving our long-term survival substantially for decades. The addition of durvalumab led to that improvement, an improvement in overall survival.

Additionally, tolerability was quite favorable. There were immune-related adverse events; the risk of pneumonitis was quite low. In addition, we saw higher response rates. When chemoradiation is completed, several months later a CT [computed tomography] scan will show an ongoing response just from the chemotherapy and radiation. With durvalumab, that response rate was higher. In placebo, we saw response rate of about 18%, the carryover from prior chemoradiation. That response rate increased to about 30% with the addition of durvalumab. We are seeing more immune-mediated responses, exploiting a potential synergy between PD-L1 inhibition and radiation. We saw a decrease in the time to distant metastases, including a decrease in the development of brain metastases, really showing a more systemic effect by the administration of PD-L1 inhibition.

We see an improvement in overall survival, an improvement in median survival, a hazard ratio of about 0.68, a 32% reduction in the risk of death with the addition of durvalumab, and a clear standard of care. We don’t yet have 5-year survival numbers, 10-year survival numbers, but it stands to reason those will be substantially higher with the incorporation of immunotherapy. This really is our current standard of care and should be adopted to all eligible patients.

It’s important to remember that the addition of durvalumab improved overall survival in the PACIFIC trial. While the improvement in progression-free survival was substantial, the improvement in overall survival is really the ultimate bar. This intervention, the addition of durvalumab after chemoradiation, did significantly increase toxicity or expose patients to great harm but improved survival. We see a hazard ratio of 0.68, a 32% reduction in risk of death, and that will carry over to better landmark survival. The study still is a little too early to say what is our median, what is our 5-year survival rate. But those numbers clearly were better than chemotherapy alone. We really anticipate seeing those long-term follow-up data.

The PACIFIC trial also improved quality of life for patients with stage III non—small cell lung cancer. This is an important finding. The addition of durvalumab improved progression-free survival, improved overall survival. It did increase toxicity versus placebo but at a modest amount. Overall, it’s a very well-tolerated regimen. But the PACIFIC trial also measured patient-reported outcomes [PROs], and what we see is that this improvement in efficacy outcomes did not come at the cost of decreasing the quality of life. It’s helping patients live longer, we know from the efficacy data. It’s also helping patients live better. That improvement in PROs, the improvement in patient-related outcomes, in quality of life, really speaks to the benefit from the addition of immunotherapy in this setting—1 more reason why this should be our standard of care.

Transcript edited for clarity.

Case: A 62-Year-Old Male With Stage III NSCLC

Initial presentation

• A 62-year-old man presented with a 2-month history of cough, wheezing, and loss of appetite
• PMH: Hypertension, medically treated
• SH: 30 pack-year smoking history; daughter to be married in 11 months, and wants to attend the wedding
• PE: Right lower lobe wheezing on auscultation

Clinical workup

• Labs: WNL
• PFT: FEV₁/FVC 60%; DLCO 55%
• Chest/abdomen/pelvic CT showed a 6.1-cm solid pulmonary lesion in the right lower lobe, right hilar and intrapulmonary lymph node involvement; no evidence of distant metastases
• PET scan showed large focal hypermetabolic activity in the right lower lobe and small hypermetabolic activity in the surrounding area
• Contrast‐enhanced MRI of the head showed no brain metastases
• Bronchoscopic biopsy of the RLL mass and hilar node revealed squamous NSCLC
• Staging: T3N1M0 — IIIA; ECOG PS 1
  • Unresectable NSCLC based on the extent and location of disease

Treatment

• Patient was started on cisplatin 50 mg/m²on days 1,8,29 and 36; etoposide 50 mg/m²days 1-5 and 29-33; concurrent RT
• No disease progression after chemoradiation
• Durvalumab 10mg/kg IV q2W was started and dose was tolerated well
• Initial follow-up at 2 months showed partial response, with shrinkage of primary and nodal lesions