Adopting PACIFIC Data Into Practice

Hossein Borghaei, DO, MS:So PACIFIC represents the first real improvement in the management of patients with locally advanced non—small cell lung cancer that’s not surgically resectable. And what I mean by that is that it is the first randomized phase III study that has shown not only improvement in PFS [progression-free survival], 17 months versus roughly 5.5 months in the control arm, but also an improvement in overall survival [OS] of these patients: 2-year survival rates of 65%, 66% versus 55%, 56% in the control arm of the study. What this represents to me is that when my patients are treated with concurrent chemotherapy radiation, I would do my best to treat them with durvalumab, again barring any major contraindications, or adverse effects, or other issues because it’s the first time we actually have a randomized phase III trial in this setting that has been proven to improve survival of the patients over standard chemotherapy and radiation. So this, as far as I’m concerned, is the standard of care for patients with unresectable, locally advanced non–small cell lung cancer.

I think the NCCN [National Comprehensive Cancer Network] guidelines were correct in, first of all, putting durvalumab on the guidelines when the initial PFS data came out, because, again, it represented the first time we had a way of treating unresectable, locally advanced disease that improved PFS significantly. I think it was a category 2A because, as we all can agree, overall survival is the most important factor for most of our patients. And really for something to become the standard of care, I think we do need to show that overall survival advantage. Appropriately, once the OS data became available and they were shown to be statistically significant in favor of the use of durvalumab, this was moved up to a category 1 recommendation, suggesting that at least according to the NCCN guidelines and the non—small cell lung cancer committee, this is the standard of care and this is the way patients with unresectable, locally advanced disease should be treated. And that is concurrent chemotherapy radiation followed by durvalumab for a year, again exactly as the PACIFIC study suggests.

So I think you have to sort of define what you mean bypractice changing, and why we say something is the standard of care. To me, something becomes the standard of care if, in a well-controlled, randomized phase III study that is adequately powered, we can look at the potential benefit of a new treatment compared with the older standard of care. If the new treatment clearly shows clinical outcomes that meet the statistically defined threshold for that particular study, then the new treatment deserves the label of “standard of care” and “practice changing.”

Why do I think PACIFIC is such a study? Because it is the first time, in many decades, we have had an intervention apply to a group of patients in whom we haven’t had any major improvement in either OS, PFS, or response rate that has shown to improve all those clinical parameters with acceptable toxicity rates.

The toxicity and the quality of life of the patients who are undergoing these treatments is of paramount significance. We don’t want to apply or give a treatment that causes so much toxicity for a patient if he or she does not really have a good quality of life once they’re done with the treatment. What we have in PACIFIC is a simple treatment strategy that is highly effective, as judged by improvement in both PFS and OS, with significant hazard ratios.

But also the toxicity profile, as presented in PACIFIC, seems to be extremely favorable for the use of durvalumab after chemotherapy radiation. We did not see a significant increase in the rate of hospitalization for various toxicities. We did not see a significant increase in the rate of pneumonitis, which is something that we all worry about. We did not get a significant increase in infections or other adverse effects that we would normally attribute to a combination of chemotherapy and radiation. Clearly, having a patient come to the office every other week and be infused with a drug that could potentially cause its own toxicities is asking a lot from our patients.

But on the other side of it, again, if we can manage to improve the clinical outcomes that we’re interested in, and again, I would emphasize survival is the most important factor, at least in my view, then I think it’s a reasonable discussion at least with the patient to say that, given all the facts that we’ve talked about, yes, there are toxicities. Yes, there could be an immune event or related adverse events with the use of durvalumab. But all of these are worth the potential clinical benefit. To me, that elevates the PACIFIC regimen to the level of a standard of care and something that at least every patient should hear about and have a discussion on and be able to decide whether they want to proceed with it or not.

We worry about every drug that we put in our patients. There’s no doubt about it. But we’ve learned how to manage a lot of the immune-related adverse events associated with checkpoint inhibitors. Again, we did not see a significant increase in those toxicities in PACIFIC, so I think it is worth the discussion, and it is worth considering for patients who have a good performance status and otherwise match the profile of the patients that we saw in the PACIFIC trial.

Transcript edited for clarity.

Case: A 72-Year-Old Female With Stage IIIB NSCLC

Initial presentation

• A 72-year-old woman presented with a 17-lb weight loss and dyspnea
• PMH: HTN and hyperlipidemia
• PSH: Laparoscopic cholecystectomy
• SH: Smoked 3 packs/day for 30 years; Quit 5 years ago
• PE: Unremarkable

Clinical workup

• Imaging:
  • Chest x-ray showed a left hilar mass with a middle lobe collapse
  • CT scan of the chest/abdomen/pelvis revealed a 4.9 x 5.4 cm left upper lobe mass with bilateral hilar and mediastinal lymphadenopathy
  • CT abdomen/pelvis negative for metastatic disease
  • PET/CT confirmed activity in the lung and lymph nodes
  • MRI of the brain was negative for metastatic disease
• CT-guided biopsy of the left lung mass revealed a differentiated invasive squamous cell carcinoma
• Molecular testing: PD-L1 20%
• Staging: T2bN3M0—IIIB
• ECOG PS 1

Treatment

• Concurrent chemoradiation with weekly carboplatin-paclitaxel
• Imaging 6 weeks after completion showed response in the lung and lymph nodes
• Durvalumab consolidation: 4 cycles with continued tumor control on imaging
• Developed dyspnea and cough after 8 cycles