Optimizing the PACIFIC Regimen

Howard (Jack) West, MD:There are some unanswered questions in the wake of the PACIFIC trial. It gave 2 cycles of chemotherapy concurrent with chest radiation—at least 2 cycles—and then patients went right on to durvalumab. About 20% to 25% received induction chemotherapy before starting that, but additional consolidation chemotherapy was not included. I would not be inclined to give chemotherapy after durvalumab, which was given for a year duration in the PACIFIC trial. The question is…I would say particularly for the patients who are getting carboplatin and paclitaxel on a weekly basis, whether we might want to give additional systemic dose. There is some question of whether the weekly carboplatin/paclitaxel regimen for 6 or 7 weeks is sufficient to address micrometastatic disease systemically. That’s an open question.

For my patients who are just getting 6 or 7 weeks of carboplatin/paclitaxel weekly without any consolidation chemotherapy, I would now consider doing it as an induction approach, which also certainly makes it easier to organize. One of the challenges in treating patients with locally advanced disease is that you need to coordinate with the radiation oncologist and get the simulation done. It often takes a few weeks, and 1 advantage of doing an induction approach, which hasn’t shown a significant improvement historically but shows trends of a favorable benefit, could be that you can give it for a couple of cycles, get a good systemic dose of, say, every-3-week carboplatin and paclitaxel, and then go on to the chemotherapy and radiation with a possibly smaller radiation field. This gives the radiation oncologist enough lead time to really get things folded in in a controlled way, rather than scrambling at the beginning to get everything started, as often is the case.

I would say that we surmise it’s particularly valuable to give the durvalumab in quick succession after completion of the radiation. It was done within 6 weeks of completion of the radiation course and in some cases within a couple of weeks, and so I would not be inclined to postpone the durvalumab by interposing consolidation chemotherapy for 2 cycles or a few months before starting durvalumab. I wouldn’t do it as a consolidation before or after durvalumab given for a year, but I would consider it for induction, particularly for the patients who are getting weekly carboplatin and paclitaxel alone.

The PACIFIC trial evaluated patients within the first few weeks after they completed chemotherapy and radiation and had them start durvalumab within 6 weeks of having completed radiation. Some of the patients, a minority, had received it just within a couple of weeks after chemotherapy and radiation, but the majority were somewhere within 2 to 6 weeks out. My practice and, I think, many other thoracic oncology specialists tend not to do repeat imaging in the first week or 2 after radiation has been completed, because we expect to see further shrinkage of the cancer several weeks out from the radiation and chemotherapy.

Historically, we might have done this 3 to 4 weeks out. I might move that up to 2 to 3 weeks and have them start durvalumab in short order after that. I will typically have them start 3 or 4 weeks out. You could do it a little earlier, or you could do it later. I would also say that if for some practical reasons they couldn’t start until after they’re 6 1/2 or 7 weeks out, that would not dissuade me. But the trial had them start within 6 weeks. It is given every 2 weeks, IV, for a year. That’s what the FDA approval is for. We don’t know whether treatment beyond a year is beneficial. The trial didn’t ask that. We will need to see the longitudinal results and whether the benefits of giving it for a year are long-lastingly sustained well beyond that or time limited, and that might suggest there would be a benefit to continuing it. But the FDA approval, and the way the trial was conducted, is to start within 6 weeks after the radiation is completed and give it every 2 weeks for up to a year.

In this particular case, she received a course of radiation up to 55 Gy, which I would say is a little on the low side. I believe the trial included a minimum of 54 Gy, and globally, that is a minimum standard. In the United States, it’s more common to see patients getting 60 to 64 Gy, or occasionally 66 Gy. In my own center, we typically do about 61 to 64 Gy. I would be inclined to try to get her up to the low 60s, and if that includes an extra week of chemotherapy on this weekly carboplatin/paclitaxel regimen, so much the better. I do think that one of the concerns we have is just hoping to give enough chemotherapy. If a patient is tolerating it well, I would be inclined to at least get up to 7 weeks of treatment and 63 or 64 Gy. I would say beyond that, more is not clearly better. There was an RTOG trial, 0617, that demonstrated a detrimental effect of radiation getting up into the 70s, and so I would say this is a setting where more is not necessarily better, at least beyond a point of 61 Gy or 60 to 64 Gy.

Transcript edited for clarity.

A 60-year-old Asian Woman With Unresectable, Locally Advanced NSCLC

• A 60-year-old Asian woman presents with complaints of chest pain and shortness of breath. She reports developing a persistent cough about 1 year ago, which she attributed to allergies. In the past month, she has “spit up” blood several times, which caused her to make the appointment.
• Her history includes:
  • Former smoker, quit smoking at age 35 when she became pregnant
  • Normal BMI, postmenopausal, no history of cardiovascular disease
  • No previous cancer history
• Evaluation and follow up testing reveal
  • Stage IIIA NSCLC in right bronchi: 3.5-cm tumor with pleural involvement and spread to mediastinal lymph nodes
  • WHO performance status 1
  • Histology: Squamous cell
  • Biomarkers:
    • EGFR,BRAF,ALK/ROS1negative
    • PD-L1 status: 10%
• After multidisciplinary evaluation, the patient was determined not to be a candidate for surgery, and completed chemoradiotherapy:
  • Carboplatin/paclitaxel doublet plus 55 Gy radiotherapy
  • Achieved stable disease without progression 14 days after completing treatment
  • Began treatment with durvalumab