PACIFIC Regimen Is Appropriate for Use in Patients With Non–Small Cell Lung Cancer After Chemoradiation

Alexander Spira, MD, PhD

During a virtual Targeted Oncology Case-Based Roundtable event, Alexander Spira, MD, PhD, discusses when the use of durvalumab (Imfinzi) followed by chemoradiotherapy is appropriate for patients with unresectable stage III non–small cell lung cancer (NSCLC).

Targeted Oncology^TM: What regimen would you choose for this patient for concurrent chemotherapy and radiation?

SPIRA: The National Comprehensive Cancer Network [NCCN] guidelines recommend cisplatin/etoposide—I remember when that was the one that everybody used; sadly, I’m getting old—and carboplatin/pemetrexed [Alimta], cisplatin/pemetrexed, and weekly carboplatin/paclitaxel.¹

I think most oncologists use weekly carboplatin/paclitaxel in a case like this. There’s a plus-minus on the adjuvant carboplatin/paclitaxel. I always find it somewhat ironic; when you’re doing definitive chemoradiotherapy for a bad stage III disease, you are giving an equivalent of 2 cycles of chemotherapy, sometimes even a bit less if you look at the doses, but if they have adjuvant therapy, you give them 4 cycles of a higher dose. This just shows the inconsistency in terms of what we know and how we really treat patients.

This patient got cisplatin/pemetrexed with concurrent radiation, and follow-up imaging showed a partial response with shrinkage and no evidence of metastatic disease.

[Many patients do not complete chemoradiotherapy.] I think the biggest reason, for me at least, is toxicity—esophagitis—especially in an older population.

Would you give this patient durvalumab (Imfinzi) after the completion of chemoradiotherapy? What does the PACIFIC study reveal about this?

The PACIFIC study [NCT02125461] was a phase 3, randomized, placebo-controlled study of patients with stage III [locally advanced, unresectable non–small cell lung cancer] who did not progress after definitive chemo-radiotherapy and were 18 or older, performance status 1, life expectancy 12 weeks or more, all-comers population, 1 to 42 days post chemoradiation.² The patients were randomized 2:1 durvalumab versus placebo, and the end points were progression-free survival [PFS] by blind review, overall survival [OS], and standard secondary end points.

This [trial] was well before we really understood immunotherapy and targeted therapy, so there was no mandate that the patients have EGFR and ALK [testing]. Many did not, and some we did not have PD-L1 status on as well.

We are now up to a 4-year update, which is great. Both the 12-month and 18-month PFS were significantly better [with durvalumab]. I call it the 2-finger rule: If I can fit 2 fingers between the Kaplan-Meier curves, it is a home run. It’s not as good as the [coronavirus disease 2019] COVID-19 Pfizer vaccine, but it’s a really good result. [The PFS was] 55.7% versus 34.4% at 12 months, and 49.5% versus 26.7% [at 18 months], with a nice tailing off of the curve as well. [Median] PFS was 17.2 versus 5.6 months [stratified HR, 0.51; 95% CI, 0.41-0.63].^3,4

What is an appropriate time interval between the completion of chemoradiotherapy and the initiation of durvalumab?

The subgroup analyses [of the PACIFIC trial favor durvalumab], which is great.5 But patients who were randomized less than 14 days after the last radiation did better [unstratified HR, 0.39; 95% CI, 0.26-0.58] than those who were randomized after 14 days [unstratified HR, 0.63; 95% CI, 0.49-0.80]. I believe that they started the durvalumab just a day or 2 after randomization.

There are 2 ways of looking at this. One is that the patients who were randomized in less than 14 days were able to get on the durvalumab sooner because they had less burden of stage III disease or were feeling better, which is a very important thing; they may have had less esophagitis, or they just did better.

I believe that [initiating durvalumab] sooner is probably better. [But] people do need a bit of break, so I want to be realistic as well. Patients are tired, patients are beaten up, they get their scan, you’re on vacation for 2 weeks because it’s summer. They’ve been going every day for a while. They just want to go out to dinner for a few nights or at least not come to the doctor’s office for a week or 2. But again, getting closer to that time point in my mind is a little bit better. So I just tell them I try and do it sooner rather than later. But usually it is within 6 weeks, and remember the PACIFIC study wanted everybody on [durvalumab] within 6 weeks.

In the old days, patients would come and get a CT scan 4 to 6 weeks after. I’m not going to go back and discuss whether or not you should be giving people consolidation chemotherapy. That is something many oncologists did a long time ago, and we should have and have gotten away from it. But my take-home message is just to [initiate durvalumab] as soon as possible, within reason. Whether it’s 14 days or 21 days probably doesn’t matter. Really look at the patient and figure out whether they are ready for it. Many patients just need a break.

What else can we learn from the PACIFIC trial?

The 4-year OS rate is pretty good: 49.6% with durvalumab versus 36.3% [with placebo (stratified HR, 0.71; 95% CI, 0.57-0.88)].⁴ I’ll call this the almost-2-finger rule. I’m sure there’ll be a 5-year update and, for those who are still practicing, probably even a 10-year update as well.

[Subgroup analyses of PFS and OS generally favor durvalumab over placebo.] For patients with stage IIIB disease, the error bars did cross the median [toward favoring placebo], so I have a little bit of concern for higher-stage disease. It’s a pretty unimpressive curve for the EGFR mutation: Both OS and PFS scores cross the median [favoring placebo]. There were only 43 patients in the entire study with EGFR mutation.

Another interesting thing is that the nonsmoking patients did even better [with durvalumab] than the smoking patients. It is a small number but it’s a pretty impressive number there, for what that’s worth.

Does the PACIFIC trial shed light on the relationship between durvalumab effectiveness and PD-L1 status?

The prespecified [PD-L1] analysis was for 25% or more, or less than 25%. Then the post hoc [analysis] was 1% to less than 25%, 1% or more, and less than 1%.⁴ Patients with PD-L1 less than 1% fell on the wrong side of the curve [favoring placebo]. The approval for the PACIFIC trial in the United States was for all-comers, so it was done regardless of [PD-L1] status. PD-L1 testing was not required, and over one-third of participants had unknown [PD-L1 status]. [The testing] was all done from prebiopsy; postbiopsy was not possible. The PD-L1 cutoff of 1% was a post hoc analysis that was unplanned, requested by the European Medicines Agency.

I think it is an interesting thing; it’s very hypothesis-generating. Whether patients with PD-L1 less than 1%really don’t need durvalumab, we don’t know because the study did not look at them specifically. But I think it does raise some important questions. I would give it to people. The reason I check PD-L1 status is that people start to have some adverse effects [AEs]. And let’s face it, you hit month 6 and month 7, you have an older patient—my biggest issue in patients who have been on durvalumab for a while—they develop myalgias and arthralgias. To me, that’s the biggest dose-limiting toxicity over time. I might have more of a threshold to stop a little bit early if the patient starts to have some of those AEs, which can go on for a while and affect their activities of daily life significantly. So that’s one of the reasons I check PD-L1. Admittedly, there are no good data, but I put that in my toolbox and just think about it as well.

What AEs are associated with durvalumab?

In the safety summary, grade 3/4 and grade 5 AEs were pretty similar in the durvalumab and placebo arms [grade 3/4 AEs, 96.8% vs 94.9%; grade 5 AEs, 4.4% vs 5.6%, respectively].⁵ There were a few more treatment-related AEs in the durvalumab arm [67.8% vs 53.4%], and a few more serious AEs [28.6% vs 22.6%].5The placebo arm had 8.1% immune-related AEs.5 So that’s the power of placebos, I like to say. There was more pneumonitis and pneumonia [in the durvalumab arm (any grade pneumonitis, 33.9% vs 24.8%; any grade pneumonia, 13.1% vs 7.7%)].⁵ We always have a tough time in clinical studies distinguishing and quantifying pneumonia versus pneumonitis, but there was a little bit more pneumonitis. For grade 3/4, the rates were still very low [grade 3/4 pneumonitis, 3.4% vs 2.6%; grade 3/4 pneumonia, 4.4% vs 3.8%].⁵

The NCCN [removed] recommendations to add full-dose chemotherapy if the patient had not received it before.¹ This was always listed as optional and was a very controversial thing. There were concerns that it would increase the risk of pneumonitis. I think that, by and large, consolidation chemotherapy went away with this study. It is an option after concurrent chemoradiotherapy, although there have been many negative studies.

What is your approach to management of pneumonitis in patients receiving single-agent checkpoint inhibitors?

[According to the American Society of Clinical Oncology guidelines for management of immune-related pneumonitis,] infectious workup should be considered, but this is different from reality.⁶ Especially because if these are outpatients, it’s always hard to get them scheduled, and by the time you get them scheduled—if this is pneumonitis—they have been on steroids and they are often better. But consider infectious workup with bronchoscopies, cultures, etc.

For grade 3/4 pneumonitis, permanently discontinue immune checkpoint inhibitors and provide supplemental oxygen. This information is all available [in the guidelines], and it [is] just a good reminder to take a look and [use] what’s out there.

REFERENCES

1. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 4.2021. Accessed April 1, 2021. bit.ly/30sRU9e

2. Paz-Ares L, Villegas A, Daniel D, et al. 5638 - PACIFIC: a double-blind, placebo-controlled phase III study of durvalumab after chemoradiation therapy (CRT) in patients with stage III, locally advanced, unresectable NSCLC. Ann Oncol. 2017;28(suppl 5):v605-v649. doi:10.1093/annonc/mdx440

3. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350. doi:10.1056/NEJMoa1809697

4. Faivre-Finn C, Vicente D, Kurata T, et al. LBA49 - Durvalumab after chemora-diotherapy in stage III NSCLC: 4-year survival update from the phase III PACIFIC trial. Ann Oncol. 2020;31(suppl 4):S1142-S1215. doi:10.1016/annonc/annonc325

5. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N Engl J Med.2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937

6. Brahmer JR, Lacchetti C, Schneider BJ, et al; National Comprehensive Cancer Network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2018;36(17):1714-1768. doi:10.1200/JCO.2017.77.6385