Roundtable Discussion: Durvalumab Regimen Shows Efficacy in NSCLC

Mark A. Socinski, MD

During a Targeted Oncology Case-Based Roundtable event, Mark A. Socinski, MD discussed treatment of non–small cell lung cancer based on the PACIFIC trial.

Targeted Oncology^TM: How do the results of the PACIFIC trial (NCT02125461) inform decisions about using durvalumab (Imfinzi) following completion of chemoradiotherapy for patients with stage III non–small cell lung cancer (NSCLC)?

SOCINSKI: The PACIFIC study included patients with good performance status and unresectable, stage III NSCLC who did not progress after definitive platinum-based chemotherapy with concurrent radiation.¹ The patients had to be randomized within 6 weeks [of completion of chemoradiotherapy]. Patients were randomized to either the placebo control arm, which was the standard of care, or durvalumab for 1 year. The coprimary end points were progression-free survival [PFS] and overall survival [OS].

The PFS data, updated to approximately 3 years, show a hazard ratio [HR] of 0.51 [95% CI, 0.41-0.63] and pretty good separation of the Kaplan-Meier curves [median PFS, 17.2 vs 5.6 months].² The 4-year update is pretty consistent [stratified HR, 0.55; 95% CI, 0.44-0.67; median PFS, 17.2 vs 5.6 months].³

What was the initiation time of durvalumab on the PACIFIC trial?

In the original design of this trial, patients had to be randomized within 2 weeks [of completing chemoradiotherapy, but] that was problematic and accrual was slow. So, they amended the trial to bump it out to 6 weeks. The patients who started within 14 days had a better HR for PFS [unstratified HR, 0.39; 95% CI, 0.26-0.58] than patients who started after 14 days [unstratified HR, 0.63, 95% CI, 0.49-0.80].⁴ This begs the question: Is it just that [these patients were in better condition and therefore could] start early? Or is there something magic about giving anti–PD-L1 therapy so quickly after radiation? People who are much better immunologists than I am have an argument that earlier is better from the immune system’s point of view. I can’t explain that because I am not a good enough immunologist. That was the reason why they originally wanted to give [durvalumab] early, but they had to change it to 6 weeks because of feasibility issues.

The updated survival [data], presented at the 2020 European Society for Medical Oncology meeting, show that the 4-year OS curves are holding pretty steady with an HR of 0.71 [95% CI, 0.57-0.88].³ It took a long time for the median survival on the durvalumab arm to be reached, but it finally was reached at almost 4 years: 47.5 months [vs 29.1 months for placebo]. This is after chemoradiotherapy...it takes 3 months to do chemoradiotherapy, and then it might be 6 weeks from the completion of chemoradiotherapy to randomization and [initiation of] durvalumab. The control arm did pretty [well], but the durvalumab arm did much better. [It’s] nice to see this consistent benefit out to 4 years now.

Do EGFR and PD-L1 status influence your decision to recommend durvalumab?

The HRs for OS and PFS by subgroup all favor durvalumab [except for the EGFR-positive subgroup].³ There was a very tiny number of patients with the EGFR mutation [43 patients], so the confidence intervals [are very large]. So, I don’t know. Many of my colleagues are not giving consolidation durvalumab to patients with the EGFR mutation. They have 2 concerns: “Will it benefit the patient?” and “If they relapse and they’ve had an anti–PD-L1 agent, is it safe to give osimertinib [Tagrisso] after an immuno-oncology combination because of the risk of pneumonitis?"

PD-L1 testing was not required in the PACIFIC trial, and PD-L1 status [was unknown for] 37% of the patients. The prespecified analysis [with a] 25% cut point [shows that patients whose tumors] were strongly PD-L1 positive had a greater benefit.

The United States label [for durvalumab] is agnostic to PD-L1 status. However, the European authorities asked them to get a bit more granular [in] post hoc analysis. Why AstraZeneca agreed to do this, I don’t know, because this is not protected by the power of either stratification or randomization. And 37% of patients had an unknown status. The small number of patients wasn’t powered to address this issue. But in the less than 1% subgroup, the PD-L1–negative group, so to speak, there is no suggestion of a benefit. So, interestingly, based on this unplanned, unprotected, retrospective subset analysis, in Europe if a patient’s cancer is PD-L1 negative, they can’t get durvalumab paid for. I think these data are hypothesis generating; I don’t think they are standard-of-care setting. But that’s my personal view.

Are you concerned about the risk of pneumonitis with durvalumab?

There was concern about giving an agent that has a risk of pneumonitis—that being a PD-L1 inhibitor, [which] following radiation has a risk of pneumonitis. But [data from the PACIFIC trial showed that] grade 3/4 pneumonitis was 3.4% [for durvalumab vs 2.6% for placebo].⁴ There was a slight increase in any-grade pneumonitis with durvalumab [33.9% vs 24.8%], but it was mostly grade 1 or 2.⁴

How are you using induction therapy and consolidation therapy?

Many of us were doing a couple cycles of chemotherapy after chemoradiotherapy, and consolidation therapy now should be durvalumab. In the PACIFIC trial, 26.8% of the patients had induction therapy,⁴ and I have a bias [toward] induction therapy. I do it; we do it at our center. Our radiation oncologists like it because it buys them 6 weeks to get the radiotherapy organized and planned. Invariably there is some degree of shrinkage, so the tumor volume is a little less, and to me that is a good reason to do it. We give 2 cycles of induction therapy. Rather than give it as consolidation, I get my 4 cycles in [by giving] 2 cycles before chemoradiotherapy. Then I consider the 6 weeks of weekly carboplatin/paclitaxel as the equivalent of another couple cycles.

The National Comprehensive Cancer Network deleted the recommendation for consolidation therapy.⁵ If, for some reason, the patient has a contraindication to immunotherapy, then giving a couple cycles of consolidation or induction therapy is reasonable.

How would you manage pneumonitis in this patient?

Julie Renee Brahmer, MD, published guidelines for the management of toxicities of immunotherapies.⁶ It’s a nice paper to be familiar with and can be helpful to guide [treatment for] patients who do have pneumonitis.

Do you have any other thoughts on the treatment of patients on durvalumab?

Most of my patients get through a full year [of durvalumab therapy]. The most common reason I stop it during the year is because of an adverse event. The FDA has given that OK to move ahead with every 4 weeks, and that provides a lot more convenience.⁷

_REFERENCES

_{1. Paz-Ares L, Villegas A, Daniel D, et al. PACIFIC: a double-blind, placebo-controlled phase III study of durvalumab after chemoradiation therapy in patients with stage III, locally advanced, unresectable NSCLC. Ann Oncol.2017;28(suppl 5):v605-v649. doi:10.1093/annonc/mdx440}

_{2. 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}

_{3. Faivre-Finn C, Vicente D, Kurata T, et al. Durvalumab after chemo-radiotherapy in stage III NSCLC: 4-year survival update from the phase III PACIFIC trial. Ann Oncol. 2020;31(suppl 4):S1178-S1179. doi:10.1016/j.annonc.2020.08.2281}

_{4. 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}

_{5. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 8.2020. Accessed April 29, 2021. https://bit.ly/30sRU9e}

_{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}

_{7. IMFINZI (durvalumab) approved in the US for less-frequent, fixed-dose use. News release. AstraZeneca. November 20, 2020. Accessed April 29, 2021. https://bwnews.pr/398dmFs}