Reflecting on Real-World Evidence for Durvalumab in Unresectable Stage III NSCLC

Article

During a Targeted Oncology™ Case-Based Roundtable™ event, Edward S. Kim, MD, MBA, and participants discussed the PACIFIC and PACIFIC-R studies of durvalumab in patients with unresectable stage III non–small cell lung cancer.

Kim headshot

Edward S. Kim, MD, MBA (Moderator)

Physician-in-Chief, City of Hope Orange County

Vice Physician-in-Chief, City of Hope National Medical Center

Professor, Department of Medical Oncology & Therapeutics Research

Construction Industries Alliance City of Hope Orange County Physician-in-Chief Chair

Newport Beach, CA

DISCUSSION QUESTIONS

  • Were you familiar with the PACIFIC-R observational study (NCT03798535) and/or its results?​
  • What is your reaction to those data? Which data is most impactful and relevant to your practice? ​
  • How do they compare to your own experiences with use of durvalumab (Imfinzi) after chemoradiotherapy? ​
  • Would you use consolidation durvalumab in patients with PD-L1 levels less than 1%?​
  • What about patients with a known EGFR mutation?​
  • How do you manage adverse events (AEs) to allow patients to receive optimal therapy of 12 months?​

EDWARD S. KIM, MD, MBA: Were you familiar with the PACIFIC-R study and/or its results? How did they compare with your experience? Would you use consolidation durvalumab in those patients with less than 1% PD-L1? What if this was stage IIIC disease? And how do you all manage those AEs?

RUPESH PARIKH, MD: Considering there are few options for maintenance [therapy], I would still tend to use durvalumab [Imfinzi] even if the PD-L1 level was less than 1%, because they usually don’t tolerate maintenance chemotherapy that well after 4 to 6 cycles unless you want to put them on pemetrexed [Alimta] maintenance.

HARRY MENON, DO: I've seen these data before and I agree. I would use durvalumab in these cases even despite that because from a maintenance standpoint, you don’t have better options here and I'm going to try and do as much as possible.

KIM: Does anyone have challenges with AEs and management? Are you going for 12 months, or do you think once you hit 6 months or 8 months you're in the clear?

PARIKH: I try and go 12 months. The challenge I have is at 12 months is whether to continue it if I still see evidence of disease that is ‘lukewarm’ on the PET scan.

THAI HO, MD: I tend to stop at 12 months because I think you're not going to deepen the responses with more immunotherapy past a year.

MENON: I would just go for the 12 months and then monitor.

DARSHIL SHAH, MD, MPH: Twelve months is the goal, but I usually do run into some kind of autoimmune toxicity before 12 months and [so I] manage [and] sometimes use prednisone, but 12 months is the goal. Once I reach that I usually stop.

KATHERINE THOMAS, MD: I don’t have anything to add. I only have ever done 12 months. I haven't gone any [longer].

KIM: I think 12 months is the goal, and I wouldn’t go past 12 months. We’re all tempted by that especially when the patient looks good. It is the same thing in the metastatic setting when we’re giving maintenance. What do you do when you stop? It's hard to say, but the study used 12 months so I would just use 12 months and then let patients go at that point and follow them with scans. Short of some of immune-related AEs like interstitial lung disease and others, [which] we know how to manage through, we want to keep going. It doesn’t surprise me that the real-world data shows it's a little bit better because I think [physicians] are more comfortable.

ROBERT YOO, DO: Did we talk about [if] a patient had the EGFR mutation?

KIM: No, we have not yet.

YOO: I’ve had 2 cases. I know the phase III LAURA study [NCT03521154] is not yet published but I'm doing…maintenance osimertinib [Tagrisso]. I looked at the subset analysis on EGFR; I think it was 9 or 10 patients from PACIFIC.1 There was no benefit from durvalumab, so I was just doing maintenance osimertinib after chemoradiation.

KIM: [This is] definitely extrapolation of the data. Biomarker testing [was not] required in PACIFIC so just as you pointed out, the data are [limited] in there. We get a little worried to give IO [immunotherapy] in the metastatic setting if we have [a patient with] an EGFR mutation [in their disease]. If you're testing, and you want to avoid giving IO in your locally advanced patients who have EGFR mutations, this study didn’t answer that question. But I think extrapolating some of those data from the other experiences across lung cancer [treatment] is rational at this point.

YOO: In your practice [would you] offer maintenance osimertinib instead of durvalumab if you have EGFR-mutated [lung cancer]?

KIM: In unresectable disease it's not necessarily a standard practice. It's very much debated, and you wonder if you just [should] wait until progression [if] there’s an EGFR mutation or if there's actual benefit in the unresectable [population] right now. That [approach] is not a standard. I didn’t say it was wrong. I just said it wasn’t standard, so let me just be clear about that.

BRIAN VICUNA, MD: In the PACIFIC-R data, most of those patients started durvalumab more than 6 weeks after the chemoradiation and their progression-free survival was 5 months better.2 Do you think that was correlated to waiting longer after chemoradiation, or a separate reason?

KIM: I don’t know if it was necessarily correlated with that. Even [with] the earlier start of the durvalumab, it’s an unsupervised analysis. It's harder sometimes in other countries to get in to start treatment after diagnosis and then to get to the next treatment. We see that in [the United Kingdom] and some European countries, etc. I don’t know if I’d necessarily say it's a correlation right now. These were just observational data.

Remember there was also sequential chemotherapy/radiotherapy that was done which we know is not as superior per se, as concurrent [chemoradiation] but those patients had some different situations physiologically. I would take it as real-world evidence that durvalumab works but those details that we talk about as far as when to start, when the optimal time to start is, duration, etc; those are still going to linger. I would just go with the protocol that was in the randomized study. We will be debating those aspects and the merits of real-world observational data vs the randomized study data.

SHAH: [I have] a theoretical question. I know in the PACIFIC study they didn’t look at the biomarkers, but if you find someone who has STK11/KEAP1 mutation and you know that IO monotherapy is not going to be that effective, would that make an impact on the decision as far as using durvalumab?

KIM: I wouldn’t use that as my guidance in stage III [disease], even in the metastatic setting. Although there are increasing data with several of these markers, it wasn’t something that stops us right now if that’s the best option, because we’re not necessarily seeing AEs as you would with the EGFR mutations of that trial. It might be less effective, but it doesn’t say it's harming the patient from that standpoint. In the stage III setting, if you happen to have those [biomarkers] in front of you, you can certainly discuss it with the patient. But there were no data out of PACIFIC that looked at those, so it's hard to say if you should use those to guide therapy, especially a therapy that has shown such benefit.

References:

1. Spigel DR, Faivre-Finn C, Gray JE, et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. J Clin Oncol. 2022;40(12):1301-1311. doi:10.1200/JCO.21.01308

2. Girard N, Bar J, Garrido P, et al. Treatment characteristics and real-world progression-free survival in patients with unresectable stage III NSCLC who received durvalumab after chemoradiotherapy: findings from the PACIFIC-R study. J Thorac Oncol. 2023;18(2):181-193. doi:10.1016/j.jtho.2022.10.003

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