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Key Studies in NSCLC: Independent Conference Coverage of the 2021 ASCO Scientific Meeting
  • CME

Zofia Piotrowska, MD, MHS
Karen L. Reckamp, MD, MS
Released: August 20, 2021

Advances in Unresectable Stage III NSCLC

PACIFIC 5-Year Update: Study Design

Karen L. Reckamp, MD, MS:
Let’s move on to unresectable stage III NSCLC. The first study is the 5-year update of PACIFIC, a randomized phase III trial evaluating consolidation durvalumab vs placebo following definitive concurrent chemoradiation for patients with unresectable stage III NSCLC.5 Results from the primary analysis of PACIFIC demonstrated significantly improved PFS and OS with consolidation durvalumab vs placebo, leading to the approval of durvalumab for this indication and establishing it as standard of care in unresectable stage III NSCLC.6-8

PACIFIC 5-Year Update: Patient Disposition

Karen L. Reckamp, MD, MS:
Here we have the patient disposition at 5 years. The percentage of patients who were off study due to death was lower with durvalumab (54.6% vs 62.9% with placebo), and the number of patients who discontinued due to AEs was slightly higher (15.4% vs 9.7% in the placebo arm).5

PACIFIC 5-Year Update: OS in ITT Population

Karen L. Reckamp, MD, MS:
The updated 5-year OS rate was 43% for patients who received durvalumab and 33% for patients who received placebo (HR: 0.72), which was highly significant and really unprecedented.5

PACIFIC 5-Year Update: PFS in ITT Population

Karen L. Reckamp, MD, MS:
PFS also was significantly improved at 5 years, with approximately one third of patients being progression free in the durvalumab arm vs 19% in the placebo arm (HR: 0.55).5 We haven’t seen survival improvements like these for unresectable stage III disease in a very long time.

KEYNOTE-799: Study Design

Karen L. Reckamp, MD, MS:
Although we have a new standard of care from PACIFIC for unresectable stage III NSCLC with significantly improved outcomes, there is still room for improvement. Other ongoing studies are testing different ways to deliver immunotherapy in this setting, including KEYNOTE-799, a nonrandomized, open-label phase II trial evaluating incorporation of immunotherapy earlier into the chemoradiation paradigm. Specifically, KEYNOTE-799 is assessing induction with pembrolizumab plus chemotherapy followed by pembrolizumab plus concurrent chemoradiation followed by pembrolizumab consolidation in 2 cohorts.9-10 Cohort A included patients with both squamous and nonsquamous histology, and cohort B included patients with nonsquamous histology only. The primary endpoints were overall response rate (ORR) and the rate of grade ≥3 pneumonitis.

KEYNOTE-799: Efficacy Outcomes

Karen L. Reckamp, MD, MS:
The ORR in both cohorts was approximately 70%, with a majority of responses being a partial response. Duration of response ≥12 months was 80% in cohort A and 76% in cohort B. In both cohorts, the 12-month PFS rate was approximately 70%, and the 12-month OS rate was >80%.9-10 Although the follow-up was relatively short, these are promising results.

KEYNOTE-799: Safety Outcomes

Karen L. Reckamp, MD, MS:
Grade ≥3 pneumonitis was 8% in cohort A and approximately 7% in cohort B, similar to what we’ve seen in other studies of this type, showing that incorporation of immunotherapy earlier into the chemoradiation paradigm does not appear to have significantly more toxicity than other approaches being evaluated in this setting.9-10

PACIFIC and KEYNOTE-799: Clinical Implications

Karen L. Reckamp, MD, MS:
Dr. Piotrowska, what do you think about the 5-year survival data from PACIFIC? Do you consider these patients cured?

Zofia Piotrowska, MD, MHS:
These data continue to look good with longer-term follow-up. It’s important to see these curves stay separated, and I would say that, yes, a subset of patients appears to be cured. Generally, in my clinic, if I see a patient who has been treated with definitive chemoradiation followed by a year of durvalumab reach 5 years without progression, I think that’s a very good sign, and the chances of recurrence after that point are quite low. However, I don’t think we’ve reached the end of gains for patients with unresectable stage III disease. It’s important to note that the 5-year OS in PACIFIC is <50%, so there’s still room for improvement. It’s interesting to look at the KEYNOTE-799 data and wonder whether, in the future, early incorporation of immunotherapy might improve outcomes even further.

Karen L. Reckamp, MD, MS:
I would agree. The 5-year survival data from PACIFIC clearly showed that we’re curing more patients with consolidation durvalumab. From the beginning, the separation of the survival curves has been impressive, and consolidation durvalumab has been one of the greatest advances with the biggest impact for stage III disease that we’ve seen in a very long time. That said, I also would agree that—even though we’re near 50% regarding 5-year OS—that’s not good enough. We have further to go and more to understand.

In the metastatic setting, when we combine chemotherapy and immunotherapy, we do have more benefit for patients, especially those who have lower PD-L1 expression. In PACIFIC, patients with <1% PD-L1 expression may have less of a benefit from durvalumab, so it is conceivable that we may capture more patients and improve outcomes by combining immunotherapy with chemotherapy earlier on, as was done in KEYNOTE-799. I’m excited to see what KEYNOTE-799 will show with longer follow-up, but this is a nonrandomized trial without a control arm, so it also will be important to see the data for some of the ongoing randomized phase III trials evaluating similar approaches. For example, PACIFIC-2 (NCT03519971) is evaluating concurrent chemoradiation with or without durvalumab followed by consolidative durvalumab or placebo. A National Cancer Institute study (NCT04092283) has a similar design of concurrent chemoradiation with or without durvalumab but followed by durvalumab in both arms. Finally, CheckMate73L (NCT04026412) is a 3-arm trial looking at nivolumab plus concurrent chemoradiation followed by consolidation with either nivolumab or nivolumab/ipilimumab compared with standard of care concurrent chemoradiation followed by consolidation durvalumab.

Zofia Piotrowska, MD, MHS:
I also was encouraged by the safety findings from KEYNOTE-799, which showed relatively low rates of severe pneumonitis in both cohorts. That always has been one of the concerns about adding immunotherapy to definitive thoracic radiation. I will say that those numbers are a little higher than what we saw in PACIFIC, even though they’re still low at <10%. It’s important to watch for this in our patients, but overall it generally appears to be safe to add immunotherapy to concurrent chemoradiation.

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Supported by educational grants from
Bristol-Myers Squibb
Daiichi Sankyo, Inc.
Ipsen Biopharmaceuticals, Inc.
Merck Sharp & Dohme Corp.

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