Updated 3-Year Data Confirm Prolonged Survival Benefit With Durvalumab in Stage III NSCLC

David Spigel, MD

David Spigel, MD

Data from a 3-year update of the phase III PACIFIC trial confirmed an improvement in overall survival (OS) with treatment of durvalumab (Imfinzi) in patients with unresectable, stage III non—small cell lung cancer (NSCLC) who did not progress after chemoradiotherapy.

In this randomized, double-blinded, placebo-controlled, multicenter phase III trial, 713 patients were randomized 2:1 to receive either durvalumab every 2 weeks or placebo following chemoradiotherapy for up to 1 year. The 2 co-primary endpoints of this trial were progression-free survival (PFS) and OS.

Based on the first planned interim analysis, the addition of durvalumab improved PFS by 11.2 months compared to placebo (HR, 0.52; 95% CI, 0.42-0.65;P<.001).¹After further follow-up, the median OS had not yet reached in the durvalumab arm compared to 28.7 months in the placebo arm (HR, 0.68; 99.73% CI, 0.47-0.997;P= .0025).²The 12-month OS rate with durvalumab was 83.1% versus 74.6% with placebo.

Findings showed that the agent was well tolerated with no new safety signals; 30.5% of patients who received durvalumab experienced grade 3/4 adverse events compared to 26.1% with placebo. Overall, 29.1% of patients in the durvalumab arm and 23.1% in the placebo arm experienced serious AEs, while 15.4% and 9.8% of patients discontinued treatment due to toxicities, respectively.

Two-year findings for the PACIFIC trialwere later presented at the 19th World Conference on Lung Cancer. At a median follow-up of 25.2 months, the 24-month OS rate was 66.3% versus 55.6%, favoring durvalumab. The updated findings for median PFS in the durvalumab and placebo arms also demonstrated a prolonged duration of 17.2 months versus 5.6 months, respectively (HR, 0.51; 95% CI, 0.41-0.63).

The 3-year OS updates to the PACIFIC trial were recently presented at the 2019 ASCO Annual Meeting; after a median follow-up of 33.3 months, the median OS had still not yet been reached in the durvalumab arm versus 29.1 months in the placebo arm. The 36-month OS rate with durvalumab versus placebo was 57.0% versus 43.5%.

Data presented at ASCO also confirmed there were still no new safety signals. Additionally, 43.3% of patients in the durvalumab arm had gone on to receive subsequent anticancer therapy after discontinuation versus 57.8% in the placebo arm.

In an interview withTargeted Oncology, David Spigel, MD, chief scientific officer at Sarah Cannon Research Institute, discussed the updated findings from the PACIFIC trial and how these data will impact the treatment landscape for patients with stage III NSCLC, as well as those with earlier-stage disease. He also highlighted controversies that clinicians face with incorporating immunotherapy into their practice for patients.

TARGETED ONCOLOGY: Please explain what the updated findings from the PACIFIC trial have shown.

Spigel:PACIFIC was a randomized, phase III study looking at the role of an immunotherapy, in this case the PD-L1 inhibitor durvalumab, following standard chemoradiotherapy or locally advanced unrespectable NSCLC. We first heard about this study a couple of years ago when the initial PFS data were released, and we knew that this study was positive, that is to say if a patient had locally advanced unresectable NSCLC, and really regardless of histology or PD-L1 expression, there was an advantage to getting durvalumab after chemoradiotherapy for both PFS and OS.

Last year, we got an update of further follow-up where that reduction and risk of death approaches about 50%, which is quite substantial. The safety continues to hold up. What we are seeing now at ASCO 2019 is an additional follow-up, where all of the efficacy data hold up and the safety data hold up; there are no new surprises.

TARGETED ONCOLOGY: Were there any controversies with these data?

Spigel:One of the controversies that has come up with PACIFIC over the last year has been the role of whether things like PD-L1 expression or even things likeEGFRexpression should be considered when you&rsquo;re making a decision about whether to use durvalumab or not. The original design of the study was not intended to look at PD-L1 status as a factor required for enrollment, but it was certainly something that was collected and looked at in a lot of patients, but not all patients retrospectively.

What happened last year was the European regulatory authorities required a post-hoc analysis of that survival advantage stratified by PD-L1 expression. What they found in that analysis was that it appeared that patients with no PD-L1 expression did not benefit from durvalumab, and so the European label has that in it, that you have to use PD-1 expression 1% or higher to get access to durvalumab.

In the United States, however, that is not required, so it&rsquo;s kind of a confusing story because there are some investigators, not just in Europe, that are confused by the PD-L1 expression status and whether you need to have it to benefit from durvalumab. My view is that in the overall intent-to-treat analysis, it was not a critical factor to suggest benefit; I think the subset analysis that was not planned is interesting, but probably more work needs to be done. There are several ongoing efforts looking at that.

TARGETED ONCOLOGY: How would you, or other healthcare providers, counsel patients who are hesitant to go onto an immunotherapy for a year after completing their chemoradiotherapy treatment?

Spigel:I think locally advanced NSCLC is a disease setting that can make patients symptomatic. It tends to be in the center part of the chest and affects your breathing, it&rsquo;s associated with frequent pneumonias, and so patients tend to be sick. You give them chemoradiotherapy, and you can make them sicker with that, so it&rsquo;s always been a difficult negotiation of adverse effects in trying to cure people. I do think there is a challenge for folks, both healthcare providers and patients, to get through that and then say &ldquo;should I do more or stop here?&rdquo; I think it all comes down to expectations, like how you set expectations in the beginning, talking to the patient about how this is the goal, to get you through chemoradiotherapy and then a year of immunotherapy every other week for a year. That&rsquo;s a big proposition, but I think it goes better if you have that discussion in the beginning, and then when you get to that kind of phase of treatment, it&rsquo;s expected and planned; you may take breaks or vacations before you do that. However, I think if you don&rsquo;t have that discussion, and you wait to do that at the end, it probably won&rsquo;t work. Patients are going to be surprised, saying &ldquo;you mean I have to do something else?&rdquo; I think they view that as the finish line, and now you&rsquo;re going and telling them they have to another year with an IV. That&rsquo;s a hard sell for anybody in any disease setting. It&rsquo;s about setting expectations and telling folks that it&rsquo;s not an absolute thing, you can take breaks and vary from the way things are laid out on a map, and help people get through that year.

TARGETED ONCOLOGY: What about physicians who are afraid to put their patients on immunotherapy?

Spigel:There can be patients who make providers fearful that immunotherapy may cause extra problems, and I think that&rsquo;s understandable and appropriate to always be, as I once had an attending say, afraid. You should always be worried that something could go wrong. I think as doctors get more experience with immunotherapy after chemoradiotherapy, they&rsquo;ll get more comfortable dealing with toxicities. [These are] things they are already used to, like pneumonitis-related events, which are quite rare in terms of severe events, or adverse effects you&rsquo;d see with checkpoint inhibitors in the advanced setting.

I don&rsquo;t think there&rsquo;s much more fear beyond the unknown—I haven&rsquo;t done this, and I&rsquo;m not sure what it&rsquo;s going to be like, but once you do it, you&rsquo;ll see it&rsquo;s actually a nice way to care for people. Really, this is a thing we haven&rsquo;t had for 20 or more years, we&rsquo;ve always just done chemotherapy, radiation, and that&rsquo;s it. We know most of the patients will progress and die from that disease, but now we have an opportunity to affect their survival in a positive way.

TARGETED ONCOLOGY: What are your thoughts on the time to initiation of durvalumab post-chemoradiotherapy?

Spigel:The original PACIFIC study was designed to bring immunotherapy in quickly after you finish chemoradiotherapy, ideally within 2 weeks. It was hard to do that, so the study was amended to allow for 6 weeks. We talk about this 42-day period you have, but there&rsquo;s nothing magic with that. That was just a number that was decided that would be best for this study. Does that mean in 43 days you shouldn&rsquo;t do it, and that you shouldn&rsquo;t do a day 2? I think it&rsquo;s just a matter of how patients are doing and whether they are ready for it. I&rsquo;ve had folks ready from day 2 to folks that wanted to wait until day 42, so I think people have different views on that.

We don&rsquo;t know that there is a benefit or disadvantage based on that time period, but there is probably some threshold where you cross and you won&rsquo;t get benefit, but is it the 43rd day, is it 60 days, or a year? We don&rsquo;t know. I think you want to be flexible. We have published data, so you want to practice evidence-based medicine, but you want to be reasonable in how you interpret that.

TARGETED ONCOLOGY: Is it hard to get patients to want to stay on therapy?

Spigel:In my experience, it has not been hard. Some of that is this idea that we are fighting and don&rsquo;t want to stay on something. In these days, at least in my view, it&rsquo;s harder to get people off immunotherapy once you start it.

I don&rsquo;t have quite the same experience as I&rsquo;ve had with folks who have gone through surgery and are ready to be done and don&rsquo;t want to do anything else. With stage III disease, at least in my experience, I haven&rsquo;t had folks that have said they&rsquo;re not ready to do that or they are done. I think they like the idea of doing as much as they can for what hopefully you&rsquo;ve told them in the beginning is an aggressive cancer.

TARGETED ONCOLOGY: Now the PACIFIC-2 trial is ongoing. Can you talk about that and any next steps that are planned for durvalumab?

Spigel:There are actually a lot of good and exciting efforts with immunotherapy, durvalumab, and other checkpoint inhibitors in earlier stages of cancer. We have had so much success in the refractory setting, in the first-line setting with NSCLC, and of course with the PACIFIC trial, in the stage III setting, but remember that trial was designed for immunotherapy after chemoradiotherapy. Now all these other questions have come up. What if we give immunotherapy from day 1 with chemoradiotherapy? These things are being looked at, also efforts are being looked at in earlier stages like stage IB and II NSCLC.

There are neoadjuvant trials in progress with durvalumab and other agents in adjuvant studies. In fact, some of the adjuvant studies have completed enrollment. I guess if you were a gambler, you would say 1 of these strategies would hit in the next few years, where we would have immunotherapy for even earlier stages of cancer, maybe stage IB or IIA cancer, so that&rsquo;s kind of exciting. We have to wait to see what those data show.

TARGETED ONCOLOGY: Is there any other research that you find important to highlight now?

Spigel:At this meeting in 2019, we have seen some more early data using immunotherapy alone or with chemotherapy in the preoperative setting, and I&rsquo;m pretty excited about those data. I think what I&rsquo;m most intrigued about is what you&rsquo;re seeing when you take the tumor out. What&rsquo;s actually happening? It looks to be quite different than what we think seems to be happening on scans. There is probably more tumor cell death in the specimen than what you are seeing and you would measure objectively on a scan of response.

That&rsquo;s exciting to see what that means, and first of all, how do you achieve that? How much immunotherapy or chemotherapy does it take to get that kind of major pathologic response? Then ultimately, what does that mean? If you get cancer to disappear, does that mean people are going to live longer? Will there be greater chances of cure? This has been a topic that has been heavily studied in other tumor settings such as breast cancer where neoadjuvant care is very common. We do neoadjuvant care for gastroesophageal cancer, so we are very used to this idea of trying to achieve deep responses pathologically, and they correlate with good outcomes in those disease settings. However, in lung cancer, we&rsquo;re not so sure; we think that&rsquo;s the case, but it&rsquo;s going to take some long-term follow-up to figure that out. We have some studies in progress enrolling right now that we think will help solve that.

References:

1. 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.
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. Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab versus placebo after chemoradiotherapy in stage III NSCLC: updated results from PACIFIC. Presented at: IASLC 19^thWorld Conference on Lung Cancer; September 23-26, 2019; Toronto, CA. Abstract PL02.01.
4. Gray JE, Villegas AE, Daniel DB, et al. Three-year overall survival update from the PACIFIC trial.J Clin Oncol.2019;37(suppl; abstr 8526). doi: 10.1200/JCO.2019.37.15_suppl.8526.