Adverse Events With Immunotherapy in Stage III NSCLC Discussed

Edward S. Kim, MD, MBA discusses immunotherapy-realted adverese events in non-small cell lung cancer in a rountable discussion with Albert Dekker, MD and Sam Yeh, MD.

Edward S. Kim, MD, MBA discusses immunotherapy-realted adverese events in non-small cell lung cancer in a rountable discussion with Albert Dekker, MD and Sam Yeh, MD.

Targeted OncologyTM: How has treatment for such patients changed over time?

KIM: The discussion we’re leading into is [about] the PACIFIC study [NCT02125461]. I always like to [note that] I don’t think anyone—[ie,] lung cancer experts—thought this study was going to [be successful]. [Some] stuff hasn’t worked, we’ve done a lot of stuff in stage III with postchemoradiation treatment, sequencing drugs, limited cycles, [etc], and this was not the sexiest immunotherapy trial that was being designed, but it is kind of the only one standing right now. This was a phase 3, randomized, double-blind, placebo-controlled study, stage III, locally advanced for [patients with non–small cell lung cancer (NSCLC)].1,2

They had to get chemoradiation, at least 2 cycles, and again, it was all-comers, and after [the patients] completed definitive therapy, between day 1 and 42, [they] were started on either durvalumab [Imfinzi] or placebo in a 2:1 fashion. The primary end points were progression-free survival [PFS] and overall survival [OS], and the other secondary end points [were objective response rate (ORR), duration of response (DOR), safety and tolerability, and patient-reported outcomes].

It was a very impressive-looking PFS curve [17.2 months with durvalumab versus 5.6 months with placebo], and every time they have updated the data [the curve] has continued to look very impressive, so it is maintaining its superiority. Originally, when the data first came out, people pointed directly to the 5.6 months PFS on the control arm and said, “See, the reason why these data look so good is because the control arm did unusually poorly.” Then they were reminded that the randomization occurred after the [chemoradiation] treatment, up to 42 days [after]. So when you added in that time, it looked like historical data in the control arm for chemoradiation. So, this dispelled that aspect, but the HR here is 0.51, so pretty impressive.

DEKKER: Is that assuming they get the 4 cycles of chemoradiation? Are you talking about the end of the chemotherapy, or the end of the radiation combined with chemo? That always tends to be a point of inflammation and discussion amongst the oncologists—should they continue with the third and fourth cycle of chemotherapy or beyond? I don’t know what your practice is.

KIM: [I’ll try to explain with the data.] In a subgroup analysis of the PFS, and again, interesting stuff, if you look at 14 days or less from the last radiation treatment to the start of durvalumab, that HR was 0.39. If you went more than 14 days, it was still a good HR of 0.63, and that was the majority of patients, but what they have shown is [that for earlier treatment] with durvalumab there seems to be a benefit. So, to answer the question [about] additional chemotherapy, I don’t think there’s any magic to the 4 cycles right now. It’s how we got into this consolidation therapy in chemoradiation and other aspects, and if you remember, David Gandara, MD, a few years ago, tried to use docetaxel as a consolidation, and then Nasser Hanna, MD, showed that it didn’t really work, and so the chemotherapy is there to help. Once the radiation is done, you want to get moving onto the adjuvant durvalumab.

What we would typically do when I was in Charlotte is talk to the patient ahead of time, as we knew they were going to get concurrent chemoradiation. We would say, “OK, this is what the plan is: You’re going to get your chemotherapy and your radiation, you’ll do that for 6 weeks. We will then plan to give you the next stage of the treatment, which is the adjuvant durvalumab. We’re going to see you within a week after you finish and then plan to start it within 2 weeks.” That was our standard of care. Obviously, [patients] recovered at different paces, but we were able to do that for the majority of our patients.

After 34 months of follow-up, the HR [for OS] is 0.71.3 There is a meaningful improvement in OS with the adjuvant durvalumab. [At 5 years, the stratified HR for PFS and OS were 0.55 and 0.72, respectively.4]

Were there any particular subgroups that benefited more or less from adjuvant treatment with durvalumab?

The updated OS and PFS in the different subgroups [show] some of the smaller subgroups do cross 1 [in terms of the HR], but, for the most part, trends are all in the beneficial range.5

What was very interesting was the European regulators wanted data on the [benefit of durvalumab with regards to] PD-L1 [expression], even though that had nothing to do with randomization, it had nothing to do with selection or treatment. They further asked for data with 1% or greater [expression] and such, and so they put some criteria around it, which many of us disagree with. In the United States, this was not required, and it almost makes you want to [decline], as a pharmaceutical company, to even collect some of the data if they are going to be used against you. Again, it was post hoc, unplanned, but they asked for it, it was not part of any of the planned analyses. There were still benefits regardless of what the [PD-L1] status was, so don’t use PD-L1 status to determine if you’re going to treat someone with durvalumab.

As we do more genomic testing, we have to stick with how the trials [were designed] and what they were testing, and I know we want to jump ahead and do some of this, and make hypotheses, but I would urge folks not to overthink some of these things. The studies we’re doing have some very good data around them, [they lead] to other things, but I think we have a pretty established standard of care [and] we want to make sure at least we’re treating patients the right way at the beginning.

What was the safety profile like in the PACIFIC trial?

If you remember back to the time when this trial was reported, durvalumab was not the preferred immuno-therapy among the 4 or 5 that were being tested, so this was, again, quite surprising to many folks. It was also surprising that you could start [durvalumab] so quickly. Many of us [thought], “Gosh, you’ve got to give people a break after chemoradiation and let them rest, and then we can think about if we’re going to do anything more,” and here we just start them right out of the gates. When you actually look overall at the grade 3/4 AEs [adverse events], [there is] not that big of a difference [29.9% with durvalumab versus 26.1% with placebo]. Grade 5s, it was actually worse in the placebo arm [4.4% versus 5.6%, respectively]. Discontinuation rates were slightly higher with durvalumab [15.4% versus 9.8%], but again, not as striking a difference. For immune-related AEs, grade 3/4 was 3.4% versus 2.6%, so not a huge difference there.

The NCCN [National Comprehensive Cancer Network] guidelines have added that for [patients] who had the 2 cycles of full-dose chemoradiation6 with durvalumab every 2 weeks—or even at the every-4-week dose that has since been approved7; you can give it just once a month for up to 12 months in these patients—[it is not recommended to give] the additional cycles of chemotherapy, as had been brought up, because there could be an increased risk of pneumonitis. And you can’t give durvalumab but you can consider consolidation chemotherapy, but the data behind consolidation chemotherapy are not very strong. Remember, the primary therapy in these unresectable stage IIIs is radiation, so radiation is the basis and the chemotherapy helps it along, so there’s nothing magical about giving 4 cycles of chemotherapy that has benefited many [patients].

KIM: So, [the patient] had some pneumonitis, and you all have undoubtedly dealt with pneumonitis or at least heard of a colleague who has. Do you start with steroids first? Obviously, you stop the immunotherapy—this could occur at any disease site, not just the lung—but do you institute a steroid taper, do you get pulmonary involved right away?

DEKKER: Vitamin E and Trental [pentoxifylline] help a lot, surprisingly, in addition to steroids.

YEH: I start steroids, too, and get my pulmonologist involved pretty early. The question is, if they improve, will you ever restart them back on the immunotherapy if their pneumonitis improves?

KIM: Yes, and I think [generally] what I do—and people agree with this; we used to talk with our melanoma expert because he had the most experience with these checkpoint inhibitors—is to resume [treatment] if you get that resolution or improvement, especially if it’s a lower grade.

The ASCO [American Society for Clinical Oncology] guidelines [for management of immune-related pneumonitis recommends that] if it’s greater than grade 2, you should get an infectious work-up as well because that can be superimposed or be the cause. So, if you have grade 1 [pneumonitis], you hold [the immunotherapy, watch the pulmonary function tests], and resume if there’s improvement.8

If there’s no improvement, then you treat it as a grade 2. Grade 2 [recommendation] is to hold [resolution to] less than grade 1, and again giving the steroids, being aggressive with that. [There’s no] guidance here on whether you should restart [therapy].

Some patients only get several doses [of immunotherapy], and their immune system generates that memory and they get this lasting effect. Other [patients] take it, it’s almost [as though] they don’t even know they’re taking it, so we’re not really sure how long—even in the metastatic setting—[to give immunotherapy]. I can tell you that all the trials were written to have 1 year of maintenance, and then you had multiple [patients] who were finishing up a year and were feeling great, so they said, “OK, let’s make it 2 years.” Then they did 2 years and you still had [patients] showing up great, and [they say,] “Well, I’m not sure if we can justify 3 years or 4 years.” So that’s where they cut it off on clinical trials.

And then grade 3/4 [pneumonitis], obviously these [patients] are sick, you’re never going to give them an inhibitor again, and you have to go with infliximab [Remicade] or some of the other techniques to help them out. I haven’t had one of these yet, but it could certainly happen. It’s no different than giving somebody a peanut butter sandwich or penicillin, you just don’t know who is going to react and how they’ll react.

KIM: Okay, so I think what I’ve seen from your polling and others is that you are getting [patients] through the chemotherapy and the radiation. You really want to work closely with your [patients], unless you’re hundreds of miles away and then you do what you can, and I think that’s perfectly reasonable to think of a sequential approach because patients then couldn’t get the radiation if they had to keep going back and forth, and the chemotherapy becomes difficult.

I think most of you believe that immunotherapy is part of the standard of care now in stage III [NSCLC], and this PACIFIC study led the way. Again, most people, I think, were looking at immunotherapy in combination with chemotherapy and radiation given concurrently, as such, but you know, none of those trials have proven efficacious enough to change the standard of care. And if you’re testing for EGFR mutations or PD-L1, there are no data to suggest that you should be treating these patients differently at this time. You know, we don’t have data in an unresectable population [to show] that treating the EGFR mutation, outside of the current standard practice of chemoradiation and immunotherapy, is better, so again, that’s what we go with at this time.

1. Paz-Ares L, Villegas A, Daniel D, et al. PACIFIC: a double-blind, placebocontrolled 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/mdx440.049
2. 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
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. Spigel DR, Faivre-Finn C, Elaine Gray J, et al. Five-year survival outcomes with durvalumab after chemoradiotherapy in unresectable stage III NSCLC: An update from the PACIFIC trial. J Clin Oncol. 2021;39 (suppl 15): Abstract 8511.
5. Faivre-Finn C, Vicente D, Kurata T, et al. Durvalumab after chemoradio- therapy 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
6. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 5.2021. Accessed June 21, 2021.
7. Imfinzi approved in the US for less-frequent, fixed-dose use. News release. AstraZeneca; November 20, 2020. Accessed June 21, 2021. https://
8. 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