Chemo-IO Over IO Alone in Patients With Advanced NSCLC

An analysis presented at the recent virtual American Society of Clinical Oncology annual meeting explored data from eight clinical trials and showed that immunotherapy plus chemotherapy (Chemo-IO) improved survival over immunotherapy (IO) alone in patients with advanced non-small cell lung cancer (NSCLC).

In this last of four exclusive episodes, MedPage Today brought together three leaders in the field — moderator Vinay Prasad, MD, of the University of California San Francisco, is joined by Chul Kim, MD, of Georgetown University and MedStar Health in Washington, D.C., and Andrae Vandross, MD, of NEXT Oncology in San Antonio and Austin — for a roundtable discussion on the abstract from the meeting that examined this data.

Episode one: What Did We Learn From IMpower010 in Resectable NSCLC?

Episode two: What the New KRAS Inhibitor Means for Lung Cancer

Episode three: Genomic Test in Lung Cancer: Waiting Is the Hardest Part

Following is a transcript of their remarks:

Prasad: Hi, I am Vinay Prasad for MedPage Today. I’m back with Dr. Chul Kim and Dr. Andrae Vandross, and we’re talking lung cancer.

There is a new abstract out. It’s out at the national meeting. It’s entitled “Outcomes of anti-PD-(L1) therapy in combination with chemotherapy versus immunotherapy (IO) alone for first-line (1L) treatment of advanced non-small cell lung cancer (NSCLC) with a PD-L1 score 1-49%: FDA pooled analysis.” This is an interesting paper and this is an interesting place to debate.

Now, Dr. Vandross, let me start with you on this one. We know there are a few options for that patient in your clinic with a PD-L1 stain, with non-small cell lung cancer and no driver mutations. Let’s say the stain is 30%. You could give him Chemo-IO. You could give them IO alone. How do you think about this dilemma? How do you choose? What guides you in this space?

Vandross: One of the things you want to do is some of the basics of a clinical assessment. You want to know how high risk the cancer is. You want to know how high risk the non-small cell lung cancer is.

We have, as we have noted earlier, the range of immunohistochemistry results with the PD-L1 staining, to be able to know whether there is going to be a benefit of the combination of chemo and immunotherapy as opposed to chemo alone. Those are the things that you have to think about in concert and in discussing with the patient and then how to move forward.

Prasad: That’s well put. Dr. Kim, what’s your practice pattern for 1-49%? What is your practice pattern for over 50? Who are you giving IO only to?

Kim: For those patients with a PD-L1 expression of at least 50%, my practice is to give pembrolizumab [Keytruda] monotherapy or IO monotherapy. I add chemotherapy to immunotherapy in that setting when the patient has a high burden of disease and is symptomatic, because this is based on the response rate.

If you give Chemo-IO in this setting, the response is in the range of 60-65% versus 45% with, for example, pembrolizumab monotherapy. I use that data to justify the use of Chemo-IO therapy. Even in the setting of PD-L1, it was 50%.

For a patient with a PD-L1 of 1-49%, my practice is to give Chemo-IO therapy, and this is based on … this is one of the cases where subgroup analysis can be helpful. If you look at the KEYNOTE-042 data, where they looked at the role of pembrolizumab monotherapy, one of the subgroups they looked at was 1-49%. The survival benefit was not really prominent, or there was no survival benefit over chemotherapy in the subgroup.

But in KEYNOTE-189 and KEYNOTE-407, the former is for the lung adenocarcinoma and the other is squamous cell carcinoma of the lung. In those subgroups of patients with the PD-L1 1-49%, the overall survival benefit was seen in that group. If the patient can tolerate chemotherapy, I use Chemo-IO for the patient with the PD-L1 1% to 49%.

Prasad: Yeah, that’s well put. I’ll give my full disclosure, which is if it’s 1-49% the patient can tolerate, I’m going to go Chemo-IO. But I’ll go even further than you, Dr. Kim: If it’s 60%, 70%, and the patient can tolerate it, I’ll go Chemo-IO too. I’ll take it up to 80%. Only when you’re getting into the 90% range … I’m even going to start entertaining for a fit patient pembro-only.

Because I’m a little worried. I’m a little worried that the 60% and 70% PD-L1 stains actually do benefit from Chemo-IO. I’m worried about the crossing of the curves, the early progression. I’m trying to avoid that as well. If they’re fit, I think that they can do it.

Now, I wonder, Dr. Kim. You might take us through this paper … I think all three of us have, I think, a similar position on this space. We’re all going to be happy, I think, with this paper, which kind of confirms what we were talking about. I wonder if you might take us really quickly through what is this analysis by the FDA investigators, by my good friend Harpreet Singh, my co-fellow. I wonder if you might talk about what did they do and what did they find. Dr. Kim?

Kim: Yeah. In this paper, in this pooled analysis, they pooled the data from several trials. There were about eight trials, two with the immunotherapy alone — so that was KEYNOTE-042 and then CheckMate 227, which was nivo-ipi [nivolumab (Opdivo)-ipilimumab (Yervoy)].

Then Chemo-IO, it’s a combination with the chemotherapy, so pembro, atezolizumab [Tecentriq], and nivo-ipi in combination with chemotherapy. What they looked at was in patients with the PD-L1 expression between 1% to 49%, what were the outcomes of these patients, comparing these two groups — those receiving immunotherapy alone versus Chemo-IO?

What they found was that there was overall survival benefit seen in those who received the Chemo-IO-based approach compared to the immunotherapy monotherapy. They looked at several subgroups, and the benefit was more distinct in those who are younger, defined by less than 75%.

Although this is a subgroup analysis, we can’t really draw hard conclusions based on this, but that was one suggestion that younger patients may be better with the Chemo-IO approach. But then the age is not an absolute thing, so you need to look at the patient as a whole and how well they are and their performance status when you think about deciding between Chemo-IO versus immunotherapy.

This really affirms my practice where I use Chemo-IO therapy in those patients with a PD-L1 of 1-49% if they can tolerate that treatment.

Prasad: Now, they use a lot of words in their abstract. “Exploratory,” “may” — I suspect they’re using those words because to some degree they are anchoring on. This is to some degree a cross-trial comparison, is it not? Is that fair to say here? It’s not a strictly randomized comparison, so that’s why they’ve inserted all the usual caveat soup.

Kim: That is correct. This is not a randomized trial. There is an ongoing randomized trial in patients with a PD-L1 of at least 1%, the INSIGNA trial. One of the subgroups that they will look at is the 1-49% comparing pembrolizumab versus pembro-chemotherapy. I think it’s an important study to look at when it’s out.

Prasad: Good. Dr. Vandross, any thoughts about this paper and if it affects your thinking in this space?

Vandross: The highlight is that, based on what you just said, which is all the caveats, the appropriate caveats, because this is pooled data. I think it was six trials with respect to chemo-immunotherapy and two trials with respect to immunotherapy. What does that actually mean?

Even though we know that it affirms current practice, it’s like do we still have to tread carefully? Is it important to wait for the results of the prospective trials? Because certainly, even in the press release, they highlighted the fact that this was a pooled analysis.

Another buzzword was this sort of “hypothesis-generating,” I believe. Like those are the things I think about when I look at that data just to have a complete conversation. Specifically, when I’m talking with patients, I always talk about like intellectual honesty with them, I say, “Here is the data. This is the way that we think about this level of data,” if it’s a meta-analysis or if it’s a pooled analysis versus a randomized controlled trial that’s blinded, etc. and try to educate them as best I can on the quality of evidence and how we really think about it.

Prasad: That’s really well put. I have one last thought and then I’ll give you guys the last word. My last thought is this is yet another example. We’ve chronicled this in a recent paper about N-of-1 data sharing … about what the FDA can do because they have access to individual patient-level data [IPD] from multiple clinical trials. They have been able to do a lot of interesting papers over the last decade — reanalysis, exploratory analysis, pooled analysis, different ways you can slice and dice the data — because the FDA has access to IPD from studies.

Now many years ago, there was a big push in biomedicine that we would have broad data-sharing. That data sharing was motivated by the impetus that patients who consent to clinical trials, they’re consenting to the greater good of the scientific community. They want people with their disease to do better in the future. They’re not consenting so that some investigators but not other scientists would have access to their data. That’s not part of the implicit social contract. Yet, we got so close to getting the IPD data sharing.

We had an ICMJE, the International Committee of Medical Journal Editors, proposal to get this data, but at the last moment it was struck down by people who like to hold their data. I like to say that IPD data from randomized controlled trials of cancer drugs, that’s important stuff. It’s like a piñata, and I know how to get it out of the piñata.

I’m wondering if this is yet one more motivation to get us these data. Because if the FDA can do this analysis, let me put it to you this way: Every day I’m on a walk or on a bicycle, I have 10 different ideas of things I could do if I had access to IPD. But I don’t have access to IPD, and so I want the IPD.

If we really want to advance science as fast as possible, you make the IPD available. That’s my parting thought.

I’ll give you the parting thought. You can bring it back to lung cancer and not go off on a tangent on IPD. Dr. Kim, any parting thoughts on this analysis? Like all great analyses it tells you that what you’ve been doing is right.

Kim: Right. I totally agree with you, Dr. Prasad, that broad sharing of data is important for scientific progress. I mean, there should be a set of rules and guidelines in terms of accessing the data, but I think it’s possible. I think it’s beneficial and it’s good for patients because we can generate a lot more data in looking at these randomized clinical trial data and answering a lot of the questions.

Prasad: Yeah. Trust me, Dr. Kim, I read Wikipedia, so I also think there should be some rules and safeguards in place.

Dr. Vandross, what do you think? Any parting thoughts on this study?

Vandross: Not much additional to say except that, again, I just think the importance is to always go back to the quality of the data that we’re looking at. Be honest about that with patients in order to know how to have a really productive conversation with respect to what their preferences are and how they’d like to proceed. Whether we are talking about adjuvant therapy or whether we’re talking about very, very deep and subsequent lines of therapy, it’s just really important.

It’s more important than ever because a lot of these patients are becoming more and more savvy. I know here in Austin, Texas, they are very savvy. They remind me of the patient population even in Los Angeles. People are reading trials. They are reading press releases. They are coming in. They are printing these things out, coming in, and asking questions about them, and so we have to be prepared to have these discussions.

Prasad: Yes, I agree with you. I think that it’s great that we have such empowered patients. It just makes us bring our A game to the table.

Dr. Kim and Dr. Vandross, thank you so much for walking us through these lung cancer abstracts. Thanks for your time.

Kim: Thank you.

Vandross: Thank you.