Neal Edward Ready, MD, PhD, professor of Medicine, member, Duke Cancer Institute, discusses factors to consider when deciding when the use the regimen of nivolumab (Opdivo) and ipilimumab (Yervoy) plus chemotherapy in metastatic non–small cell lung cancer (NSCLC).

The phase 3 CheckMate-9LA trial (NCT03215706) evaluated nivolumab and ipilimumab plus chemotherapy vs chemotherapy alone in the first-line treatment of patients with metastatic NSCLC. Updated data from the trial, which were presented during the 2022 ASCO Annual Meeting, showed that the chemoimmunotherapy combination continued to provide prolonged overall survival (OS) benefit compared with chemotherapy alone, according to Ready.

If a patient has low a PD-L1 expression, but has a high tumor burden and is symptomatic, Ready shares that he would leverage the CheckMate-9LA combination of nivolumab and ipilimumab with chemotherapy rather than immunotherapy alone.

Clinicians may be concerned about combining a PD-1 checkpoint inhibitor with a CTLA-4 inhibitor, according to Ready, since earlier regimens examined in melanoma reported substantial toxicity. This concern is especially prominent when considering this approach for an older population with NSCLC who could have more comorbidities, Ready adds. However, the CheckMate trials deliberately and methodically identified the combination of nivolumab plus ipilimumab that was tolerable in patients with NSCLC, Ready concludes.

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Neal Edward Ready, MD, PhD, discusses factors to consider when deciding when the use the regimen of nivolumab and ipilimumab plus chemotherapy in metastatic non–small cell lung cancer.


Dr. Ready on Leveraging Nivolumab/Ipilimumab Plus Chemotherapy in NSCLC

Neal E. Ready, MD, PhD, head and neck oncologist, medical oncologist, Duke Health, professor of medicine, member of the Duke Cancer Institute, Duke University School of Medicine, discusses the role of frontline chemoimmunotherapy in lung cancer.

Prior to pivotal phase 3 trials in lung cancer, patients were treated with up-front chemotherapy, Ready says. Upon progression, patients were treated with immunotherapy in the second-line setting and other chemotherapeutics, such as topotecan, in the third-line setting, Ready says. Currently, most patients with lung cancer receive immunotherapy as a part of first-linetreatment, Ready explains. Moreover, immunotherapy is being administered much less in the second-line setting and should be reserved for patients who received chemoradiation for early-stage non–small cell lung cancer where immunotherapy is not currently indicated, Ready explains.

Additionally, second-line immunotherapy could be considered for patients who had a borderline contraindication for up-front immunotherapy because of an autoimmune condition, for example, Ready says. In those cases, immunotherapy could be held until no other effective options were available, Ready concludes. 

Neal E. Ready, MD, PhD, discusses the role of frontline chemoimmunotherapy in lung cancer. 


Dr. Ready on the Role of Frontline Chemoimmunotherapy in Lung Cancer 

Neal E. Ready, MD, PhD, head and neck oncologist, medical oncologist, Duke Health, professor of medicine, member of the Duke Cancer Institute, Duke University School of Medicine, discusses selecting between frontline chemotherapy plus atezolizumab (Tecentriq) or durvalumab (Imfinzi) in extensive-stage small cell lung cancer (ES-SCLC).

In March 2019, the FDA approved atezolizumab for use in combination with carboplatin and etoposide for the frontline treatment of patients with ES-SCLC. In March 2020, durvalumab in combination with etoposide plus either carboplatin or cisplatin was FDA approved for frontline use in patients with ES-SCLC.

Both regimens offer effective and tolerable frontline options for patients with ES-SCLC, Ready says. Moreover, comparative data are needed to determine whether a clinically meaningful difference in efficacy or toxicity exists between the regimens.

However, some differences in the inclusion criteria of the phase 3 studies that led to the FDA approvals of atezolizumab and durvalumab could be referenced during treatment selection, Ready explains. For example, if a patient with ES-SCLC in need of frontline therapy better fits the patient population included in one study vs another, they may be better suited to receive that regimen.

Ultimately, both regimens represent significant advancements in the treatment of patients with ES-SCLC because the field was stagnant for decades prior to these approvals, Ready concludes.

Neal E. Ready, MD, PhD, discusses selecting between frontline chemotherapy plus atezolizumab or durvalumab in extensive-stage small cell lung cancer.  



Dr. Ready on Selecting Between Frontline Atezolizumab and Durvalumab in ES-SCLC 

: When we look at second-line treatment for non–small cell lung cancer, it has changed with the recent approvals of frontline immunotherapy. Outside of patients with autoimmune disease, with an organ transplant, or some other contraindication receiving immunotherapy, most of our patients now are receiving some form of immunotherapy as initial treatment, unless they’re a non-squamous patient with a targetable mutation or fusion or other actionable alteration. I want to emphasize that, if you have a non-squamous lung cancer, we should be doing molecular testing, and oral therapy would be the first choice if you get an actionable alteration. The good news is we have better frontline treatment and patients are living longer, especially with the combination immunotherapies. The flip side of that is that we’re back to standard second-line regimens such as docetaxel or docetaxel with ramucirumab that we’re not that excited about.

This is one of our major areas of unmet need in non–small cell lung cancer. The goal is finding a way in the post-I/O setting to reignite the immune system and get additional prolonged immune responses, to continue to look for new molecular targets, and find ways to enhance the second-line chemotherapy options like docetaxel. The use of second-line therapy is more limited, but for a good reason that we have better initial treatments including immunotherapy, but the second-line setting now is really a challenge.

There’s clinical development now. There will be new immune options in the second line. We’re learning more about how cancers are able to evade the immune system. People will now get some form of I/O therapy first, and if the cancer progresses, then obviously if it was an initial response then it’s evaded the immune system somehow. There are a lot of ongoing scientific evaluations that let us understand is this down regulation of MHC-1 to evade the immune system? Is it local tumor effects with an increase in T reg cells or MDSCs [myeloid-derived suppressor cells]? Is it other changes in the tumor microenvironment? We are rapidly progressing to understand how immune evasion occurs, and there are a lot of pipeline therapies that are now available that will let us test different strategies for overcoming the secondary immune resistance.

That’s where things are headed, and the clinical trials are ongoing, so hopefully we’ll find some new strategies that will let us reignite the immune system in patients where progression has occurred and get secondary and tertiary immune responses that are helpful.

 When we look at second-line therapy, some of the big characteristics determining our approach are the prior treatment delivered, patient comorbidities, and performance status. When we look at performance status comorbidities, it drives the suitability of further therapy. Our role as an oncologist is not to see how much treatment we can deliver. It is to help patients. If patients have poor performance status or if they’re weak, I know they’re not going to derive the benefit from further therapy. In my effort, the best way to help that patient might be to focus on symptoms or more of a hospice-based approach. For patients who have a good performance status, there are an increasing number of options. Our previous second-line therapy had been docetaxel-based treatment, either alone or in combination with ramucirumab. It depends on what initial treatment was given. For example, if pembrolizumab alone or atezolizumab alone were given, or if dual checkpoint inhibitors such as nivolumab and ipilimumab were used in the frontline setting, my second-line regimen would really become platinum-based chemotherapy.

Now, whether to continue the checkpoint inhibitor in the setting of second-line platinum doublet chemotherapy is a question that the INSIGNA trial will look at to see if continuation of a checkpoint inhibitor beyond progression provides any value or only cost and toxicity. Right now, our standard approach after progressing on immunotherapy alone, either mono or dual checkpoint blockade, would be platinum doublet chemotherapy histology specific. If chemo immunotherapy were given continuously in our second-line option—really docetaxel-based treatment—we’re certainly always exploring clinical trials, novel immunomodulatory agents, and different strategies to really recapture those long-term benefits.

NSCLC Management: Second-Line Options

: For squamous cell cancers, squamous cell lung cancers, we don't have any actionable alterations to allow oral therapy. Typically, the biomarker that we would test outside of a clinical trial would be for PD-L1. If the PD-L1 is high, then it would be reasonable to treat with pembrolizumab alone. When the tumor is inflamed, with high PD-L1 scores 70, 80, 90, 100%, single agent immunotherapy can be effective with minimal toxicity.

For the rest of the patients, initiating combination therapy is indicative. KEYNOTE-407 was a large randomized phase 3 trial that compared standard histology-based chemotherapy with or without pembrolizumab. It showed that the chemo I/O combination was superior to chemotherapy alone with a modest increase in toxicity, and certainly an important new standard of care.

In that same squamous cell population, we now have the CheckMate 227 regimen of nivolumab and low-dose ipilimumab, and also the CheckMate 9LA where we have an FDA approval for 2 cycles of chemotherapy plus nivolumab and ipilimumab.

In summary, for this metastatic squamous cell population that doesn't have active autoimmune diseases or some other contraindication or immunotherapy, it would be consideration of single-agent immunotherapy for the inflamed tumors with a high PD-L1 score, and then some type of combination therapy, either standard chemotherapy plus immunotherapy or nivolumab, ipilimumab with or without 2 cycles of initial chemotherapy, depending on the clinical circumstances and the preference of the patient.

Squamous Cell Frontline Therapy: IMpower 131, KEYNOTE-407

: CheckMate 817 was a trial that was done to expand the use of nivolumab and ipilimumab in looking at different dosing regimens, and regimens that could be every 3 weeks rather than every 2 weeks, and to look at special populations. It was a large population of patients who were untreated and who received a standard dose of nivolumab and ipilimumab. That is providing useful information, understanding the dosing, other drugs, and how they combine.

There was also a cohort A1 that was done to look at special populations. And the special populations were patients who had either performance status 2, HIV, or hepatitis. The outcome for that cohort was interesting because there was a question, would it be effective? Would the nivolumab and ipilimumab combination be effective in these patients, and would the combination be tolerated, or would we see excess toxicity in these patients with poor performance status or specific comorbid medical problems?

The toxicity was remarkable in that it was no different than what we had seen in the large randomized trials of patients with performance status 0 or 1. We looked at the data for CheckMate 227, CheckMate 9LA, and CheckMate 568; the performance status 2 patients didn't seem to have any significant increase in toxicity for grade 3 and 4 toxicities or discontinuation of treatment compared with patients with good performance status. There were a substantial number of patients who had responses to the treatment and the responses were durable.

This was an important study looking at these special populations. I recently reviewed some of the literature, and there's truly little data for performance status 2 patients with immunotherapy. I was able to find 1 trial looking at pembrolizumab alone out of the United Kingdom that showed that pembrolizumab was tolerated and effective in this population. I couldn't find any data for chemotherapy plus I/O in the performance status 2 population, so this is some of the little data that we have really showing that a combination immunotherapy can be safe and effective in these special populations. That's useful for a practicing clinician.

CheckMate 817 Overview

: KEYNOTE-189 was a groundbreaking study in which patients with non-squamous lung cancer received carboplatin, pemetrexed, standard histology-based chemotherapy with or without pembrolizumab. And all outcome measures were better. Overall survival, response rate, progression-free survival, and duration of response: this is a very positive trial. Certainly, in the United States this has become a major standard of care for upfront treatment of metastatic lung cancer. It does have prolonged exposure to chemotherapy, so it has 4 cycles of platinum-based chemotherapy, and then potentially going pemetrexed. It’s a groundbreaking study and a standard of care that has improved the outcome of a lot of patients with lung cancer.

The IMpower130 was another randomized trial in non-squamous lung cancer. And it was carboplatin, nab-paclitaxel, or Abraxane, with or without atezolizumab. It was a positive trial where the overall survival and other outcomes were clearly superior to chemotherapy. It is a different chemotherapy backbone than other trials in the non-squamous setting. Most of the other trials, the KEYNOTE trial and CheckMate-9LA, use pemetrexed-based treatment. It’s a positive trial, but with a different chemotherapy backbone with immunotherapy added into it.

The IMpower150 study was a more complicated study and was looking to push the envelope with treatment for non–small cell lung cancer. One of the standards of care for lung cancer, adenocarcinomas, is for platinum, a platinum chemotherapy, a taxane with bevacizumab. And a major component of this trial was to look at the Taxol, paclitaxel, bevacizumab regimen with or without atezolizumab. It did show an improvement in survival compared with the triplet backbone. It was a positive trial, FDA approved. What's not clear from this is whether the quadruplet therapy is better than, for instance, chemotherapy plus pembrolizumab or the 130 regimen of carboplatin, nab-paclitaxel, and atezolizumab. It’s a positive trial and FDA approved. Exactly where it fits in for standard of care is not entirely clear, but certainly interesting and promising therapy.

One subset analysis in this trial was particularly interesting. In general, immunotherapy does not work so well in EGFR-mutated lung cancers, for various reasons. And in this trial there were about 100 patients who were EGFR positive who were included, and the experimental regimen with atezolizumab looked better compared with the chemotherapy and bevacizumab alone. It’s a retrospective and wasn't powered to answer the question whether this was better. It has an intriguing result, and there are additional studies coming out now to test the hypothesis that this might be the best combination in EGFR-mutated lung cancer.

PD-L1 Combination Therapy Clinical Trials 

KEYNOTE-042 was a randomized trial looking at pembrolizumab monotherapy in a select patient population, and it has influenced care. This was a large study of over 1200 patients with advanced non–small cell lung cancer, excluding patients with sensitizing 

 fusions. All patients did have PD-L1 expression defined in that study by at least 1% of cells positive using the [Agilent Technologies, Inc] Dako 22C3 clone. They’re randomized to pembrolizumab monotherapy or histology-specific chemotherapy.

We saw an improvement in overall survival with this approach leading to its FDA approval for patients with PD-L1 of 1% or greater. This was driven, as expected, by the PD-L1–high cohort that we saw in KEYNOTE-024. The population of interest was PD-L1 low. Are we really providing a better option for more patients? If we analyze patients with PD-L1 expression between 1% and 49%, where the use of pembrolizumab wasn’t clear prior to this trial, there was not a clear benefit over chemotherapy. It didn’t appear significantly worse, but it didn’t appear significantly better. The study wasn’t designed or powered to look at that subset, although clinically that is the subset of interest. It is an option for patients, particularly if patients aren’t eligible for other therapies. But in this day and age we have other options that I would say offer a clearly superior benefit to chemotherapy. Strategies including dual-checkpoint blockade or combinations of chemotherapy-immunotherapy. In a world where those options exist, I really think those have a leg up over pembrolizumab monotherapy for PD-L1 low, but that is an option for patients under certain circumstances.

IMpower110 was a randomized phase 3 trial looking at single-agent atezolizumab, a PD-L1 antibody, versus histology-specific chemotherapy. This was a relatively large study. Patients were randomized 1:1 to receive atezolizumab at a dosage of 1200 milligrams every 3 weeks or histology-specific chemotherapy. If we look at the PD-L1–high group looking at PD-L1 expression on tumor cells or on neighboring immune cells, which was about 35% to 40% of the entire population, there was a clear and overwhelming survival benefit. The median overall survival was 20.2 months compared with 13.1. That’s an impressive hazard ratio of 0.59 for the PD-L1–high group. One-year survival rates of 65% versus 50.6%. Response rates were higher, over 38%. Outcomes favoring the use of atezolizumab monotherapy in that PD-L1 high.

They also explored outcomes using the Dako 22C3 antibody, and the results were very consistent. In patients with PD-L1–high disease, atezolizumab is a reasonable option. It was FDA approved, and it is another option for patients. It’s not wise to compare it directly with other agents in this setting, such as pembrolizumab. Those outcomes are very comparable. Although there may not be a compelling reason to change—if there were, for example, nonclinical reasons, formulary restrictions that guided 1 over the other—I feel comfortable with either approach.

Frontline PD-L1 Monotherapy: KEYNOTE-042 and IMpower110 

 When we look at CheckMate 9LA, this trial did include both squamous and nonsquamous histology. It’s important to look at those ratios. About 30% of patients were squamous, which is a bit higher than some of the other studies. We know from multiple randomized trials, including some cross-trial comparisons, that our outcomes in the squamous histology are a bit worse. Factoring in those numbers, the outcomes are really impressive. When we break it down by histology, we did see a consistent benefit, a survival benefit in both the squamous and nonsquamous histologies with fairly comparable outcomes and comparable improvements. This is a regimen where histology will dictate which chemotherapy you deliver with those first 2 cycles. But the overall approach of giving 2 cycles, a limited course of histology-specific chemotherapy with dual-checkpoint blockade, should apply across histologies.

 It’s natural for us to compare trials. The CheckMate 227 trial and the CheckMate 9LA trial were for all histologies, whereas the other randomized trials in this setting—for instance, KEYNOTE-189, KEYNOTE-407, IMpower150, IMpower130—were histology specific. We have data for chemotherapy–I/O [immuno-oncology] in nonsquamous lung cancer and chemotherapy–I/O in squamous cell lung cancer, and overall survival tends to be better in the nonsquamous setting compared with the squamous setting.

Keep in mind that for CheckMate 227 and 9LA, what we see is a composite. If we look at histology-based outcomes like 227 and 9LA, we see better survivals in the nonsquamous group. In the CheckMate 227 study, nivo-ipi [nivolumab-ipilimumab] had a median survival of over 19 months for the nonsquamous group, and in CheckMate 9LA survival was over 17 months. A better outcome for the nonsquamous compared with the squamous.

We shouldn’t be carefully comparing the different trials because they’re not exactly in the same population or in the same countries. They have slightly different eligibility criteria, but it’s only natural that when we’re choosing treatment for patients we’re trying to get the most effective treatment. It is useful for the different studies to make sure you’re looking at the outcome for the specific histologies, because that can be helpful in guiding appropriate choice of treatment.

 The CheckMate 9LA regimen giving 2 cycles of histology-specific chemotherapy with dual-checkpoint blockade is another option, and we have to tailor the treatment options to the specific patients we see. In someone with aggressive disease, a high burden of disease, that initial use of chemotherapy is appealing to prevent that early drop-off, that early progressive event. When you think you may only have 1 opportunity to deliver treatment for those patients, I think including cytotoxic chemotherapy is of value. It’s an interesting strategy limiting chemotherapy to those first 2 cycles. By preventing continued chemotherapy, will we avoid more cumulative toxicity? Will we enable more development of memory T cells by preventing the potentially detrimental effect of cytotoxic chemotherapy over time?

When we’re adding chemotherapy to dual-checkpoint blockade, there will be a cost. There is certainly more toxicity when we’re adding treatments to it. The rates of grade 3/4 adverse events and the discontinuation rates were higher certainly with the CheckMate 9LA regimen compared with chemotherapy alone, but some of the toxicity rates were better. The rates of anemia and neutropenia were a bit lower with the 9LA regimen, reflecting less cumulative toxicity from chemotherapy, perhaps less long-term neuropathy. It has to be for the right patient in the right clinical circumstance. There will be a role for it. Defining a specific role for all patients is challenging, and in the right clinical context it certainly can provide value.

The true measure for all these regimens will really be long-term survival and which approach leads to more durable survival at landmark rates. But we simply don’t have those data yet.

 It will make a big impact. Many patients want to avoid chemotherapy when they can or minimize exposure to chemotherapy. This will give clinicians an option when the patient has a significant tumor volume and they’re symptomatic from their cancer, and the clinician is concerned that if the initial treatment doesn’t control the cancer, the patient will get into trouble and then we won’t be able to get additional treatment. Have that option of giving the 2 cycles of chemotherapy first with the immunotherapy to make sure there isn’t early progression. But have the double immunotherapy onboard to try to get a high level of durable-immunotherapy responses, so the clinician can feel confident they’re minimizing the likelihood the cancer is going to progress early. Then maximizing the chance that they’ll get a durable immune response to therapy. This will help clinicians have an option where they’re trying to avoid or minimize toxicity from chemotherapy, maximize response to immunotherapy, and do it safely and effectively.

Another thing I’ll just point out is that when we initially had the results of CheckMate 227, we had anticipated that the best outcome might be in the PD-L1–positive lung cancers, which is evidenced by the fact that that was the primary end point of the study. But then we found that perhaps the most promising result was in the PD-L1–negative population, where it really looked there was a marked benefit compared with chemotherapy. CheckMate 9LA confirmed that, because when you look at the outcome for the experimental therapy in the PD-L1–negative lung cancer population, it does look quite positive and promising and really confirms the result in the PD-L1–negative patients from CheckMate 227, at least in my mind when I look and say, “Are these in agreement, or was the CheckMate 227 result just an outlier to me?” The 9LA regimen results confirm that and make me feel more confident about that result.

Personally and as an institution, we have a lot of experience with that combination. We were involved with the phase 1 study, CheckMate 012, which went back to 2013 and 2014. We have put a lot of patients on this treatment over many years. We’ve really learned how to use this regimen. The low-dosage ipilimumab 1 mg/kg every 6 weeks is very different from the regimen used in melanoma, where you might give 3 mg/kg of ipilimumab every 3 weeks.

Even in the lung cancer population, we all feel very confident using this kind of therapy. I have extensive experience using this regimen on patients in their 70s, and I have had a significant number of patients receive a full 2 years of treatment and come off therapy because they finished their 2 years but did not develop any substantial toxicity.

CheckMate-9LA: Histology and Frontline Impact 

 The CheckMate 9LA regimen is the most recent regimen that was added to our treatment arsenal. This was the first time in my knowledge that we had approval of the drug before we see any of the data. This is a combination of platinum doublet chemotherapy, histology specific, combined with dual-checkpoint blockade using the PD-1 inhibitor nivolumab and the CTLA4 inhibitor ipilimumab. The unique wrinkle here is that chemotherapy was given only with the first 2 cycles, not the first 4, and there was no indefinite maintenance chemotherapy.

The rationale and strategy is to provide a means to get that initial rapid cytotoxic control, to avoid that initial drop in PFS [progression-free survival] to provide that benefit for patients with aggressive disease or high burden of disease and facilitate an initial response. Then, toward the cycles beyond the second round, to lean more on that dual-checkpoint blockade for durable benefit and for more meaningful duration of response. When we look at the outcome from this phase 3 registrational trial, over 700 patients randomized, there was a survival benefit. Now, it’s important to look at the patient characteristics. About 30% were squamous, a little different from studies like KEYNOTE-024, where it was closer to 20%. If you look at the PD-L1 breakdown, we would typically expect about a third negative, a third positive low, and a third positive high. Here it was about 40% PD-L1 negative, so you just want to keep those populations in mind when we look at absolute numbers.

It was a randomized trial. Compared with chemotherapy alone, the chemotherapy–nivo-ipi [nivolumab-ipilimumab] approach did provide a survival benefit. Overall survival was 15.6 months versus 10.9 months with a hazard ratio of 0.66. The 1-year survival rate was 63% compared with 47% with chemotherapy. Broken down by histology in the nonsquamous group, we saw 17-month OS versus 11.9, hazard ratio of 0.69. In the squamous, 14.5 months versus 9.1, hazard ratio of 0.62. In both squamous and nonsquamous histologies, really across PD-L1 subsets, the addition of nivo-ipi [nivolumab-ipilimumab] to 2 cycles of chemotherapy provided a clear benefit over chemotherapy alone. The control arms didn’t necessarily underperform. If we look at the PD-L1–negative group, the survival hazard ratio was 0.62. In the PD-L1–high group, 0.66, which is remarkably similar across. One-year survival rates across PD-L1 subsets were 60% to 70%. We also saw the PFS benefit, 6.7 months with nivo-ipi [nivolumab-ipilimumab]–chemotherapy versus 5 months with chemotherapy alone with a hazard ratio of 0.68. When we look at those Kaplan-Meier curves for PFS, and we don’t see that initial drop. We don’t see that crossing of the early curves, just 2 cycles of chemotherapy preventing benefit. Some propose that may be countering hyperprogression, but in any case we see the favorable early benefit from adding chemotherapy in that long-term tail with a dual-checkpoint blockade.

 I’m going to talk about CheckMate 9LA. While CheckMate 227 was a long time coming and it took awhile to have approval for nivolumab and ipilimumab on the CheckMate 227 regimen, 9LA came on us all of a sudden. CheckMate 9LA was a randomized phase 3 trial for all-histology lung cancer, and the control arm was standard histology-based chemotherapy. The experimental arm was nivolumab and low-dose ipilimumab regimen from CheckMate 227 plus 2 cycles of chemotherapy.

The reason for the 2 cycles of chemotherapy is that with immunotherapy, sometimes we will see early progression. That’s particularly a concern in patients who have a high tumor volume or are symptomatic from their cancer, so this regimen gave only 2 cycles of chemotherapy. To prevent early progression, avoid long-duration toxicity from chemotherapy, then also provide the double immunotherapy for a chance for a higher number of immune responses that will give us a really long duration of benefit, a long-term benefit of 3, 4, and 5 years.

In this trial, the 9LA regimen was positive. It was superior to chemotherapy, and it was superior for overall survival, progression-free survival, and overall response rate. The duration of response was better for those who responded to treatment, and progression-free survival was better for the 9LA regimen compared with the chemotherapy.

For 9LA, the primary end point was overall survival compared with chemotherapy for all PD-L1 types. The FDA approval for the 9LA regimen is for any PD-L1 type, positive or negative, in non–small cell lung cancer.

The CheckMate 9LA regimen was unique in that it looked to give some chemotherapy at the beginning to avoid early progression of the cancer but minimize the exposure to chemotherapy toxicity, so only 2 cycles of chemotherapy were given. This is the period where in immunotherapy-alone trials we will sometimes see rapid progression of the cancer and in which the immunotherapy arm looks inferior to the chemotherapy arm.

I think this 9LA strategy with 2 cycles of chemotherapy was successful. We can look at the progression-free survival curve, and early on the nivo-ipi [nivolumab-ipilimumab]–containing arm was not inferior to the standard chemotherapy arm, but we gave the chemotherapy for only 2 cycles. And we don’t see as much cumulative grade 3 and 4 toxicity that we see in some of the chemotherapy doublet trials, where patients receive a standard course of chemotherapy plus a new therapy. The strategy for 9LA was successful, and it minimized the exposure of chemotherapy but prevented the early progression that we sometimes see with immunotherapy alone.

Recent Combination Approval: CheckMate-9LA Regimen 

: There was a good overall response rate, the immunotherapy. It was clearly better than we would have thought from single agent PD-1 checkpoint treatment, it was over 30%, which was very respectable. The duration of response was excellent. The duration of response was around 18 months which was very strong. The progression-free survival looked about the same as chemotherapy, which is not surprising for an immunotherapy alone combination. The response rate for the nivo/ipi was good, better than for chemotherapy. The duratioThe safety of the nivo/ipi combination was that it was safe and feasible. So certainly when you give combination immunotherapy you're going to have more side effects then if you give a single PD-1 checkpoint treatment. Originally when nivolumab and ipilimumab was developed, it was developed in melanoma patients and higher doses of ipilimumab were used, a more frequent dosing of ipilimumab was used. And that combination of nivolumab and ipilimumab was not safe or feasible in lung cancer patients. We did a large phase 1 trial called CheckMate-12 and we carefully evaluated the combination of these immunotherapies and determined that if we gave the ipilimumab, 1 mg/kg, every six weeks, that that was safe and feasible in lung cancer patients.

The safety of the nivo/ipi combination was that it was safe and feasible. When you give combination immunotherapy you're going to have more adverse effects then if you give a single PD-1 checkpoint treatment. Originally when nivolumab and ipilimumab was developed, it was developed in melanoma patients and higher doses of ipilimumab were used, a more frequent dosing of ipilimumab was used. And that combination of nivolumab and ipilimumab was not safe or feasible in lung cancer patients. We did a large phase 1 trial called CheckMate-12 and we carefully evaluated the combination of these immunotherapies and determined that if we gave the ipilimumab, 1 mg/kg, every six weeks, that that was safe and feasible in lung cancer patients. And this large randomized phase III trial confirmed that and so did a large phase II trial, CheckMate-568. You'll see about 30% to 40% grade 3 or grade 4 toxicity with a nivolumab and ipilimumab combination, which is more than you'd expect for instance than nivolumab alone. But less than 20% of patients discontinued any component of their treatment due to toxicity, which was a solid result. And there were no significant more deaths, in fact, there were very few deaths and comparable to the chemotherapy arm. While the combination immunotherapy is clearly more toxic than a single immunotherapy, it was safe and feasible and generally comparable to what one might expect for chemotherapy treatment.

: CheckMate-227 looking at dual checkpoint blockade with nivolumab and ipilimumab is chemotherapy-free, but it’s not toxicity-free. If you look at treatment-related adverse events, 77% incidence, although that’s lower than chemotherapy, which was just over 80%. Grade III to IV adverse events, similar, 33% versus 36%. If you look at treatment-related tox leading to discontinuation of therapy, that occurred about 18% of the time versus 9% with chemotherapy. The toxicity that we see with dual checkpoint blockade tends to be early. In my own practice I’ve been pleasantly surprised. I think a lot of it has to do with ipilimumab dosing. Using CTLA-4 in different cancers is challenging, and the dosing regimens vary from disease to disease. This low-dose approach using ipilimumab at a dose of one milligram per kilogram every six weeks has been much better tolerated than my previous efforts.

How the CheckMate 227 nivolumab-ipilimumab regimen fits into a first-line treatment of lung cancer is complex, which is good. We have a lot of good choices in first-line treatment. For tumors that have very high PD-L1s, so 50% or higher, and particularly for ones that are 70%, 80%, 90%, 100%, pembrolizumab alone is an approved therapy, and it can be very effective in that population with minimal toxicity. For patients with non–small cell lung cancer, a chemotherapy doublets with an immunotherapy such as pembrolizumab or atezolizumab were approved, and those are good options. The CheckMate 227 regimen of nivolumab and low-dose ipilimumab will give us an effective chemotherapy-free combination that we can offer to our patients who are not good candidates for chemotherapy, or for patients who for 1 reason or another want to avoid chemotherapy. A lot of people from personal experience or experiences with their families will want to avoid chemotherapy if they can. There may be patients who have particular aversions to nausea or hair loss or some other toxicity that is common with chemotherapy, so they would really prefer to have a chemotherapy-free option. The CheckMate 227 combination provides that, and you feel confident about that for most non–small cell lung cancer patients.

CheckMate-227 Regimen Safety Profile 

 CheckMate 227 was a randomized trial that included patients with stage IV or recurrent non–small cell lung cancer and no prior systemic therapy for advanced disease. Patients with known 

 fusions were excluded, as were patients with untreated, unstable brain metastases. It did include patients with both squamous and nonsquamous histologies. About 30% of patients in this trial had squamous non–small cell lung cancer. It’s a bit higher than some other studies, like KEYNOTE-024, where it was about 20%. You want to factor that in when you look at the numbers, as some populations do have a slightly worse prognosis.

In the 3-year update, the median survival for the PD-L1–positive group was 17.1 months, compared with 14.9 months with chemotherapy. That’s a hazard ratio of 0.79 for death. The landmark survival rates favored duel-checkpoint blockade. The 2-year OS [overall survival] rate was 40% versus 33% with chemotherapy, and the 3-year survival rate was 33% versus 22%. What I thought was maybe more compelling was the PD-L1–negative cohort, where the hazard ratio was better at 0.64. The difference in hazard ratio for death, 0.64 in PD-L1 negative, 0.79 in PD-L1 positive, was primarily because of the performance of the chemotherapy arm. The nivo-ipi [nivolumab-ipilimumab] arm was remarkably consistent when we compare the PD-L1 positive and negative. In the positive group, 17.1 months was the median survival; in the negative, 17.2. We usually expect a bit of a drop-off in the PD-L1–negative cohort. We didn’t see that with nivolumab and ipilimumab. While chemotherapy was factoring in a bit worse in the PD-L1–negative group, nivolumab and ipilimumab performed consistently well.

CheckMate 227 was a large, randomized phase 3 trial, and a major component of that trial was looking at the immune combination of nivolumab plus ipilimumab compared with chemotherapy. And the overall survival end point was the primary end point for this trial in PD-L1–positive lung cancer. This trial met its primary end point. It was clearly an improvement in overall survival for the immune combination, compared with chemotherapy that was both clinically and statistically significant.

In CheckMate 227, progression-free survival [PFS] was superior with dual-checkpoint blockade. Using nivolumab and ipilimumab compared with histology-specific chemotherapy, hazard ratio for PFS was 0.81 in the PD-L1–positive group, 0.75 in the PD-L1–negative group. The 3-year PFS rate was 18% among positive patients, 13% among negative. Response rate was also higher with just the nivolumab-ipilimumab combination, at 36% in the positive versus 27% in the negative group. What was most impressive, looking at the outcomes in CheckMate 227, was the duration of response. In the PD-L1–positive group, that duration of response was 23.2 months, almost 2 years, for a median duration of response. The PD-L1 negative cohort had an 18-month duration of response. These responses are remarkably durable when we consider the responses we’re achieving with dual-checkpoint blockade compared with chemotherapy-immunotherapy. When we look at chemotherapy-immunotherapy, some of the responses we see are those durable immunotherapy-based responses. But some are just chemotherapy responses, which are somewhat transient. When we’re using only dual checkpoint, the responses we see are immunotherapy-based responses, and those tend to be more durable. A duration of response of almost 2 years is quite compelling, and it’s difficult to ignore that.

ASCO 2020 Data Update: CheckMate 227

 We now have several FDA-approved immunotherapy-based regimens for patients with metastatic non–small cell lung cancer that lacks an actionable driver. We have checkpoint inhibitor monotherapy. We have dual-checkpoint blockade and multiple chemotherapy-immunotherapy strategies. We know that all these are superior to chemotherapy, but they haven’t been compared to one another. Our charge as oncologists is choosing among the available options. I’ve seen some very complex flow charts, but I find it challenging to devise a straightforward algorithm. We need to employ a very individualized patient approach. We have the most options for the PD-L1–positive subset. Although there are some advantages to chemotherapy-immunotherapy in terms of response rate and progression-free survival, particularly in those first 3 months of treatment, not all the patients we see are candidates for chemotherapy. Especially during the coronavirus pandemic, there was some value in avoiding myelosuppressive chemotherapy. That said, if there’s a clinical need, a sense that the disease is advancing quickly or there’s a large burden of disease, these combined chemotherapy-immunotherapy strategies do seem more appropriate. In the PD-L1–negative subset, chemotherapy-immunotherapy remains our standard, but the data for dual-checkpoint blockade are intriguing. Although nivolumab and ipilimumab are not technically approved for the PD-L1–negative subset, that’s where its use may be most valued.

There are many factors to consider in choosing an initial immunotherapy-based strategy. With regard to the tumor, I do factor in PD-L1 expression. At our institution we use the Agilent Technologies, Inc Dako 22C3 clone. Many lab-derived tests are utilized appropriately. Generally, we consider 3 groups: 0, low, and high. There is emerging evidence that the ultrahigh PD-L1 expression carry additional predictive power showing that PD-L1 expression is a continuous variable but is not perfect. It is dynamic. It is inconsistent.

We look at other factors among the tumor histology, particularly when you’re selecting chemotherapy backbone for combinations, as well as overall prognosis. Tumor mutational burden initially had some interest, but it’s been difficult to interpret, and there are a lot of differences among those panels. It does not factor into my decision-making. Increasingly, we also have to look at the host, looking at the patient. Patient characteristics are critical. Performance status [PS], comorbidities, these are going to influence suitability for specific regimens, particularly those that involve chemotherapy. We have to consider patient values, and I anticipate a lot of nonclinical factors as well that will come into the fold—schedule, cost, formulary restrictions—and those may end up tipping the scales when all other factors are equal. Each case really needs to be considered in its own context.

Performance status does factor into my treatment decision. We know patients with a poor performance status will have worse outcomes. In addition, they’re going to tolerate therapy less. When I look at performance status, I try to get a sense of how quickly the performance status is changing and how much of that performance status is related to the cancer. How much of that performance status decline is, in my opinion, reversible? Unfortunately, we don’t live in a world where all our patients are PS 0 or even PS 1, so we have to make some extrapolation. Our comfort with that extrapolation changes but also varies with the specific regimens that we’re choosing. If we feel a regimen is relatively well tolerated and safe, even in the context of a borderline performance status, we can go forward carefully. We all take certain measures to watch those patients a little more closely.

Nondriver Adenocarcinoma: Determining Therapy

Neal E. Ready, MD, PhD, professor of medicine, Duke University School of Medicine, member, Duke Cancer Institute, discusses emerging treatment approaches in small cell lung cancer (SCLC).

DLL3 is a potentially important target in SCLC as it is expressed in about 70% of cases. Importantly, DLL3 is not typically expressed on normal cells. An antibody-drug conjugate called rovalpituzumab tesirine (Rova-T) has shown activity when targeted against DLL3. However, it has yet to receive regulatory approval because it has modest activity and a significant toxicity profile, says Ready. Nonetheless, the agent has validated DLL3 as a target.

Several pharmaceutical companies are now looking at targeting DLL3 with bispecific T-cell engager antibody approaches. DLL3 may also serve as a good target for CAR T-cell therapy, an approach that has shown activity in some leukemias and has become standard therapy in some lymphomas, explains Ready.

PARP is also under investigation as a potential target since it is an important enzyme in DNA repair and therein cancer cell growth and survival; it may also be related to the development of antigens that the immune system can respond against. The combination of PARP inhibitors and chemotherapy has shown promise, but not enough to warrant an approval in all comers, says Ready. Additional research is looking at PARP inhibitors with temozolomide (Temodar), and there is preclinical research evaluating the use of PARP inhibitors with immunotherapy.

Dr. Ready on Promising Treatment Approaches in SCLC

Neal E. Ready, MD, PhD, professor of medicine, Duke University School of Medicine, member, Duke Cancer Institute, discusses the benefit of PD-L1 inhibition in small cell lung cancer (SCLC).

Immunotherapy activates the body’s own immune system to fight the cancer, Ready says. Traditionally, there had only been anecdotal success with this therapy in the form of vaccines as well as other approaches across tumor types. Over the last 2 decades, basic science has indicated that there are checkpoints on immune cells that allow the tumor to turn off the immune system. The use of checkpoint inhibitors such as the PD-L1 inhibitor atezolizumab (Tecentriq) are ways in which to overcome this.

In extensive-stage SCLC, atezolizumab is being combined with chemotherapy. Data from the pivotal IMpower133 study showed that chemoimmunotherapy improved overall survival for these patients, notably extending survival beyond 1 and 2 years for select patients.

Neal E. Ready, MD, PhD, professor of medicine, Duke University School of Medicine, member, Duke Cancer Institute, discusses the benefit of PD-L1 inhibition in small cell lung cancer.

Neal E. Ready, MD, PhD, Duke University Medical Center

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