Apar Kishor Ganti, MD, chair of the National Comprehensive Cancer Network Guidelines panel in small cell lung cancer, explains the thinking behind several new recommendations.
The past year has been eventful in small cell lung cancer (SCLC). Two years after Bristol-Myers Squibb received an accelerated approval for nivolumab in patients with metastatic SCLC who had received at least 1 prior treatment, it withdrew the indication in late December,1 after a later trial did not meet its endpoint. In March, Merck did the same for its checkpoint inhibitor, pembrolizumab.2
Both actions came ahead of hearings by an FDA panel, where experts discussed what to do when an accelerated approval speeds a drug to market, but later studies fail to confirm early results.3 An added wrinkle: cancer drugs that have accelerated approvals are often included in guidelines from the National Comprehensive Cancer Network, the gold standard for clinical care. Such was the case for the SCLC indications with nivolumab and pembrolizumab.
So, with these indications withdrawn, what would the NCCN do? The path was not clear. As Martin J. Edelman, MD, chair of the Department of Hematology/Oncology of Fox Chase Cancer Center, said in an AJMC® interview this spring, the lost indications did not mean that nivolumab and pembrolizumab were not effective in SCLC. It did mean, however, that knowledge gained after the accelerated approvals might shift how these drugs were used for patients whose disease had relapsed, depending on how they had been treated previously.4
On August 9, 2021, NCCN’s Guidelines Panel for Small-Cell Lung Cancer released its update: in patients with SCLC who relapsed after 6 months or less, the preferred regimens remained lurbinectedin, topotecan, or a clinical trial. Despite the withdrawn indications, nivolumab and pembrolizumab remained recommended regimens, and their evidence level increased from level 3 to level 2A; this means based on lower-level evidence, there is consensus that the intervention is appropriate. For patients who progress after 6 months, the patient’s original regimen is preferred, except checkpoint inhibitors are not recommended if patients have previously received checkpoint inhibitors.5
To understand the recommendations, The American Journal of Managed Care® spoke with Apar Kishor Ganti, MD, who is professor of internal medicine in the Division of Oncology & Hematology at the Fred & Pamela Buffett Cancer Center at the University of Nebraska. Ganti, who also serves as a staff physician at the Omaha VA Medical Center, is chair of the NCCN Guidelines Panel for SCLC.
The following interview is edited lightly for clarity.
AJMC®: Can you discuss the most recent NCCN recommendations for nivolumab and pembrolizumab in light of the withdrawn indications earlier this year?
Ganti: There was a major change in the role of checkpoint inhibitors in relapsed small cell lung cancer from a pharmaceutical perspective, in the sense that the makers of both pembrolizumab and nivolumab decided to withdraw their FDA application for an indication in small cell lung cancer in patients who had been previously treated. And while that was their decision, it does not necessarily change the data that have been presented using those 2 drugs in the second-line and beyond setting.
If you look at the other recommended drugs for subsequent therapy, all of them have similar efficacy and toxicity, probably more toxicity than the checkpoint inhibitors, pembrolizumab and nivolumab. We felt that for those patients who have not received a checkpoint inhibitor, pembrolizumab or nivolumab would still would be reasonable options in that particular setting. As time passes, and as the data from PACIFIC6 and IMpower1337 mature—and more and more patients with extensive stage small cell lung cancer get checkpoint inhibitors in the first-line setting, the NCCN recommendations may be revised. But to date, there is a significant minority of patients with extensive-stage small cell lung cancer who do not get checkpoint inhibitors in the first-line setting. In patients with limited-stage small cell lung cancer, the majority of whom who will progress after their initial treatments, they have not received a checkpoint inhibitor. And for those patients, pembrolizumab or nivolumab are still reasonable options to try. That was the thinking of the committee when we decided to leave them in the guidelines, even though the companies that make them decided to withdraw their application for indications.
AJMC®:There are different levels of evidence in the NCCN guidelines. What was the committee's thought process and discussion before you settled on Level 2A?
Ganti: If you look at the NCCN levels of recommendation, it basically depends on the consensus of the panel. Level 1, obviously, means that there is high quality evidence; clearly, that does not exist in this case. But as group, for these drugs, the NCCN panel felt that this was a reasonable indication. And there were no major dissenters in the panel, and that's why [pembrolizumab and nivolumab] got a designation of 2A. … The way NCCN Guideline panel levels of recommendation work is that if there is uniform consensus [85% or more] with low-level evidence, that's a category 2A; less consensus is 2B [50%-<85%]. Major disagreement is a category 3.
AJMC®: Given this procedure, what can we expect going forward with lurbinectedin, which also has an accelerated approval in metastatic SCLC?
Ganti: We currently have 1 published study that shows that in this particular setting of relapsed, small cell lung cancer on 105 patients in the trial that was published in The Lancet last year,8 the response rates and the progression-free survival [and] overall survival for lurbinectedin all seem to be similar, or maybe slightly better than what's currently available. That’s why lurbinectedin is in the guidelines. Based on the FDA’s indication/labeling, lurbinectedin is a preferred agent for patients who have a longer duration, treatment-free interval of greater than 90 days.
If the data change, [NCCN may revise the recommendation]. There’s been a press release; we haven't seen the full data yet about the Atlantis trial not meeting its endpoint. The Atlantis trial was designed as a combination of lurbinectedin and doxorubicin, using a lower dose of lurbinectedin than what is currently recommended by the FDA. I think they chose the lower dose because they were combining it with doxorubicin. It’s not necessarily comparing apples to apples. We have not seen that data yet—all we know is based on a press release. I am told that it will be presented at a future meeting; I'm hoping it shows up in the World Lung Meeting [in September]. … We will evaluate that data and compare it with the data that we already have, knowing that those trials are not directly comparable, because the doses were low and for cytotoxic chemotherapy drugs, we know that those matter to a certain extent.
If that trial was really negative, was it inferior? We don't know that yet. All we know is that it was not superior to topotecan. So, we'll look at that data and decide what to do with it. But if the data do not show that there was a significant detriment to lurbinectedin, we may elect to keep it on the guidelines. Of course, that's a decision that the guidelines committee will have to take. What I'm telling you right now is my personal opinion, that we may elect to keep it just to allow patients to have another option. What I personally would like to see is a head-to-head comparison of lurbinectedin at a current dose of 3.2 milligrams-per-meter-squared with topotecan, and see if there is benefit or not with that combination. And that probably would be the definitive trial that would determine what happens with lurbinectedin, as far as the guidelines.
AJMC: Can you discuss some of the other recommendations, such as not using checkpoint inhibitors in certain circumstances if there is disease progression?
Ganti: We do not currently have any data to recommend the use of a checkpoint inhibitor in the second-line setting in patients who have previously received a checkpoint inhibitor. All of the data that I told you earlier with nivolumab and pembrolizumab was in patients were who were naive to checkpoint inhibitors. … Those trials were done before the results of the CASPIAN9 study and IMpower133 were available, so those patients did not get a checkpoint inhibitor in the frontline setting. We currently do not have any evidence to show that checkpoint inhibitors work in patients who have previously received a checkpoint inhibitor. And that was the reason for the change in recommendation, based on the new results that we have from CASPIAN and IMpower133 and comparing them with what we knew from the Checkmate-032 and the KEYNOTE-158 trials. So, we decided to change that to only those patients who are naive to checkpoint inhibitors.
AJMC: Are there any concerns that clinicians and patients may have encountered some issues with payer coverage in SCLC with checkpoint inhibitors, given the withdrawn indications?
Ganti: If they have, we are not privy to that, because NCCN keeps the Guidelines committees completely separate from their discussion with the payers. So, if they have, I'm not aware of any such discussions. Our charter is to strictly go by the available data and develop guidelines using the best possible scientific evidence available.
AJMC®:Is there any discussion at NCCN about a broader umbrella policy for what happens when an indication is withdrawn? Or do you anticipate that updates will be handled on a case-by-case basis within the individual guideline committees?
Ganti: I am not aware of a blanket policy on that regard. Like I said, our charter is to look at the data and make scientific decisions based on the best available evidence. The NCCN has not given us any mandates or any guidelines as to what to do if an indication is withdrawn. Half of the drugs on the list of drugs that we recommend for relapse in small cell lung cancer do not have that particular indication to the best of my knowledge, such as bendamustine. We look at the trials that are published or presented in abstracts and use that to make our decisions; every once in a while, we get a submission from a pharmaceutical company asking us to look at the evidence. We go by the published evidence that has been presented at a scientific meeting or published in a peer-reviewed journal to make our recommendations of whether or not to include drugs in the guidelines.
AJMC®:Is there anything else you would like to add?
Ganti: Personally, I think that [pembrolizumab or nivolumab] are still useful drugs in the right context. Clearly they are not for everyone, especially if patients have received first-line checkpoint inhibitors with their chemotherapy. But all of the limited-stage patients who relapse relatively quickly after completion of their chemoradiation, and patients who for whatever reason, have not received a checkpoint inhibitor in the first-line setting [may benefit]. A common scenario, especially in the current payer environment, is if a patient starts chemotherapy in the hospital and needs 1 or 2 cycles in the hospital. Most hospitals as part of the [diagnosis-related group] will not allow the use of checkpoint inhibitors while the patient is inpatient due to payment- related issues. It’s not uncommon for these patients to be sick and need treatment right away. And since the trials were not done to exclude those patients who got the first cycle in the hospital, there may be some physicians who believe that if the patient did not get [a checkpoint inhibitor] in the first cycle, they should not get it in the first-line regimen. And those patients would still benefit from getting pembrolizumab or nivolumabin the second-line setting or beyond.