Borghaei Discusses Long-Term Pembrolizumab NSCLC Data, Broadening Clinical Trial Eligibility

Hossein Borghaei, DO, MS

The PD-1 inhibitor pembrolizumab (Keytruda) increased overall survival by more than 10% over historical rates for patients with advanced non—small cell lung cancer (NSCLC), according to long-term follow-up in the KEYNOTE-001 study,¹ explained Hossein Borghaei, DO, MS.

In the trial, researchers evaluated 550 patients who were either treatment-naïve (n = 101) or received prior treatment (n = 449) with advanced or metastatic NSCLC. Patients received 2 mg of pembrolizumab once every 2 weeks or 10 mg once every 2 or 3 weeks.

The updated results, which were presented at the 2019 ASCO Annual Meeting, showed that the 5-year overall survival (OS) rates were 23.2% for treatment-naïve patients and 15.5% for those who had prior therapy, which is a significant increase compared with the historical rate of about 5% for patients with advanced NSCLC.

Findings of an additional trial that were presented at the meeting found that trials for NSCLC currently have strict eligibility requirements for patients, preventing many of them from participating in research for new treatment methods.²

The study identified 10,500 patients and found that 5005 (47.7%) would be excluded from participating in trials based on the current requirements, while only 154 (1.5%) patients would be excluded with the expanded criteria, which is being proposed by ASCO and Friends of Cancer Research. Expanded criteria patients were older (67.5 years vs 66.1 years), more likely to be female (44% vs 40%), have stage IV disease (60% vs 55%), have nonsquamous histology (47% vs 45%), and were never smokers (16% vs 13%). Expanding the eligibility requirements provide researchers with more participants and allow them to study more diverse patient populations.

Studies such as these are helping physicians address the unmet needs of NSCLC, according to Borghaei, chief of the Division of Thoracic Medical Oncology, professor of the Department of Hematology/Oncology, and co-director of the Immune Monitoring Facility at Fox Chase Cancer Center.

“The biggest challenges we face in lung cancer now are all the patients who were treated with chemotherapy and immunotherapy upfront, and now have progression of their disease. If we don't have a clinical trial, we're looking at going back to old-fashioned chemotherapy, such as docetaxel and gemcitabine, which none of us are excited about,” Borghaei said. “We still have plenty of unmet needs and challenges to overcome, but it's hopeful. There's research, there's interest, and there's work. There are new drugs and new combinations that the science is advancing. Overall, I'm very optimistic that in another couple years we're going to come and have answers for another 15% to 20% of our patients.”

In an interview with OncLive, Borghaei highlighted long-term single-agent pembrolizumab data and the overall state of immunotherapy in NSCLC, as well as the prospect of making clinical trial eligibility less restrictive.

OncLive: Could you provide insight on of the long-term OS data for pembrolizumab in KEYNOTE-001?

Borghaei: KEYNOTE-001 looks at the long-term OS data for patients with advanced NSCLC who are treated with pembrolizumab. We're beginning to see some of our results from the other studies with checkpoint inhibitors in the same patient population and it is amazing to see that anywhere from 15% to 16% of these patients with metastatic lung cancer are now alive at the 4- to 5-year mark, which is a remarkable accomplishment for a disease in which we have not had these kinds of treatments.

If you take patients with molecularly driven tumors out of the equation, unfortunately, the survival rate for the majority of the patients with advanced NSCLC has been rather limited. It is very intriguing to see that at least a portion of these patients could have very long-term control of the disease without recurrences. That leads to obvious questions: “Who are these patients? What is it about their tumors that is so special that they respond so well? How can we learn from these patients and what these tumors are doing so that we can apply the knowledge to a broader patient population?”

More of our patients are in that category as opposed to the 15% or 16% that we are seeing. That is the ongoing work and research in many different institutions—to try and better understand the tumor microenvironment, and what the mechanisms of resistance to different immuno-oncology drugs that we have available are, especially the checkpoint inhibitors. I'm hopeful we are going to find ways to improve the outcome for the majority of our patients with that disease.

Another abstract presented at the 2019 ASCO Annual Meeting focused on broadening clinical trial eligibility. Could you share your thoughts on this?

We all have realized our eligibility criteria for entering a clinical trial has been extremely stringent. There was a time when there was a need for that. Now that we have drugs that are better tolerated and can closely monitor patients, it's very reasonable to broaden the patient population. As an example, traditionally, if there is any evidence of brain metastases, we would normally say a patient is not eligible for any of the trials. We've come to realize with small asymptomatic brain metastases, including [many of the] targeted drugs or immunotherapy drugs, it is possible to closely monitor a patient with small asymptomatic brain metastases and stop treating if we see a deterioration in the clinical scenario or imaging.

However, if the patient is benefitting and there is no deterioration, we continue with the treatment. Those kinds of examples have led to this broader interest in looking at some of the eligibility criteria we have traditionally put in lung cancer trials and see if we can eliminate them to make these trials accessible to a wider patient population.

Do you find that there are there any current challenges or stigma in the community on whether patients may be eligible for a trial or not?

There is a little subjectivity when an investigator evaluates a patient for participation in the trial. To me, someone might have an ECOG performance status of 1. Even though that should not be the point of a lot of discussion, in the eye of another investigator, the patient might be cause for an ECOG performance status of 2. We have seen examples like that, even in our own institution, with different investigators.

While there are going to be issues like that, we are talking about more specific eligibility criteria, such as demanding the lack of a secondary cancer diagnosis going back 5 years. Is that necessary in a patient with metastatic NSCLC who wants to get into a clinical trial? Those are the [criteria] we would consider to be an unnecessary burden and something we should carefully look at to see if we can eliminate.

However, as investigators, our number one job is patient safety. Therefore, if there's any question that a patient might not benefit from a study, by all means an investigator should exercise their right and say no to a clinical trial for that patient. However, we all know the only way we're going to make progress is through clinical trials. Hopefully, we will be able to get more of our patients to participate.

How would you describe the impact of checkpoint inhibitors on the NSCLC paradigm?

The impact of checkpoint inhibitors on patients with lung cancer cannot be underestimated. I don't think any of us imagined that we would find a treatment that could potentially be useful in such a broad patient population. A one-drug regimen that out-competes traditional chemotherapy was something we never thought we would have with available drugs. Also, the tolerability of drugs is also a selling point, or another strength, of these drugs that we have seen.

Then, you look at studies with chemotherapy plus immunotherapy, and you see the superb response rates and improvement in PFS and OS. You get a feel that the introduction of the checkpoint inhibitors has had a huge impact on patients in terms of their quality of life, disease control, and now based on the data available, their OS. They're not benign drugs; there is no such thing in oncology. Clearly, they have toxicities associated with them, but the risk-benefit ratio in almost all of the studies that we looked at favors the use of checkpoint inhibitors, either monotherapy or in combination with chemotherapy, for this specific patient population.

Understanding who the patients are, who benefits the most, and how can we improve the outcomes in patients who are not necessarily benefitting will be the next challenge. [This is] something that hopefully the next generation of immunotherapy-based drugs will answer for us.

References

1. Garon EB, Hellmann MD, Costa EC, et al. Five-year long-term overall survival for patients with advanced NSCLC treated with pembrolizumab: results from KEYNOTE-001. J Clin Oncol. 2019;37(suppl; abstract LBA9015).
2. Harvey RD, Rubinstein WS, Ison G, et al. Impact of broadening clinical trial eligibility criteria for advanced non-small cell lung cancer patients: real-world analysis. J Clin Oncol. 2019;37(suppl; abstract LBA108).