Studies Continue to Evaluate Potential With Pemetrexed in NSCLC

Mary Jo Fidler, MD

First-line treatment with pemetrexed and a platinum-based therapy followed by maintenance pemetrexed led to a 5-year overall survival (OS) rate of 11% in patients with nonsquamous non—small cell lung cancer (NSCLC), according to results of a single-center retrospective analysis.¹

Additionally, OS rates at 1, 2, 3, and 4 years were 54.5%, 35%, 21%, and 14%, respectively. The median progression-free survival (PFS) was 6.2 months and absence of disease progression at 1, 2, 3, 4, and 5 years was 33%, 14%, 7.5%, 4%, and 3%, respectively. Moreover, results showed that patients with a baseline neutrophil-lymphocyte ratio (NLR) ≤5 had a median PFS of 13.2 months compared with 5.6 months in those whose NLR was >5. Additionally, patients with baseline albumin (HR, 0.7722; P = .024) and hemoglobin (HR, 0.904; P = .0046) had improved PFS.

“Although the PFS was in the single digits, PFS at 5 years with patients not needing to move on to a second-line treatment is very significant,” said Mary Jo Fidler, MD, an associate professor of medical oncology at Rush University and author on the study.

Additionally, other studies are evaluating pemetrexed as a maintenance approach in NSCLC. The ECOG-ACRIN 5508 trial compared pemetrexed, bevacizumab (Avastin), and the combination of both agents, all as maintenance therapy, in patients with advanced nonsquamous NSCLC. Results showed that pemetrexed and bevacizumab should not be used in combination; instead, each agent alone is an optimal approach for this patient population.

In an interview with OncLive, Fidler discussed these intriguing data with pemetrexed in patients with nonsquamous NSCLC.

OncLive: Could you provide an overview of the study evaluating maintenance pemetrexed following first-line pemetrexed and a platinum-based therapy?

Fidler: We wanted to look at the tail-of-the-curve concept in patients who were treated with pemetrexed as chemotherapy. This concept has become more and more important, especially in the realm of immunotherapy where we just saw about 25% 5-year survival rate in patients who were treated with pembrolizumab (Keytruda).

We looked to see if you could see that same tail of the curve up in patients treated with chemotherapy, particularly with pemetrexed. We have patients in our practice at Rush University Medical Center who seem to have done very well, sometimes even coming off chemotherapy and still being in remission. Our abstract looks at patients at our institutions treated with platinum-based therapy and pemetrexed. Some patients did get bevacizumab, but the main factor was pemetrexed and pemetrexed maintenance.

Just to comment on the general population we included, the median PFS mirrors what we see in pemetrexed-based trials, which was a little more than 6 months. However, we did see an impressive tail of the curve with 14% and 11% of patients surviving at 4 and 5 years out, respectively. Not all of these patients were on chemotherapy, or they had switched to another regimen.

What will these data tell us about use of pemetrexed in the real-world setting?

The combination of carboplatin and pemetrexed is still a real-world regimen, especially in patients who may not have the opportunity to access immune checkpoint inhibitors. The ECOG-ACRIN 5508 trial looked at the comparison of maintenance bevacizumab, maintenance pemetrexed, and maintenance pemetrexed/carboplatin. Pemetrexed does seem to add something to the maintenance population, but this is encouraging for long-term survival patients who are exposed to this regimen. [In our single-center] study, baseline albumin and baseline hemoglobin were predictive of long-term benefit.

How the real-world population differ from who might be involved in these trials?

Many clinical trials still restrict enrollment to an ECOG performance status of 0 or 1 for patients. Those trials may be difficult to interpret because the performance statuses are a little subjective. It's easy to say someone is in excellent shape and has a performance status of 0 or 1, but if someone is not, then they may have a performance status of 2 that some patients would be classified as a performance status of 3 depending on the treating physician and investigator. These were all patients who were treated with platinum-doublet chemotherapy. It's also a well-tolerated regimen.

Are there other studies similar to these ones that you are interested in pursuing?

It’s important to study these patients who have long-term outcomes, whether it be on chemotherapy or immunotherapy. With time, we can report on these long-term survivals and whatever subsequent therapies they may have had, to see if the benefit they originally have with their first-line treatment regimen can persist with subsequent lines of therapy. We have subsequent immunotherapies available, and we have subsequent immunogenic chemotherapy combination strategies available, too.

What other maintenance strategies may be ongoing that you are interested in?

In today's world, most patients who are eligible for a platinum doublet are receiving a platinum doublet and an immune checkpoint inhibitor, unless there's a reason they cannot receive them. It's still unclear if the benefits of maintenance are due to pemetrexed or due to continuing on a checkpoint inhibitor. We can see evidence of the checkpoint inhibitors in patients' systems for months after discontinuation of therapy, and we know chemotherapy patients typically have the drug processed out of their system a little quicker.

However, we don’t know the optimal maintenance strategy for patients who received a combination of platinum doublet chemotherapy and immunotherapy. It's a question that is worth the study. It has financial implications as well as potential toxicity implications.

What other lung cancer abstracts presented at the 2019 ASCO Annual Meeting would you like to share your perspective on?

We saw 5-year OS results with pembrolizumab, an immune checkpoint inhibitor. About 25% of patients [were alive] at 5 years, which is unheard of compared with studies that were being presented a number of years ago. We also saw some posters that highlight an area of my personal research interest, which is a concept that some patients may have rapid progression and early death on immunotherapy. The FDA had a very nice poster showing early mortality and early progression on patients receiving immune checkpoint inhibitors. There's a question of whether adding chemotherapy could potentially rescue those patients.

The other area of excitement is the improvement of targeted therapies. We've seen a glimmer of hope for exon 20 insertion mutations and KRAS mutations, which are subsets in which we haven't made any inroads to treating in the past.

We found the engine with a compound that can target one specific pretty common KRAS mutation subset in NSCLC. Historically, this protein has been very difficult to target due to its shape and structure. I'm hoping that with more patient data and perhaps more generations of KRAS-targeted agents, we can target these patients even more successfully in the future.

References

1. Bhatt PK, Fughhi I, Basu S, et al. Mature, real world progression-free survival (PFS) and overall survival (OS) milestones in stage IV, non-squamous, non-small cell lung cancer patients (nsqNSCLC) treated with first line pemetrexed(Pem)/platinum(Plat) followed by pem+/-bevacizumab(Bev) maintenance. J Clin Oncol. 2019;37(suppl; abstr e20721) doi: 10.1200/JCO.2019.37.15_suppl.e20721.
2. Ramalingam SS, Dahlberg SE, Belani CP, et al. ECOG-ACRIN 5508: Pemetrexed, bevacizumab or the combination as maintenance therapy for advanced non-squamous NSCLC. J Clin Oncol. 2019;37(suppl; abstr 9002). doi: 10.1200/JCO.2019.37.15_suppl.9002?af=R.