Standards of Care Shifting in Early-Stage NSCLC

Alexander R. Menter, MD

Recent clinical trial results are starting to redefine the treatment paradigm for patients with early-stage non—small cell lung cancer (NSCLC), explained Alexander R. Menter, MD.

“There are...studies that are showing improved survival rates in patients with lung cancer, and we need to be listening to those,” said Menter, an oncologist at Kaiser Permanente.

Data from the 2018 ASCO Annual Meeting showed that the use of lymph node collection kits during lung resection resulted in improved survival rates compared with centers where they were not available. In a prospective, staggered-implementation study, 1171 patients underwent resection in 11 participating hospitals. The 3-year overall survival (OS) rates at a median follow-up of 20 months were 80% and 73% in kit and non-kit cases, respectively (P = .0051).¹

Following the results of the phase III PACIFIC trial, the FDA approved durvalumab (Imfinzi) for patients with locally advanced, unresectable stage III NSCLC who have not progressed after chemoradiotherapy. The PD-L1 inhibitor improved the median progression-free survival (PFS) by 11.2 months versus placebo at 16.8 and 5.6 months, respectively (HR, 0.52; 95% CI, 0.42-0.65; P <.0001). At 18 months, the PFS rate was 44.2% versus 27.0%, favoring single-agent durvalumab.²

Immunotherapy’s influence was also seen in the neoadjuvant setting in a pilot study of nivolumab (Opdivo) monotherapy in patients with treatment-naïve, resectable, early-stage NSCLC. Results revealed a 45% major pathological response in both PD-L1—positive and –negative tumors following resection. Tumor mutational burden assessment prior to surgery showed a strong correlation with pathological response.³ Though not yet a standard of care, Menter said the study has funneled interest toward neoadjuvant therapy as a more effective means to improve historically low cure rates.

OncLive: What were some advances that we have seen in the past year?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Menter discussed treatment advances in early-stage NSCLC.Menter: The first thing was from the 2018 ASCO Annual Meeting. There was a study looking at the implementation of a lymph node collection kit for surgeons who were planning lung resections. They found that the rate of successful lymph node acquisition for patients going to surgery was much higher if they used a very simple kit at the time of surgery. More surprisingly, they found that the survival rates were higher for patients who had these kits as part of their surgery compared with those who had not had this implemented at their center yet. More extensive lymph node dissection may be impacting survival in these patients.

The next study was the PACIFIC study, which was published in the New England Journal of Medicine in May 2018. This was a study of patients with stage III lung cancer who received chemoradiotherapy and were then randomized to immunotherapy with durvalumab (Imfinzi) versus observation. This was a real “gangbuster” study that showed a nearly 1-year improvement in PFS. [The study showed] a 20% improvement in PFS at 1 and 2 years and it received an FDA approval earlier in the spring. There was also a press release in May that there was a positive survival endpoint as well. This has quickly become a standard of care in a setting where we've been trying to improve outcomes for many years. We have not made much progress until this came along.

The third study is a neoadjuvant immunotherapy study. It's not yet a practice-changing study, but it was published in the New England Journal of Medicine in May. What was interesting about this study was just how robust a response there was in the tumors with just 2 rounds of immunotherapy prior to surgery. It did not delay surgery significantly. There was a large number of responders. They also showed with nivolumab that tumor mutational burden (TMB) was highly important in terms of the responses that were seen.

This points to the potential that this could be paradigm changing. There is not a lot of neoadjuvant chemotherapy being given for lung cancer right now. If we can predict that there will be high response rates to chemoimmunotherapy or immunotherapy alone, there will be much more interest in sending patients with early-stage disease to treatment first and surgery later—with the hope of making those surgeries more successful. It's also possible that immunotherapy may be more effective in patients whose tumors are still in place since there are more antigens for the immunotherapy and the immune system to react against. There is more to come on that, but it's possible that neoadjuvant immunotherapy may be a more successful strategy compared with adjuvant therapy.

Finally, I provided an update on a non-drug, non-surgery topic that was presented at the 2018 ASCO Annual Meeting. The researchers looked at patients who had early-stage lung cancer and they set up sort of a minimal follow-up schedule with scans and visits. Half of the patients were randomized to a more aggressive scan and visit schedule. The other half of patients were randomized to a weekly electronic questionnaire that was sent out to them.

What other neoadjuvant immunotherapy combinations look promising?

Is TMB ready for clinical use?

Will physicians have to rely on combinatorial biomarkers moving forward?

Can you elaborate more on the PACIFIC study?

Surprisingly, they found recurrences sooner even with fewer scans. Patients had a better performance status when their recurrences were found. These patients had better symptom control. They also had better survival by about 1 year. People would be jumping all over this if this was a new medication. Sometimes, it's hard to change our clinical practice. Updating technology takes time, too. Looking at patient-reported outcomes in the patient’s home on their smartphone or computer is something that we'll be looking into in the years ahead.Ipilimumab (Yervoy) and nivolumab in patients with high TMB looks interesting. Pembrolizumab (Keytruda) would be expected to have a lot of activity in patients with high PD-L1 expression. The question is whether or not people will be moving chemoimmunotherapy—with carboplatin, pemetrexed, and pembrolizumab—into this setting. That's a rational thought, but we don't have any data in this setting yet.It's a little bit of a mess as far as I understand, in terms of the different vendors with the next-generation sequencing platforms and establishing the cutoffs. In addition, the clinician should have a clear understanding of what the appropriate cutoff is. Are the data clean enough now that we can really say that someone with a low TMB should not or never see immunotherapy? People would like to see more maturity in the data before we can move it more into practice. It's something that we can start bringing in, watching, and incorporating into our clinical thinking.Yes. I know there are a number of companies that are trying to come up with multi-gene assays that predict for immunotherapy response. Beyond just TMB or PD-L1 staining, what signals from the microenvironment and from the immune response within the tumor might predict for response? Within a few years, we will have groups of patients for whom we can say you definitely will not need this therapy, and other patients who will definitely benefit from it as a frontline treatment. Then, there will probably still be that group of patients in the middle where we're not quite sure until we do large randomized studies.It's been 20 years of looking at different combination strategies for stage III lung cancer and chemoradiation without much in the way of progress, [coupled with] a low rate of cure and a lot of toxicity. It's very exciting to see something have a clinically meaningful impact on patients' lives and their recurrence rates.

There are still some questions out there in terms of what the tail on the curve will be when you stop the PD-L1 inhibitors. In melanoma, there seems to be some concern that if you stop the PD-L1 inhibitors, there might not be the same tail on the curve as there is with ipilimumab. We'll need more data to see that. Even if it turns out that there are not as many cures with 1 year of a PD-L1 inhibitor, it is a clinically meaningful improvement in response rates and in outcomes.

Can you elaborate on the kits?

With regard to toxicity, there was a lot of concern about increased risk for pneumonitis. Clinically, that will continue to be a change for the physicians treating these patients, but the rate is not so high that we should shy away from giving this to patients.The [study included] 11 hospitals in the Southeast. There were a number of experienced thoracic surgeons at these centers. They collected data on patients for approximately 1 year using their standard of care. Then they did a sort of randomized study where each center would open up the study with the kit and then collect that data going forward. It would be staggered, so that you could look across similar time points at what the outcomes were based on whether or not the kits were available at that hospital.

What is the biggest challenge that you have encountered in treating patients with stage III disease?

It showed a much higher compliance rate with the National Comprehensive Cancer Network and other guidelines for lymph node removal. The more surprising outcome was that there was an improved survival rate with the surgeons who were using these kits at the time of surgery. The SWOG group is planning a National Institutes of Health-sponsored trial to look at this in a randomized fashion on a bigger scale.One of the most challenging populations in lung cancer are stage III patients, in part because many of them are frail and have comorbidities. Traditionally, we've had this very toxic therapy that wasn't very active and we were sort of giving it reluctantly. It's exciting to be moving things forward in that arena.

For community oncologists, what do you hope they apply to practice?

Beyond that, as a clinician who works in a large group of physicians who are engaged with our electronic medical records, we're trying to figure out how we can do these patient-symptom assessments electronically. It's more complicated than just having the tool handed over. There's a lot of backend work that needs to be done on working out pathways and determining what happens to results on the weekends, what the alarm results are, who's processing the results, and when it goes to the doctor versus supportive care. It's a lot of work, but there are a couple studies that are showing improved survival rates in patients with lung cancer or advanced cancer, and we need to be listening to those.Immunotherapy is coming. We hope that long-term data will suggest that we are curing more patients over time. Clearly, there will be some patients who aren't going to get long-term benefit from immunotherapy. We'll have to figure out who those patients are in the adjuvant or stage III setting as well. This will continue to evolve at a rapid pace, similar to what we've seen with stage IV lung cancer.

References

1. Osarogiagbon R, Smeltzer M, Faris N, et al. Pragmatic study of a lymph node (LN) collection kit for non—small cell lung cancer (NSCLC) resection. J Clin Oncol. 2018;36(suppl; abstr 8502).
2. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non—small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929 doi: 10.1056/NEJMoa1709937.
3. Forde P, Chaft J, Smith K, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med. 2018;378:1976-1986. doi: 10.1056/NEJMoa1716078.