Immunotherapy Data Lead Lung Cancer Landscape Following ASCO 2018

Apar Kishor Ganti, MD

Immunotherapy has risen to the forefront of thoracic oncology; however, challenges exist with comparing checkpoint inhibitors and how to best select patients for this class of agents, whether alone or in combination. This is a good problem to have, according to Apar Kishor Ganti, MD.

Over the past year, positive data have been presented from several clinical trials in lung cancer. Checkpoint inhibitors like pembrolizumab (Keytruda) and atezolizumab (Tecentriq), when combined with standard chemotherapy, have been clinically proven to improve patient response compared with chemotherapy alone.

Updated data from the KEYNOTE-189 trial, presented at the 2018 AACR Annual Meeting and published in the New England Journal of Medicine, indicated that frontline pembrolizumab plus carboplatin/pemetrexed reduced the risk of death by more than 50% in patients with nonsquamous non—small cell lung cancer (NSCLC) without EGFR or ALK abnormalities.^1,2 At a median follow-up of 10.5 months, the estimated 12-month overall survival (OS) rate was 69.2% (95% CI, 64.1%-73.8%) with pembrolizumab versus 49.4% (95% CI, 42.1%-56.2%) with chemotherapy alone (HR, 0.49; 95% CI, 0.38- 0.64; P <.001). The combination was granted an accelerated approval in this setting off of prior data in May 2017.

Moreover, in May 2018, the FDA granted a priority review designation to a supplemental biologics license application for atezolizumab in combination with bevacizumab (Avastin), carboplatin, and paclitaxel for first-line treatment of patients with nonsquamous NSCLC.

This decision was based on findings from the phase III IMpower150 trial, which showed that the addition of atezolizumab improved progression-free survival (PFS) compared with bevacizumab and chemotherapy alone. A 41% reduction in the hazard for progression or death (HR, 0.59; 95% CI, 0.50-0.70; P <.0001) was induced by the addition of the checkpoint inhibitor.^3,4

Several other advancements in the field have resulted in an “exciting time for lung cancer treatment,” said Ganti, a professor of internal medicine in the Division of Oncology/Hematology at University of Nebraska Medical Center.

OncLive^®: What are some of the major updates in lung cancer research?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on A Summer of Progress: Updates from ASCO 2018, Ganti discussed some of the most intriguing abstracts in lung cancer recently presented.Ganti: There have been a lot of exciting changes in the management of patients with lung cancer over the past year. The biggest change has been the increasing use of immunotherapy, mainly the checkpoint inhibitors such as pembrolizumab and atezolizumab. A lot of exciting data have been presented in the last several months, whether at the 2018 ASCO Annual Meeting or other [meetings]. What I spoke about was a summary of some of those abstracts.

One of the big abstracts [at the 2018 AACR Annual Meeting and the 2018 ASCO Annual Meeting] was KEYNOTE-189, which showed for the first time [in a phase III setting] that adding pembrolizumab to chemotherapy was better than pembrolizumab alone in patients with advanced nonsquamous NSCLC who did not have EGFR or ALK driver mutations. What this study did was take patients with treatment-nai&#776;ve stage IV disease and randomize them to either chemotherapy or chemotherapy and pembrolizumab. The trial showed that regardless of PD-L1 expression, the addition of pembrolizumab improved OS. Another study presented at the 2018 ASCO Annual Meeting was similar, looking at a similar patient population. This time the combination used was standard chemotherapy and bevacizumab with or without atezolizumab. Again, in this trial, there seemed to be an improvement in OS with the addition of atezolizumab to the background of carboplatin/paclitaxel and bevacizumab.

In addition, a presentation at the 2018 ASCO Annual Meeting that looked at patients who had a PD-L1 expression of ≥1%. That study looked at comparing pembrolizumab alone with the combination of carboplatin/pemetrexed. This showed that if you had a PD-L1 expression of ≥1%, pembrolizumab was better than the combination. However, most of this benefit seemed to be in the patient population with a PD-L1 expression of ≥50%. When they looked at the other subset of patients, there was still a small benefit with pembrolizumab, but it did not reach statistical significance.

There was also a study [conducted in Southeast Asia] of EGFR-mutant patients [that] looked at gefitinib (Iressa) versus dacomitinib. They found that dacomitinib was associated with a better OS than gefitinib. One thing we don’t know is how dacomitinib really fits into the treatment of EGFR-positive disease because there have been other studies with many different agents. It’s unclear what works best at this time, but it’s good that we have options.

Would you consider tumor mutational burden (TMB) and PD-L1 to be effective biomarkers?

Lastly, there was a study presented in mesothelioma, which is a rare disease in the United States but is fairly lethal. This trial found promising results with immunotherapy, namely durvalumab (Imfinzi). In the small trial of 31 patients, they found response rates of around 55%. The biggest disappointment was that there was no major change in small cell lung cancer.PD-L1 seems to be the best available biomarker, but that is by no means a great marker. Even if you look at PD-L1—high patients, even in the studies we’ve discussed, it does not seem to correlate very well with responses. For example, in early pembrolizumab studies, we looked at PD-L1 expression. Even in those with high PD-L1 expression, responses were not very high. They were higher than what we see with chemotherapy, but not enough. When you use a biomarker, you would expect predictive rates of higher than 30% or 40%.

It is the same thing with TMB; that is an emerging field. The biggest challenge with TMB is that we don’t know the best way to measure it. There was a specific study that looked at TMB, and what they did was divide patients into high TMB—more than 10 mutations/megabase—and low TMB. What they found was that when you look at high TMB, those who were treated with nivolumab and ipilimumab (Yervoy) had a better PFS and OS than those who had chemotherapy alone.

Will it become difficult to decide what the best immunotherapy combination is?

What could be achieved by the 2019 ASCO Annual Meeting?

The biggest thing that was disappointing in this study was that when they looked at nivolumab alone and used a higher TMB, that did not correlate with response. You would think that when you have a higher cut-off, this would be a better predictor. However, CheckMate-227 did not show that. Therefore, could it be that TMB is a marker just for ipilimumab response? We don’t know. As for as newer markers, we’re on the lookout all the time. As of right now, I’m not aware of any good markers that are available. It would be better, though, to have a number of reliable markers as opposed to just 1 that works.It is difficult to choose even now. Pembrolizumab seems to be the leader, at least in the lung cancer world. We have increasing data, which is exciting, about atezolizumab. It’s a challenge to decide if there are any true differences between the chemotherapy and immunotherapy combinations. Others are in the works with clinical trials. This could change the landscape.I would expect to see updated results on the KEYNOTE-407 trial, which looked at squamous cell carcinoma; we only saw interim results this year. I would expect to see more mature results on the IMpower studies, and I would also expect to see some data on the role of immunotherapy in lung cancer that is driven by molecular mutations. As of now, we don’t believe that immunotherapy works very well in those patients. However, further data could change how we feel about that.

References

1. Gandhi L, Rodgri&#769;guez-Abreu D, Gadgeel S, et al. KEYNOTE-189: randomized, dou- ble-blind, phase 3 study of pembrolizumab (pembro) or placebo plus pemetrexed (pem) and platinum as first-line therapy for metastatic NSCLC. In: Proceedings from the 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT075.
2. Gandhi L, Rodgri&#769;guez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemother- apy in metastatic non—small-cell lung cancer. N Engl J Med. 2018;378(22):2078- 2092. doi: 10.1056/NEJMoa1801005.
3. Socinski MA, Jotte R, Cappuzzo F, et al. Overall survival (OS) analysis of IMpow- er150, a randomized Ph 3 study of atezolizumab (atezo) chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC. J Clin Oncol. 2018;36 (suppl; abstr 9002).
4. Socinski MA, Jotte R, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301. doi:10.1056/NEJMoa1716948.