Pembrolizumab Plus Chemoradiation Therapy Elicits Strong Responses in Stage III NSCLC

Pembrolizumab (Keytruda) plus chemoradiation therapy (CRT) represents a promising therapy for patients with previously untreated, locally advanced, stage III non–small cell lung cancer (NSCLC), according to radiation oncologist Salma K. Jabbour, MD, lead author for the phase 2 KEYNOTE-799 trial (NCT0363178). She added that the benefit was observed regardless of histology and PD-L1 expression.

Investigators in KEYNOTE-799 recruited 216 adults with measurable, previously untreated, unresectable, pathologically confirmed stage IIIA-C NSCLC an ECOG performance status of 0 or 1, adequate pulmonary function, and no prior systemic immunosuppressive therapy within 7 days. Cohort A included patients with both squamous and nonsquamous NSCLC (n = 112); cohort B included patients with nonsquamous NSCLC only (n = 102).¹

The median follow-up was 18.5 months (range, 13.6-23.8) in cohort A and 13.7 months (range, 2.9-23.5) in cohort B, with a cutoff date of October 28, 2020.

All patients received up to 17 cycles of 200 mg pembrolizumab every 3 weeks. Patients in cohort A also received one cycle of carboplatin and paclitaxel followed by added standard thoracic radiology for cycles 2 and 3, and subsequent pembrolizumab monotherapy. Patients in cohort B received the same dosing for pembrolizumab plus cisplatin and pemetrexed, along with thoracic radiotherapy in cycles 2 and 3, followed by single-agent pembrolizumab for cycles 4 through 17.

The overall response rate was 70.5% in cohort A (95% CI, 61.2%-78.8%) and 70.6% in cohort B (95% CI, 60.7%-79.2%). The incidence of grade 3 or higher pneumonitis was 8.0% in cohort A and 6.9% in cohort B.

“These patients require a lot of attention and care to make sure that their treatment goes smoothly and [the] side effects from chemoradiation can be managed, such as esophagitis or dermatitis and pneumonitis,” Jabbour said. “[A multidisciplinary approach] helps to carry the patient through [treatment] with a tolerable toxicity profile and tolerable side effect profile, allowing them to achieve a successful and manageable therapy.”

In an interview with OncLive^®, Jabbour, professor and vice chair of clinical research and faculty development at The Rutgers Cancer Institute of New Jersey, discusses the validity and clinical implications of using pembrolizumab plus platinum CRT in patients with stage III NSCLC.

OncLive^®: What served as the basis for KEYNOTE-799?

Jabbour: KEYNOTE-799 serves an important purpose for patients who have stage III NSCLC cancer that's locally advanced and unresectable. The reason it's important is because we know that the standard of care for [this patient population] is a combination of CRT, followed by consolidation with durvalumab [Imfinzi] immunotherapy. However, about 22% to 30% of patients do not go on to receive the durvalumab after completion of CRT, partially explained by disease progression or toxicity from therapy. KEYNOTE-799 looks at incorporating pembrolizumab immunotherapy from the onset of treatment as opposed to waiting until after the completion of CRT.

What prior data have we seen from pembrolizumab plus platinum chemotherapy and radiotherapy that supported its use in this setting?

These are updated results from KEYNOTE-799 with the entirety of both cohort A and cohort B, [with] a median follow-up of over 18 months in cohort A and over 13 months in cohort B. So, the results are more updated, [with] more patients to report on. The primary objectives of KEYNOTE-799, were to evaluate objective response rate by blinded independent central review using RECIST v1.1, as well as the rates of grade 3 or higher pneumonitis. As far as the objective response rates, which was one of the primary endpoints, we found that the objective response rates were about 70% in both cohort A and B.

The median duration of response was not reached for cohort A nor B and the median progression free survival [PFS] and median overall survival were also not reached quite yet, which is very promising. We know that the 12-month overall survival was over 80% in both cohorts, and we also know the 12-month PFS was about 70% in both cohorts. We know that the 12-month duration of response was over 75% as well. [These are] very [promising] results that we are excited to see mature further.

Did the benefit extend across histologies and different levels of PD-L1 expression?

Yes, that's a very interesting part of the results as well. Both cohorts A and B included patients with nonsquamous NSCLC, and cohort A included patients with squamous NSCLC. We found that the response to therapy was independent of PD-L1 status in the patients who were evaluated in this study. There is really no difference in outcome by histology as far as we can tell so far, which is great.

It's interesting that PD-L1 expression doesn't seem to be as important a biomarker in the stage III setting as in the stage IV setting.

Yes, and that could be for a variety of reasons. We are giving multiagent therapy, both platinum doublet chemotherapy, as well as radiation therapy and pembrolizumab, so it's possible that when we're using a combination of therapies, it allows the therapy to be more effective regardless of PD-L1 status.

How would you characterize the tolerability of the regimen?

The second primary endpoint of KEYNOTE-799, were the rates of grade 3 or higher pneumonitis. In cohorts A and B, the rates of grade 3 or higher pneumonitis were under 10%.

Those rates of pneumonitis are very consistent with what we would expect the rates of pneumonitis to be with chemoradiation therapy alone, or even with pembrolizumab monotherapy. We really do feel that these results are consistent with what we would normally see in this setting of therapy.

Looking at treatment related adverse events overall, cohort A was around 65%, which is not insignificant.

No, but we also have to remember this is one of the first studies that's really studying CRT from the onset of therapy. In general, we've seen results of the PACIFIC trial [NCT02125461] that have looked at immunotherapy after chemoradiation, but this is one of the first studies to really account for the chemoradiation backbone and we know that there is toxicity that's inherent to that therapy and expected, so this study just measures what we would expect in those settings.

Was there anything about the analysis that surprised you?

I'm pleased, maybe not so much surprised about the favorable results, and how impressive the results looked in at this early stage, a little bit past the 1-year mark for cohort A. What I'm really excited to see is kind of the longer-term results and new studies that will incorporate these therapies in the phase III setting that could really change the paradigm of how we manage patients. I'm excited to see that and I look forward to further results. I think that these were very promising results for this time.

Are there any phase 3 studies already planned?

Yes, the follow up study to KEYNOTE-799 is KEYLYNK-012 [NCT04380636], which is a phase III trial that will [evaluate] the combination of CRT followed by a PARP inhibitor, olaparib [Lynparza]. A third arm in that study will look at the standard of care with outback durvalumab [Imfinzi]. In the first 2 arms, we will see continued use of pembrolizumab concurrent with CRT. In one of the arms, patients will receive consolidation pembrolizumab as well as a PARP inhibitor, and in another arm, they will receive pembrolizumab and olaparib placebo. We will basically be trying to increase the outcomes and improve outcomes for patients using both pembrolizumab and PARP inhibitors in NSCLC.

From a multidisciplinary approach to care, what would you say is the key takeaway from this trial?

It's really important for stage III patients to be evaluated in a multidisciplinary setting and to be managed in a multidisciplinary setting. It is very much a team approach from the onset of the patient's care.

How might we reconcile the results that we're seeing from KEYNOTE-799 with the data that we're now seeing from IMpower010 (NCT02486718), which also evaluated a stage III patient population?

This is in a slightly different patient population than the stage III locally advanced unresectable NSCLC patients. [Impower010] looked at stage II to III NSCLC who had undergone surgery and adjuvant chemotherapy. Patients were randomized to observation or best supportive care compared to atezolizumab (Tecentriq) and there was an improvement in disease free survival, which is very exciting for that group of patients. The therapy seemed to be well handled overall and consistent with the prior toxicity profiles of most immunotherapies, including atezolizumab.

It's exciting that we're seeing these great improvements for our patients with lung cancer. [The trials] will certainly open the door to look at other therapies for these patients and now that [patients will] be living longer, there’s a greater need to continue to study new therapies to continue to improve longevity of patients.

Reference

1. Jabbour SK, Lee KH, Frost N, et al. KEYNOTE-799: phase 2 trial of pembrolizumab plus platinum chemotherapy and radiotherapy for unresectable, locally advanced, stage 3 NSCLC. J Clin Oncol. 2021;39(suppl 15):8512. doi:10.1200/JCO.2021.39.15_suppl.8512