Immunotherapy Agents Demonstrate Groundbreaking Data in GI Cancers

In patients with gastrointestinal (GI) cancers, immunotherapeutics such as nivolumab (Opdivo) and pembrolizumab (Keytruda) have demonstrated statistically significant improvements in disease-free survival (DFS) when used as an adjuvant treatment, as well as in overall survival (OS) and progression-free survival (PFS) when used in combination with chemotherapy, according to Lakshmi Rajdev, MD, MS.

Data from potentially practice-changing trials examining their use were presented during the 2020 European Society for Medical Oncology Virtual Congress, added Rajdev.

Adjuvant nivolumab was found to signifi cantly improve median DFS vs placebo in patients with resected esophageal cancer and gastroesophageal junction (GEJ) cancer who received it after neoadjuvant chemoradiation, at 22.4 months vs 11.0 months, respectively, according to data from the phase 3 CheckMate 577 study (NCT02743494).¹

“[This] really is the fi rst adjuvant therapy to provide a statistically signifi cant and clinically meaningful improvement in DFS vs placebo in [patients with] resected esophageal cancer and GEJ cancer following neoadjuvant chemoradiation,” Rajdev explained. “The impressive 31% reduction in the risk of recurrence or death and the doubling in median DFS is really a landmark outcome. Not only that, but the benefi t observed was seen regardless of PD-L1 status.”

Additionally, data from the phase 3 KEYNOTE-590 trial (NCT03189719) showed that when pembrolizumab was added to platinum-based chemotherapy, it led to improvements in response rates, PFS (HR, 0.65; 95% CI, 0.55-0.76; P <.0001), and OS (HR, 0.73; 95% CI, 0.62-0.86; P <.0001) compared with chemotherapy alone in patients with advanced esophageal cancer, irrespective of their combined positive score (CPS).²

Notably, pembrolizumab is also approved for the treatment of patients with PD-L1–positive recurrent or advanced gastric or GEJ adenocarcinoma who have received 2 or more lines of chemotherapy. However, this indication will be subject to review by the FDA in an upcoming Oncologic Drugs Advisory Committee hearing.³

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on gastrointestinal malignancies, Rajdev, the chief of hematology and oncology at Northwell Health’s Lenox Hill Hospital, further discussed some of the key developments made with immunotherapy in GI cancers and the groundbreaking data that have recently read out to support their use.

OncLive®: Could you speak to the growing role of immune checkpoint inhibitors like pembrolizumab and nivolumab in GI cancers?

Rajdev: Pembrolizumab and nivolumab both have indications in gastric and esophageal cancer. Pembrolizumab is approved for recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma with a PD-L1 CPS of 1 or more, following progression on 2 prior therapies; [that includes] 5-fl uorouracil [5-FU] and platinum-containing chemotherapy, plus or minus HER2-targeted therapy. It is also approved for [patients with] recurrent locally advanced and metastatic esophageal squamous cell carcinoma [with] a CPS of 10 or more [who progressed] after 1 line of systemic therapy.

There are tumor-agnostic approvals, as well, for patients with unresectable or metastatic microsatellite instabilityhigh or mismatch repair defi cient solid tumors and for patients with an elevated tumor mutational burden of 10 or more who have progressed after standard therapy.

Nivolumab is approved for unresectable advanced recurrent and metastatic esophageal squamous cell carcinoma after prior 5-FU and platinumbased chemotherapy.

Data from the CheckMate 577 trial read out during the 2020 European Society for Medical Oncology Virtual Congress. What is their clinical signifi cance?

This was among the most interesting and pivotal studies that were presented at the meeting. CheckMate 577 was done in patients with resectable stage II and stage III esophageal and GEJ cancers following neoadjuvant chemoradiation and surgical resection. Patients with residual disease were randomized to adjuvant nivolumab or placebo, stratifi ed by histology, pathological lymph node status, and PD-L1 status. The trial’s primary end point was DFS, and the secondary end points were OS and OS rate at 1, 2, and 3 years.

Seventy percent of the patients had adenocarcinoma and 50% had residual lymph node disease. Only about 17% had PD-L1–positive disease. Interestingly, nivolumab demonstrated superior DFS [vs placebo], with a 31% reduction in the risk of recurrence or death; there was also a doubling in median DFS, going from 11.0 months to 22.4 months, respectively. Interestingly, the benefit [with this approach] was observed in all patient subgroups, regardless of PD-L1 status.

Would you say that these data are practice changing?

It is important to note that in esophageal trials, OS, but not DFS, is a validated end point. However, one can observe flattening of the curve in DFS in patients who received nivolumab. It is pretty clear that a subset of patients will derive a survival benefit with this agent. The study follow-up is short [so far], and clearly the OS data are awaited.

In my mind, this really represents the first advance in years for this group of patients—a new standard for nivolumab as an adjuvant therapy in patients with esophageal cancer who demonstrate residual disease following neoadjuvant chemoradiation. I clearly view it as a practice-changing study.

The phase 3 KEYNOTE-590 trial was another big trial that read out during the meeting. What should be taken away from this research?

KEYNOTE-590 involved treatment-naïve [patients with] locally advanced, unresectable or metastatic esophageal cancer. It was open to [those with] squamous cell [carcinoma and] adenocarcinoma, and it also allowed [those with] metastatic GEJ Siewert type I adenocarcinoma [to enroll]. Patients were randomized to pembrolizumab and chemotherapy vs chemotherapy alone. Patients were stratified by [disease] location and histology. [The] coprimary end points of the trial were OS and PFS, [whereas the] secondary end point [was] response rate.

About half of the patients who were enrolled to the trial were of Asian descent, and half of the study population had a CPS of 10 or more. About three-fourths of patients had squamous cell carcinoma. PFS was improved in patients who had a CPS of 10 or more, as well as in [all patients]; in these groups, the PFS was 7.5 months vs 6.3 months, respectively, compared with chemotherapy, at 5.5 months vs 5.8 months, respectively.

Similarly, the OS was improved in all subgroups examined. Patients with a CPS of 10 or more had a median OS of 13.5 months [with pembrolizumab], whereas it was 12.4 months in all-comers. [The median OS with placebo in these groups was 9.4 months vs 9.8 months, respectively.] The patients who derived the greatest benefi t were those with squamous cell carcinoma who had a CPS of greater than 10.

Do you believe that this combination can be applied to patients with adenocarcinoma? How about all patients with esophageal cancer?

KEYNOTE-590 showed that the addition of pembrolizumab to platinum-based chemotherapy improves response rate, PFS, and OS over chemotherapy alone in patients with advanced esophageal cancer. Clearly, the benefi ts observed were regardless of CPS score. The patients who derive the greatest benefi t, as we discussed previously, were those with squamous cell carcinoma and a CPS of greater than 10. Now, only about 26% of the patients had adenocarcinoma, and about half of the patients had a CPS of 10 or more.

[Therefore], yes, the question remains: Is this something that can be applied to patients with adenocarcinoma? A greater number of patients had a CPS of 10 or more. Is this something that we can apply to all patients with esophageal cancer? This does represent a new standard, but it remains to be seen how the regulatory agencies [will] approve this agent in this particular indication.

References

1. Kelly RJ, Ajani JA, Zander T, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiation therapy (CRT): first results of the CheckMate 577 study. Ann Oncol. 2020;31(suppl 4):S1142-S1215. doi:10.1016/annonc/annonc325
2. Kato K, Sun J-M, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: the phase 3 KEYNOTE-590 study. Ann Oncol. 2020;31(suppl 4):S1192-S1193. doi:10.1016/j.annonc.2020.08.2298
3. FDA in brief: FDA Oncologic Drugs Advisory Committee to review status of six indications granted accelerated approval. FDA. March 11, 2021. Accessed April 3, 2021. https://bit.ly/3cgG1bm