Immunotherapy Agents Demonstrate Groundbreaking Data in GI Cancers

April 5, 2021
Hayley Virgil
Hayley Virgil

Senior Editor, OncLive®
Hayley Virgil heads OncLive's feature article efforts and specializes in social issues and equality in oncology. Prior to joining the company in early 2020, she worked as an editor in numerous industries, including media, marketing, hospitality, and computer science, and freelanced in subjects such as history, culture, and the natural sciences.

Partner | Cancer Centers | <b>Northwell Health</b>

Lakshmi Rajdev, MD, discusses some of the key developments made with immunotherapy in gastrointestinal cancers and the groundbreaking data that have recently read out to support their use.

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, respectively, in patients with gastrointestinal (GI) cancers, according to Lakshmi Rajdev, MD.

Data from potentially practice-changing trials examining their use were presented during the 2020 ESMO Virtual Congress, added Rajdev.

Adjuvant nivolumab was found to significantly 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 first adjuvant therapy to provide a statistically significant 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 benefit 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

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on Gastrointestinal Cancers, Rajdev, chief of hematology and oncology at Lenox Hill Hospital, Northwell Health, 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 greater than or equal to 1, following progression on 2 prior therapies; [that includes] 5-fluorouracil [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 greater than or equal to 10 and [who progressed] after 1 line of systemic therapy.

There are tumor agnostic approvals as well, for patients with unresectable or metastatic microsatellite instability–high or mismatch repair deficient solid tumors or patients with elevated tumor mutational burden greater than or equal to 10, progressing after standard therapy.

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

Data from the CheckMate-577 trial read out during the 2020 ESMO Virtual Congress. What is the clinical significance of these data?

This was one of the most interesting and pivotal studies that was 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. They were stratified by histology, pathological lymph node status, and PD-L1 status. The primary end point of the trial 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% of patients were PD-L1 positive. 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] were 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 and 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 there is going to be a subset of patients who will derive a survival benefit with this agent. The study follow-up is short and clearly the OS data are awaited.

However, in my mind, this really represents a new standard for nivolumab as an adjuvant therapy in patients with esophageal cancer who demonstrate residual disease following neoadjuvant chemoradiation. This really represents the first advance in years for this group of patients. 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 was a trial done in 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 location and histology. [The] co-primary end points of the trial were OS and PFS, [while 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 greater than or equal to 10. About three-fourths of patients had squamous cell carcinoma. PFS was improved in patients who had a CPS of greater than or equal to 10, as well as in [all patients]; in these groups, the PFS was 7.5 months and 6.3 months, respectively, compared with chemotherapy, at 5.5 months and 5.8 months, respectively.

Similarly, the OS was improved in all subgroups examined. Patients with a CPS of greater than or equal to 10 had a median OS of 13.5 months [with pembrolizumab], while it was 12.4 months in all comers. [The median OS with placebo in these groups was 9.4 months and 9.8 months, respectively.] The patients who derived the greatest benefit were those with squamous cell carcinoma and 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 demonstrated 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 benefits observed were regardless of CPS score. The patients who derive the greatest benefit, 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 greater than or equal to 10.

[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 greater than or equal to 10. 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

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