Alese Covers Treatment in the First, Second, and Third Lines for Patients With Late-Stage Gastric Cancer

Olatunji B. Alese, MD

During a virtual Targeted Oncology Case-Based Roundtable event, Olatunji B. Alese, MD, assistant professor in the Department of Hematology and Medical Oncology at Winship Cancer Institute of Emory University, discussed the various options for patients with late-stage gastric cancer in the early- to late-line settings.

Targeted Oncology^TM: What is the first-line therapy for patients with stage IV gastric adenocarcinoma? What important trial data back these therapies?

ALESE: The first-line therapy in the National Comprehensive Cancer Network [NCCN] guidelines is oxaliplatin [Eloxatin]. This is generally preferred over cisplatin [Platinol], which has been the backbone for most of the randomized chemotherapy trials on gastric cancer.¹

The NCCN guidelines now include nivolumab [Opdivo] for patients with PD-L1 CPS of 5 or greater. CheckMate 649 [NCT02872116] was a randomized, open-label, phase 3 global study that randomized patients with previously untreated, advanced metastatic gastric and gastroesophageal junction tumors with good ECOG performance status and HER2-negative status.² The patients were originally randomized 1:1:1 [to nivolumab/ipilimumab (Yervoy)], nivolumab plus chemotherapy, or chemotherapy alone]. The nivolumab/ ipilimumab arm was closed after the interim analysis. The remaining 2 arms moved along until the end of accrual. Patients were treated with either nivolumab with capecitabine [Xeloda] plus oxaliplatin [XELOX] or fluorouracil, leucovorin, and oxaliplatin [FOLFOX]. The control arm was chemotherapy only. The trial had dual primary end points of overall survival [OS] and progression-free survival [PFS], specifically [for] patients with PD-L1 CPS of 5 or greater.

[For OS], the delta survival advantage was 3.3 months, which is the practice-changing aspect that led to the NCCN guideline inclusion of nivolumab and [this has been approved by the FDA.]

All randomized patients, including those with CPS 1 or greater, also benefited from the addition of nivolumab to chemotherapy.

The coprimary end point [of PFS] shows that the patients who got immunotherapy also did better than those who got chemotherapy only. The superior PFS with a 32% reduction [of death] is why a lot of people feel good about this being a practice-changing trial.

Patients who got chemoimmunotherapy overall did better in terms of the overall response rate [ORR] and had a lot more complete responses [CRs], significantly [more] partial responses [PRs], and longer durations of response [DORs].

Which trials looked at second-line therapy for patients with stage IV gastric adenocarcinoma?

The phase 3 RAINBOW trial [NCT01170663] was also a large, randomized trial. Patients who had disease progression on platinum first-line therapy were randomized 1:1 to paclitaxel [Taxol], which was one of the standard-of-care options at the time of trial activation, or ramucirumab [Cyramza] with paclitaxel.³ The patients were treated until disease progression or [intolerable] toxicity. They were stratified by geographic region, the presence of measurable disease, and the time to [disease] progression on first-line therapy.

The differences in both PFS and OS [were compared] between the patients who got the doublet, [ramucirumab plus paclitaxel], versus those who got placebo and paclitaxel. The [median PFS was] 4.4 versus 2.9 months, respectively [HR, 0.635; 95% CI, 0.536-0.752; P < .0001]. The median OS in those who got the doublet was superior to the OS in those who got the single-agent paclitaxel: 9.6 versus 7.4 months, respectively [HR, 0.807; 95% CI, 0.678-0.962; P = .017].

For the best response, there were a few CRs and some PRs, but the strength of the doublet therapy was in disease control rate [DCR], which measures the total percentage of those with CRs, PRs, and stable disease on treatment. For the doublet, the DCR was 80%, versus 64% in those who got single-agent paclitaxel. The median DOR was about 18 weeks, but within the first 3 to 4 months, a lot of patients derived some benefit from the combination.

What are the later-line chemotherapy options in this setting?

Once patients have disease progression on the combination of ramucirumab plus paclitaxel, the [next] chemotherapy option is based on the TAGS trial [NCT02500043], a randomized phase 3 study of TAS-102 [trifluridine/tipiracil; Lonsurf]. Patients with measurable disease who had progressed on 2 or more prior lines of therapy were randomized to either best supportive care or TAS-102.⁴

The PFS [HR, 0.57; 95% CI, 0.47-0.70; P < .0001] and the OS [HR, 0.69; 95% CI, 0.56-0.85; P = .00058] both had statistical significance and showed the advantage of TAS-102 in these patients.⁵

What is the third-line or subsequent immunotherapy for patients with stage IV gastric adenocarcinoma?

Immunotherapy has a role for those who are checkpoint inhibitor–naive, mostly in the third-line setting. KEYNOTE-059 [NCT02335411] was a phase 2 basket trial that looked at different characteristics of patients with advanced metastatic gastric or gastroesophageal disease.⁶ Cohort 1 included patients who had 2 or more prior lines [of therapy] and had PD-L1–positive or –negative disease. Cohort 2 included patients who were [treatment] naive. Cohort 3 restricted enrollment to patients who were treatment naive or PD-L1–positive.

Cohort 1 patients received single-agent pembrolizumab [Keytruda]; cohort 2 patients with no prior therapy received pembrolizumab in addition to cisplatin and either 5-FU [5-fluorouracil; Adrucil] or capecitabine; and cohort 3 patients received single-agent pembrolizumab. The patients were treated for a couple of [cycles]. Depending on how they tolerated the treatments and whether any toxicity concerns arose, there was subsequent follow-up.

As in most phase 2 trials, the primary end points were safety and objective response rate. Secondary end points were the response rates and DOR, with particular attention to OS.

The objective response rate for those who had a PD-L1– positive CPS score of 1 or greater was remarkable in the third-line setting: about 11%. The DCR in the chemotherapy refractory patients was about 27%, [which didn’t include] a lot of CRs, but the DORs for those who did well on the treatment was longer, at about 8.4 months.⁷

What is your view of the gastric landscape overall?

In summary, for the frontline setting, we have the option of nivolumab for those with CPS of 5 or greater. We still need clarification for those with CPS 1 or greater, but we have fluoropyrimidines, either capecitabine or 5-FU with oxaliplatin, preferably, or even cisplatin.

In the second-line setting, we have ramucirumab with paclitaxel. There are data to support either docetaxel [Taxotere] or single-agent paclitaxel. For those with contraindications to antiangiogenic agents, irinotecan [Camptosar] or even FOLFIRI [folinic acid, fluorouracil, irinotecan] [are options]. Data support the use of TAS-102 in the third-line setting [or] pembrolizumab for those who did not get nivolumab in the front-line setting. If they have a PD-L1 CPS of 1 or greater, we have the approval in that setting.

Next-generation sequencing will allow [us to identify] a small percentage of patients who can benefit from targeted therapy at some point in their [treatment course]—patients with NTRK [mutations] or even microsatellite high disease.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Gastric cancer, version 2.2021. Accessed May 3, 2021. https://bit.ly/31QtZAS}

_{2. Moehler M, Shitara K, Garrido M, et al. Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/ gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC):first results of the CheckMate 649 study. Ann Oncol. 2020;31(suppl 4):S1142-S1215;abstr LBA6_PR. doi:10.1016/annonc/annonc325}

_{3. Wilke H, Muro K, Van Cutsem E, et al; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol}. 2014;15(11):1224-1235. doi:10.1016/S1470-2045(14)70420-6

4. Ilson DH, Tabernero J, Shitara K, et al. TAGS, a randomized, double-blind, phase 3 study evaluating TAS-102 plus best supportive care vs placebo plus best supportive care in patients with metastatic gastric cancer refractory to standard treatments. J Clin Oncol. 2016;34(suppl 15):TPS4141. doi:10.1200/JCO.2016.34.15_suppl.TPS4141

5. Shitara K, Doi T, Dvorkin M, et al. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, doubleblind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018;19(11):1437-1448. doi:10.1016/S1470-2045(18)30739-3

6. Wainberg ZA, Jalal S, Muro K, et al. KEYNOTE-059 update: efficacy and safety of pembrolizumab alone or in combination with chemotherapy in patients with advanced gastric or gastroesophageal (G/GEJ) cancer. Ann Oncol. 2017;28(suppl 5):v616-v617. doi:10.1093/annonc/mdx440.220

7. Fuchs CS, Doi T, Jang RW, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 2018;4(5):e180013. doi:10.1001/jamaoncol.2018.0013