Novel approaches in gastric cancer

LEAP-005: lenvatinib plus pembrolizumab in gastric cancer

With more than 1 million newly diagnosed cases in 2020, gastric cancer was at the fifth place (5.6 %) of the most frequent malignant diseases and accounted for nearly 8 % of cancer deaths worldwide [1].

The multicohort, non-randomized, open-label, phase II LEAP-005 study (NCT03797326) was designed to evaluate the safety and efficacy of a combination – the anti-angiogenic multikinase inhibitor lenvatinib plus the anti-PD-1 antibody pembrolizumab – in patients with previously treated advanced solid tumors. Among the seven different cohorts, the results of the gastric cohort have been presented at the virtual scientific ASCO 2021 meeting [2]. The eligibility criteria were adults with confirmed metastatic and/or unresectable gastric cancer (GC), who received at least two prior lines of therapy, had measurable disease per RECIST v1.1, had a good performance status (ECOG PS 0‒1) and provided a tissue sample evaluable for PD-L1 (programmed cell death-ligand 1) expres­sion. For up to 35 cycles (approximately 2 years) or until confirmed disease progression, unacceptable toxicity, or withdrawal of consent, lenvatinib was administered daily (20 mg, orally), while patients received pembrolizumab (200 mg, IV) every three weeks; if patients experienced a clinical benefit, lenvatinib could be continued beyond two years. Objective response rate (ORR) according to RECIST v1.1 criteria assessed by a blinded independent central review (BICR) and safety were the co-primary endpoints. Secondary endpoints included disease control rate (DCR), duration of response (DOR), PFS (progression-free survival), and OS (overall survival).

Among the 31 eligible patients recruited, the mean age was 62 years (range, 28-83), most of them (87 %) were male and 71 % had a combined PD-L1 positive score (CPS) ≥ 1. At the time of the analysis (April 10, 2020), patients were for 7.0 months (range, 1.9-11.9) on treatment. An ORR of 10 % (95 % CI, 2-26) and a DCR of 48 % (95 % CI, 30-67) were achieved by the study population; in total, one patient (3 %) experienced a complete response (CR), while two patients (6 %) experienced a partial response (PR) and twelve patients (39 %) a stable disease. Median DOR was not reached yet. A median PFS of 2.5 months (range, 1.8-4.2; 6-month rate, 22 %) and a median OS of 5.9 months (range, 2.6-8.7; 6-month rate, 46 %) were attained (Figure 1). The most common treatment-related adverse events (TRAEs) observed in ≥ 20 % of patients were diarrhea (26 %) and fatigue (26 %). Immune-mediated AEs, which were experienced by seven patients (22 %), included hypothyroidism (n = 5) and hyperthyroidism (n = 2). In total, twelve patients (39 %) experienced grade 3 AEs, while no AE of grade 4 severity was seen; one patient died due to a gastrointestinal hemorrhage considered to be tumor-related by the investigator.

According to these data, the combination of lenvatinib plus pembrolizumab demonstrated promising antitumor activity and a manageable safety profile; therefore, the enrollment in the gastric cohort has been extended to 100 patients.

Figure 1: Median PFS and median OS in the LEAP-005 study in patients with gastric cancer

PARALLEL 303: pamiparib as maintenance monotherapy in GC

Some gastric cancer present platinum sensitivity, as well as genomic instability (HRD, homologous recombination deficiency). Considering that cells with HRD are sensitive to poly (ADP-ribose) polymerase protein (PARP) inhibition [3], the use of PARP inhibitors as maintenance following platinum-based chemotherapy might be an efficient therapeutic strategy. The efficacy of PARP inhibitors in other cancer showing platinum sensitivity and higher levels of HRD has been already described, inclusive as maintenance therapy [4-6]. Pamiparib is an investigational PARP inhibitor showing sensitivity to HRD cells, which demonstrated its efficacy and tolerability in early-phase clinical study in advanced solid tumors [7, 8].

The double-blind, randomized, global, phase II PARALLEL 303 study (NCT03427814) compared the efficacy, safety, and tolerability of pamiparib against placebo as maintenance treatment in responders, who were defined as having a PR for ≥ 4 weeks or a CR after platinum-based fist-line chemotherapy [9]. Eligible patients had histologically confirmed inoperable locally advanced or metastatic GC (adenocarcinoma of the stomach or gastroesophageal junction) and were enrolled in 128 sites worldwide. The primary endpoint was PFS per RECIST v1.1, while time to subsequent treatment, ORR, DOR, time to response, OS and safety were the secondary endpoints. Data about PFS and safety were presented at ASCO 2021.

Overall, 136 patients were randomized 1:1 to receive either pamiparib (60 mg orally, twice daily) or placebo (twice daily) in 28-day cycles. At the time of the analysis, 51.5 % of patients in pamiparib were still on treatment against 16.9 % in the control arm. After a median follow-up of approximately 8.0 months in both arms, median PFS was longer with the investigational drug than with placebo, also not significantly different (3.7 vs 2.1 months; HR, 0.799; p = 0.1428). Likely, no significant clinical benefit was observed for median OS (10.2 with pamiparib vs 12.0 months with placebo) or ORR (7.7 vs 6.3, respectively) between both arms. Anemia (36.6 %) and nausea (32.4 %) among pamiparib-treated patients, as well as abdominal pain (18.5 %) in the control arm were the most frequently observed treatment-emergent adverse events (TEAEs). TEAEs led to treatment discontinuation in 11.3 % (n = 8) of patients in investigational arm and 3.1 % (n = 2) in placebo arm. Although pamiparib did not meet its primary endpoint in this study, it showed a favorable safety profile consistent with that of other PARP inhibitors and no new safety signals were detected.

Biomarker relevance in second line therapy of GC

In the phase III GOLD study, the combination olaparib plus paclitaxel missed its primary endpoint – improvement of OS – compared to paclitaxel alone for the treatment of patients with gastric and gastroesophageal junction tumors, who progressed following the frontline therapy [10]. The PARP inhibitor olaparib not only induce DNA damage and cell death but is also involved in the upregulation of PD-L1. Based on these findings, the authors hypothesize that the combination of a cytotoxic chemotherapy (paclitaxel) plus a PARP inhibitor (olaparib) plus an immune checkpoint inhibitor (durvalumab) might potentiate the antitumor activity in gastric cancer [11]. Therefore, a biomarker-oriented study was designed to explore the changes of tumor environment and to evaluate if the anti-PD-L1 addition might enhance the antitumor activity.

An ongoing phase II trial (NCT03579784) is enrolling patients with measurable lesions and histologically confirmed unresectable GC, who have failed to one prior chemotherapy. Patients previously exposed to anti-PD(L1)-1 or PARP inhibitors are excluded. Following the administration schema described on Figure 2, patients receive olaparib (150 mg twice daily on Day 1-28) plus paclitaxel (80 mg/m² intravenously, IV, on Day 1/8/15) for four cycles, with the addition of durvalumab (1.5g IV on Day 1) on cycles 2 to 4. At the time of progression, biopsy is mandatory; additionally, blood samples for biomarker analysis are collected at each treatment cycle. The DCR per RECIST v1.1 is the primary study endpoint, while the key secondary endpoints include ORR, PFS, OS, quality of life (QoL) and safety. This trial is intended to recruit 40 patients in Korea.

Figure 2: Study design of durvalumab combined to olaparib and paclitaxel

Adjuvant therapy in patients with resected GEA

Esophageal cancer is the sixth most common cause of cancer mortality globally; together, gastric and esophageal cancers were responsible for more than 1.3 million deaths in 2020 [1]. In patients with resectable gastroesophageal carcinoma (GEA), ESMO guidelines recommend a neoadjuvant chemotherapy as standard of care [12, 13], which might also be further administered after surgery; however, this regimen leads to suboptimal outcomes. In the CheckMate 577 study, adjuvant immunotherapy with nivolumab – an anti-PD-1 (programmed cell death protein 1) – has proven to be efficient in poor risk patients with GEA treated with neoadjuvant chemotherapy [14]. Moreover, nivolumab and ipilimumab – a CTLA-4 inhibitor – combined therapy showed antitumoral activity in advanced GEA. High risk patients with GEA are defined as those presenting metastatic lymph nodes or a microscopically incomplete surgical resection (R1). According to the data previously presented, high risk GEA patients treated with this dual adjuvant immunotherapy post-resection might have a better disease-free survival (DFS) than those who received standard post-operative chemotherapy [15].

In the international, open-label, randomized, phase II EORTC VESTIGE study (NCT03443856), nivolumab plus ipilimumab versus chemotherapy are currently investigated as adjuvant therapy in high-risk GEA patients [16]. After a post-surgery recovery period of two months, eligible patients are randomized 1:1 to receive for a year either nivolumab (3 mg/kg IV, biweekly) plus ipilimumab (1 mg/kg IV, every six weeks) or the same chemotherapy regimen as pre-operatively (Figure 3). DFS will be primarily analyzed, and OS, safety, toxicity, and QoL secondarily evaluated. As the recruitment opened in August 2019, 95 out of 240 planned patients have been already enrolled until May 2021 in 22 sites in Europe and Israel.

Figure 3: Design of the EORTC 1707 VESTIGE trial

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