Nimotuzumab plus gemcitabine prolongs survival in KRAS wild-type pancreatic cancer
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CHICAGO — The addition of nimotuzumab to gemcitabine prolonged OS and PFS among patients with KRAS wild-type locally advanced or metastatic pancreatic cancer, according to randomized phase 3 study results presented at ASCO Annual Meeting.
Researchers observed the greatest survival benefit among those who had not been treated for biliary obstruction. Nimotuzumab also appeared safe.
“These results implied that the addition of nimotuzumab to current treatment regimen will provide benefit and great value to [patients with pancreatic cancer],” Shukui Qin, MD, PhD, of the department of medical oncology at Cancer Center of Jinling Hospital, told Healio. “Nimotuzumab is worthy of using in clinical practice.”
Background and methods
Pancreatic cancer remains one of the deadliest cancers, with 80% of cases diagnosed at an advanced stage, and current treatment regimens have proved ineffective, conferring median OS of 6 to 8 months.
“Nimotuzumab, a humanized anti-EGFR monoclonal antibody, can disrupt the interaction of the EGFR with its ligand, specifically block the EGFR signaling pathway, mediate antibody-dependent cellular cytotoxicity ... and other immune effects, and induce EGFR endocytosis and degradation,” Qin told Healio.
In a phase 2 study Schultheis and colleagues conducted in Germany, nimotuzumab plus gemcitabine significantly improved median OS compared with placebo and gemcitabine (8.6 months vs. 6 months) as first-line therapy among patients with locally advanced or metastatic pancreatic cancer, especially for patients with KRAS wild-type vs. KRAS-mutant disease (11.62 months vs. 5.67 months), Qin said.
Qin and colleagues sought to further evaluate the safety and clinical efficacy of nimotuzumab, an EGFR-directed humanized, in combination with gemcitabine among 82 Chinese patients with KRAS wild-type locally advanced or metastatic pancreatic cancer.
Researchers randomly assigned patients 1:1 to 400 mg nimotuzumab or placebo once a week, followed by 1,000 mg/m2 gemcitabine on days 1, 8 and 15 of 4-week cycles. Treatment continued until disease progression or unacceptable toxicity.
The nimotuzumab and placebo groups had similar demographic and clinical characteristics, including median age of patients (55 years vs. 57.5 years), percentage of men (65.9% vs. 58.5%) and prior surgery (56.1% for both).
OS served as the primary endpoint. Secondary endpoints included PFS, objective response rate and safety. The researchers used restricted mean survival time (RMST) log function for survival analysis when the proportional hazards assumption was untrue.
Key findings
Results of the full set analysis, including 82 patients, showed patients who received the nimotuzumab-gemcitabine vs. placebo-gemcitabine combination had significantly longer median OS (10.9 months vs. 8.5 months; HR = 0.5; 95% CI, 0.06-0.94) and median PFS (4.2 months vs. 3.6 months; HR = 0.56; 95% CI, 0.12-0.99).
“This result surprised us and implied that some drugs with immune activation might have long-term benefit,” Qin told Healio.
OS results for the per-protocol set showed a 40% decrease in mortality risk with nimotuzumab (median, 11.5 months vs. 8.5 months; HR = 0.6; 95% CI, 0.34-1.04). The nimotuzumab group had higher survival rates at 1 year (43.6% vs. 26.8%) and 3 years (13.9% vs. 2.7%).
Results of subgroup analyses showed a larger median OS benefit among patients who had not undergone treatment for biliary obstruction (11.9 months vs. 8.4 months; HR = 0.54; 95% CI, 0.33-0.89) and those who had no surgical history (15.8 months vs. 6 months; HR = 0.4; 95% CI, 0.19-0.84). Patients without biliary obstruction treatment also had significantly longer median PFS (5.5 months vs. 3.4 months; P = .008).
“This implied that some drugs with immune activation might have more benefit to those patients without injury from procedures,” Qin said.
Median time to progression was 4.7 months with nimotuzumab vs. 3.7 months with placebo (HR = 0.67; 95% CI, 0.39-1.15).
The difference in ORR between the treatment groups did not reach statistical significance (7.3% vs. 9.8%).
The groups had similar incidence of adverse events. The most common grade 3 treatment-related adverse events in the nimotuzumab group included neutropenia (11.1%), leukopenia (8.9%) and thrombocytopenia (6.7%). No grade 4 treatment-related adverse events occurred.
Implications
Qin said the results represent a “breakthrough in treatment of advanced pancreatic cancer” and new era of targeted, biomarker-based therapy for the disease.
“As a next step, we are thinking of conducting another study in patients with advanced pancreatic cancer with EGFR-high expression to investigate if the addition of nimotuzumab has benefit in this kind of enriched population, based on the mechanism of nimotuzumab,” Qin told Healio.
References:
- Qin S, et al. Abstract LBA4011. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
- Schultheis B, et al. Ann Oncol. 2017;doi:10.1093/annonc/mdx343.
Perspective
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Deirdre Cohen, MD
KRAS wild-type represents a small (8% to 12%) yet important subset of patients with pancreatic cancer. The study by Qin and colleagues is a good start at targeting this molecular subset in order to expand therapeutic options for this devastating disease. It provides further evidence of how critical it is to identify and target molecular subsets in pancreatic cancer.
It will be important to understand the efficacy and safety of nimotuzumab in combination with more standard chemotherapy combinations, such as FOLFIRINOX and gemcitabine plus nab-paclitaxel (Abraxane, Bristol Myers Squibb), in this patient population. In addition to targeting EGFR, future studies in KRAS wild-type pancreatic cancer should explore other enriched alterations within this subset.
The Tisch Cancer Institute at Mount Sinai
Perspective
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Todd C. Knepper, PharmD
This study adds to our understanding that there are molecular differences between KRAS wild-type and KRAS-mutated pancreatic cancers that one day may help guide therapy.
Interestingly, researchers observed longer OS with nimotuzumab-gemcitabine than placebo-gemcitabine despite no statistically significant difference in response rates.
Beyond the statistically significant improvement in median OS, the Kaplan-Meier curves noticeably separated after the median OS endpoint was reached. Researchers reported higher survival rates in the nimotuzumab group at 12 months (44% vs. 27%) and 36 months (14% vs. 3%), so there seems to be some sort of exceptional responder or long-term responder cohort that exists within the nimotuzumab group.
Overall, Qin and colleagues reported a 2.4-month difference in median survival between the nimotuzumab and placebo groups. The decision about whether a statistically significant improvement in survival also is clinically meaningful is quite personal. Generally speaking, when the OS improvement for one agent vs. another may not seem overwhelming, it is important to make sure members of the treatment team are having those conversations with their patients. No drug is benign — there is always an expectation of at least some type of toxicity — and the balance between duration of life and quality of life requires patients to make an individualized decision about what is most important to them.
This regimen is not approved in the United States, however the promising results we see in this study provide a rationale and justification for a potential multinational study to see if these data could be replicated.
Several abstracts presented at ASCO — this one included — reinforce the idea that molecular testing can be used to guide therapy for pancreatic cancer. More research in this area certainly is needed. However, the data presented at this meeting suggest a new era for targeted, biomarker-based therapy may be on the horizon.
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Qin S, et al. Abstract LBA4011. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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