Elsevier

Clinical Lung Cancer

Volume 15, Issue 6, November 2014, Pages 405-410
Clinical Lung Cancer

Original Study
Phase II Study of the GI-4000 KRAS Vaccine After Curative Therapy in Patients With Stage I-III Lung Adenocarcinoma Harboring a KRAS G12C, G12D, or G12V Mutation

https://doi.org/10.1016/j.cllc.2014.06.002Get rights and content

Abstract

Introduction

Patients with early-stage lung cancer have a high risk of recurrence despite multimodality therapy. KRAS-mutant lung adenocarcinomas are the largest genetically defined subgroup, representing 25% of patients. GI-4000 is a heat-killed recombinant Saccharomyces cerevisiae yeast–derived vaccine expressing mutant KRAS proteins. The present phase II study assessed the feasibility, immunogenicity, and safety of the GI-4000 vaccine in patients with early-stage, KRAS-mutant lung cancer.

Materials and Methods

Patients with stage I-III KRAS-mutant lung cancer who completed curative therapy were enrolled. The patients received the genotype matched GI-4000 vaccine for ≤ 3 years or until intolerance, disease recurrence, or death. The KRAS antigen T-cell response was assessed using the interferon-gamma enzyme-linked immunospot assay in peripheral blood mononuclear cells. The study was powered to detect an immune response in ≥ 25% of patients.

Results

A total of 24 patients were enrolled over 28 months. No vaccine-related serious adverse events occurred. One patient withdrew consent because of pain at the injection site. The study met its primary endpoint, with 50% of patients developing an immune response to mutant KRAS. The median number of vaccinations received was 15 (range, 1-19). Ten patients experienced disease recurrence, and 6 died. Compared with the genotypically matched historical controls, the recurrence rates were equivalent but overall survival showed a favorable trend.

Conclusion

GI-4000 was well tolerated and immunogenic when used as consolidation therapy in patients with stage I-III KRAS-mutant lung cancer. The patterns of recurrence and death observed in the present study can be used to design a randomized study of GI-4000 with overall survival as the primary endpoint.

Introduction

Patients with early-stage non–small cell lung cancer (NSCLC) treated with surgery alone have had relatively poor overall survival, with 5-year survival estimates ranging from 73% for stage IA to 9% for stage IIIB.1 For patients with inoperable or unresectable stage I-III NSCLC, external beam radiation therapy can be used with curative intent. Stage for stage, patients with NSCLC treated with radiation therapy have had a slightly lower chance of cure than patients treated with complete surgical resection.2, 3 Cisplatin-based chemotherapy improves the 5-year overall survival for patients with completely resected stage II-III NSCLCs by approximately 4% to 15% compared with surgery alone.4, 5 Thus, better consolidation therapies, such as therapeutic vaccines or targeted therapies, are sorely needed.

One area of drug development currently under investigation is the manipulation of the immune system to target cells harboring mutant proteins through vaccine therapy. One of the largest immunotherapy trials for patients who received curative intent treatment of locally advanced lung cancer was recently reported6—1513 patients were randomized to receive tecemotide (L-BLP25), a MUC1 antigen-specific immunotherapy capable of inducing a T-cell response to MUC1, versus placebo after completing chemoradiotherapy for unresectable, stage III NSCLC. No significant difference was found in overall survival with the administration of tecemotide after chemoradiotherapy compared with placebo in this patient population. However, for the predefined subgroup of patients who had received concurrent chemoradiotherapy, consolidation therapy with tecemotide improved median overall survival by 10 months, and confirmatory studies are planned.

Vaccines that target KRAS proteins are another venue of active exploration. The proto-oncogene KRAS (Kirsten rat sarcoma viral oncogene homolog) is the most commonly mutated oncogene in lung cancers, with mutations detectable in approximately 25% of tumors, most of which occur in codon 12, 13, and 61.7 Unlike patients with lung cancers harboring epidermal growth factor receptor (EGFR) mutations, patients with KRAS-mutant lung cancer do not have a targeted treatment option and may have a worse prognosis.8, 9, 10, 11 Because of the frequency and therapeutic implications of KRAS mutations for patients with lung cancer, the Molecular Diagnostic Laboratory at Memorial Sloan-Kettering Cancer Center has offered reflex testing of every lung adenocarcinoma specimen for the presence of a KRAS mutation since 2006.12

GI-4000 is a series of 4 heat-inactivated Saccharomyces cerevisiae yeast products, each expressing a unique combination of 3 RAS mutations and collectively targeting 7 RAS mutations commonly observed in human cancers. The RAS fusion proteins expressed in yeast contain 2 of 3 mutations at codon 61 (glutamine to arginine [Q61R] plus glutamine to leucine [Q61L] or glutamine to histidine [Q61H]), plus 1 of 4 different mutations at codon 12 (glycine to valine [G12V], glycine to cysteine [G12C], glycine to aspartate [G12D], or glycine to arginine [G12R]). Thus, GI-4000 is manufactured as 4 individual product configurations with the subnames of GI-4014, GI-4015, GI-4016, and GI-4020, depending on the mutated RAS oncoprotein the product is engineered to express.

In preclinical studies, GI-4000 has been administered to mice and rabbits in both live and heat-killed forms, and no significant toxicity has been observed.13 When the present study was designed, a phase I study of GI-4000 in patients with solid tumors had been conducted, with complete data on file at GlobeImmune, Inc. Of 31 subjects treated, 18 (58%) had advanced colorectal cancer and 13 (42%) advanced pancreatic cancer. No patients with NSCLC were included in that study. Dose escalation proceeded throughout the entire dose-escalation scheme without dose-limiting toxicity or therapy-related serious adverse events. The highest dose tested in the phase I study (40 yeast units or 40 YU, with 1 YU = 107 yeast cells) was selected for use in subsequent phase II studies. Most subjects (> 72%) in the phase I study had measurable immune responses as assessed using the lymphocyte proliferation assay and/or intracellular cytokine staining for interferon-gamma (IFNγ) during treatment.

The primary objective of the present study was to evaluate the T-cell–mediated immune response to GI-4000 in patients with stage I-III NSCLC and GI-4000–related mutation in KRAS after completion of potentially curative therapy (surgery and/or radiation therapy and/or chemotherapy). The secondary objectives were to evaluate the tolerability of GI-4000 in this setting and to compare the recurrence rates and overall survival to those of matched controls.

Section snippets

Patient Selection

The Memorial Sloan-Kettering Cancer Center institutional review board approved the treatment protocol. To qualify for enrollment, the patients had to have stage I-III NSCLC and KRAS G12C, G12V, or G12D mutations by direct sequencing of exon 2. All patients were treated with curative intent and were disease free at their first post-treatment assessment based on history, physical examination findings, and computed tomography (CT) findings (1-4 months after completion of all therapy). Patients

Patient Characteristics

A total of 24 patients were enrolled into the study from February 2008 to July 2010. The characteristics of the 24 subjects are summarized in Table 1. Thirteen patients had single KRAS G12C mutations, 3 patients had single G12V mutations, and 6 patients had single G12D mutations. Two patients had synchronous primary lung tumors with 2 distinct KRAS mutations (1 with KRAS G12C and G12A and 1 with KRAS G12C and G12V). Twelve patients were treated with surgery alone, 8 patients with surgery

Discussion

Our study has provided the first data on the toxicity, feasibility, and immunogenicity of consolidation therapy with GI-4000 in patients with stage I-III KRAS-mutant lung cancer who had completed curative therapy. The most important finding we have reported is that 50% of patients (12 of 24) mounted an immune response to the vaccine. No serious adverse events or autoimmune disease were attributed to the vaccinations. Finally, the observed rates of death tended to be lower than those in the

Disclosure

A.M. and C.C. are employees of GlobeImmune, Inc. At the time of study conduct, D.M.A. was an employee of GlobeImmune Inc and had stock in the company. All other authors declare that they have no competing interests.

Acknowledgments

Thanks to Bibi Levine and Suzanne Maltz of Marty's Fund whose generous philanthropic support made this research possible and Dr Jean Boyer from the Pathology and Laboratory Medicine Department, University of Pennsylvania, for isolation of PBMCs. This research was funded by Marty's Fund/Stand Up for a Cure and by GlobeImmune, Inc.

References (18)

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