3390 - Survival Prolongation by Rationale INnovative Genomics (SPRING): An international WIN Consortium phase I study exploring safety and efficacy of avelumab, palbociclib, and axitinib in advanced non-small cell lung cancer (NSCLC) with integrated genomic and transcriptomic correlates.

Background

In prior published work, the Worldwide Innovative Network (WIN) Consortium described the Simplified Interventional Mapping System (SIMS) algorithm, based on the hypothesis that both genomic and transcriptomic data are important for matching to a tri-therapy regimen. To account for variation in transcription levels between different tissues, gene by gene tumor RNA levels are normalized against RNA levels in analogous biopsied normal tissue. SPRING is the first trial to assess a SIMS-based tri-therapy regimen in advanced NSCLC.

Methods

Patients with metastatic NSCLC (no EGFR or ALK alterations; no ROS1 alteration if tested; PD-L1 unrestricted; ≤2 prior therapy lines) were treated with avelumab, palbociclib, and axitinib (3 + 3 dose escalation design). After consent, biopsies of tumor and normal endobronchial mucosa were obtained on all patients for analysis on a central genomics/transcriptomics platform and retrospective SIMS algorithm validation. A safety monitoring committee reviews study conduct at least weekly.

Results

Twelve patients have been treated (3 at dose level 1; 6, dose level 2; 3, dose level 3). Three dose-limiting toxicities (DLTs) at least possibly drug related occurred: 1 DLT at dose level 2 (Grade 3 (G3) infusion reaction); 2 DLTs at dose level 3 (G3 hand/foot syndrome and a G5 respiratory failure). The partial response (PR) rate was 44% (4/9 patients who have reached restaging including 2/3 patients at dose level 1; two PRs are in patients who failed prior pembrolizumab). The maximum tolerated dose was avelumab 10 mg/kg IV q2weeks, axitinib 5 mg po bid, palbociclib 75 mg po daily (7 days off; 21 days on) (dose level 2).

Conclusions

The tri-therapy combination of avelumab, axitinib, and palbociclib is tolerable with early evidence of activity including in NSCLC patients who failed a prior checkpoint inhibitor. Expansion cohorts are being added to further explore safety of a recommended phase II dose. Transcriptomic and genomic correlates of response are being assessed.

Clinical trial identification

NCT03386929; First posted: December 29, 2017.

Editorial acknowledgement

Legal entity responsible for the study

Worldwide Innovative Network (WIN) Association - WIN Consortium.

Funding

ARC Foundation for Cancer Research and Pfizer.

Disclosure

B. Solomon: Travel / Accommodation / Expenses: Elekta. A. Callejo: Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boerhinger; Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Speaker Bureau / Expert testimony: KYOWA KIRIN ; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Celgene. J. Bar: Honoraria (self), Advisory / Consultancy: Roche; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Genentech; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: AbbVie; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Takeda; Advisory / Consultancy: Vascular Biogenics; Research grant / Funding (institution): MedImmune. G. Berchem: Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Celgene. L. Bazhenova: Advisory / Consultancy: Takeda; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Loxo Oncology; Shareholder / Stockholder / Stock options: Epic Sciences; Research grant / Funding (institution): Beyondspring Pharma. P. Saintigny: Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses: BMS; Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): HTG Diagnostics. E. Raymond: Full / Part-time employment: Genoscience; Full / Part-time employment: Scor; Advisory / Consultancy: Pharmaengine; Travel / Accommodation / Expenses: Merck. N. Girard: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Hoffmann-La Roche; Advisory / Consultancy: Lilly; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Takeda; Advisory / Consultancy: GSK; Advisory / Consultancy: AbbVie. R. Sulaiman: Full / Part-time employment: Physicians Laboratory . E. Rubin: Travel / Accommodation / Expenses: Roche. V. Lazar: Licensing / Royalties: Worldwide Innovative Network Association. E. Felip: Advisory / Consultancy, Speaker Bureau / Expert testimony: ABBVIE; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Blue Print Medicines; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy: Guardant Health; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck MGaA; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Domme; Advisory / Consultancy, Speaker Bureau / Expert testimony: NOVARTIS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy: JANSSEN; Research grant / Funding (institution): Fundation Merck Salud; Research Grant / Funding (Institution): Grant For Oncology Innovation Emd Serono. A. Onn: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca. B. Leyland-Jones: Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony: Exelixis; Speaker Bureau / Expert testimony: Genentech; Speaker Bureau / Expert testimony: Puma; Travel / Accommodation / Expenses: NFCR; Travel / Accommodation / Expenses: AkesoGen. R. Kurzrock: Shareholder / Stockholder / Stock options, Co-founder: CureMatch; Shareholder / Stockholder / Stock options: IDbyDNA; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Soluventis; Advisory / Consultancy: Gaido; Advisory / Consultancy: Loxo Oncology; Advisory / Consultancy: Xbiotech; Advisory / Consultancy: Acurate Therapeutics; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: NeoMed; Research grant / Funding (institution): uardant Health; Research grant / Funding (institution): Grifols; Research grant / Funding (institution): Konica Minolta; Research grant / Funding (institution): OmniSeq; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Sequenom; Research grant / Funding (institution): Foundation Medicine. All other authors have declared no conflicts of interest.