new trial featuring anti-her2 vaccine plus lapatinib (phase I published)

[Lani]

J Transl Med. 2012 Feb 10;10(1):28. [Epub ahead of print]
Phase I clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibtion.
Hamilton E, Blackwell K, Hobeika AC, Clay TM, Broadwater G, Ren XR, Chen W, Castro H, Lehmann F, Spector N, Wei J, Osada T, Lyerly HK, Morse MA.
Abstract
ABSTRACT:
BACKGROUND:
Patients with HER2-overexpressing metastatic breast cancer, despite initially benefiting from the monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib, will eventually have progressive disease. HER2-based vaccines induce polyclonal antibody responses against HER2 that demonstrate enhanced anti-tumor activity when combined with lapatinib in murine models. We wished to test the clinical safety, immunogenicity, and activity of a HER2-based cancer vaccine, when combined with lapatinib.
METHODS:
We immunized women (n = 12) with metastatic, trastuzumab-refractory, HER2-overexpressing breast cancer with dHER2, a recombinant protein consisting of extracellular domain (ECD) and a portion of the intracellular domain (ICD) of HER2 combined with the adjuvant AS15, containing MPL, QS21, CpG and liposome. Lapatinib (1250 mg/day) was administered concurrently. Peripheral blood antibody and T cell responses were measured.
RESULTS:
This regimen was well tolerated, with no cardiotoxicity. Anti-HER2-specific antibody was induced in all patients whereas HER2-specific T cells were detected in one patient. Preliminary analyses of patient serum demonstrated downstream signaling inhibition in HER2 expressing tumor cells. The median time to progression was 55 days, with the majority of patients progressing prior to induction of peak anti-HER2 immune responses; however, 300-day overall survival was 92% (95% CI: 77-100%).
CONCLUSIONS:
dHER2 combined with lapatinib was safe and immunogenic with promising long term survival in those with HER2-overexpressing breast cancers refractory to trastuzumab. Further studies to define the anticancer activity of the antibodies induced by HER2 vaccines along with lapatinib are underway. Trial registry ClinicalTrials.gov NCT00952692.
PMID: 22325452 [PubMed - as supplied by publisher] Free full text

[Rich66]

The median time to progression was 55 days, with the majority of patients progressing prior to induction of peak anti-HER2 immune responses

Looks like another situation where the typical RECIST criteria might be jumping the gun.

[bejuce]

Hum? What do you mean Rich?

[Rich66]

There has been more than one instance with immune/biological therapies ( I think one was in PCa) where early progression doesn't necessarily mean benefit, even overall survival (OS), won't accrue later. In the study above, calling "progression" before the measured immune response peaks seems premature. Seems telling they follow with

however, 300-day overall survival was 92%

I suspect once progression (according to RECIST criteria) was called, the therapy was discontinued. The issue of continue benefit of Herceptin past progression seems likely related.
There are even instances with non-traditional therapies where tumors have internal necrosis with fluid build up that can actually increase the radiologic (CT) size while it is dying. I'm not clear on whether PET can fully escape that issue.