Roche's broad oncology therapy portfolio and diagnostic testing expertise make it a natural sponsor for histology-independent basket trials. It is following the VE-BASKET trial of Zelboraf (vemurafenib) for non-melanoma BRAF V600-mutated cancers with "My Pathway," a basket trial to identify potential new uses for four of its marketed targeted therapies.

VE-BASKET found signals of efficacy in only two of the 10 cohorts studied, non-small cell lung cancer and Erdheim-Chester disease/Langerhans'-cell histiocytosis (see below). Anecdotal responses were seen in several more cancers, but the small numbers make interpretation difficult.

The limited results were not surprising given the rarity of the BRAF V600 mutation in many cancers and the exclusion of the groups where the mutation is more common, including V600-mutated melanoma and hairy cell leukemia. The larger numbers of patients with actionable mutations allow for dedicated clinical trials directed at biomarker-selected patients with those specific histologies.

Roche reported preliminary data from VE-BASKET at the American Society of Clinical Oncology meeting in 2014 ([A#00140609013]).

Roche has started a histology-specific trial of vemurafenib in BRAF-mutant colorectal cancer even though CRC patients in VE-BASKET did not have a response rate indicative of efficacy. VE-BASKET first treated CRC patients with monotherapy, as it did in the other cohorts, but then added a combination arm with cetuximab when laboratory data emerged suggesting that "resistance in colorectal cancer might be mediated through feedback activation of epidermal growth factor (EGFR) signaling," the VE-BASKET researchers reported in the New England Journal of Medicine.

Even without a signal in the basket trial, "given the highly aggressive and chemotherapy-resistant nature of BRAF V600-mutated colorectal cancers, strategies using dual EGFR and BRAF inhibition deserve further evaluation," the researchers said. A Phase II combination study is ongoing in BRAF-mutant CRC.

The vemurafenib basket trial treated a total of 122 patients with BRAF V600 mutations. Enrollment was too low in some cohorts, including breast cancer, to draw conclusions. The trial used objective response rate as the primary endpoint. Roche considered a response rate of 15% at week 8 to be low, 45% to be high, and 35% to be low but still indicative of efficacy.

Roche's VE-BASKET
A Phase II basket trial of Roche's Zelboraf (vemurafenib) in patients with BRAF V600 mutation-positive non-melanoma cancers.
Cohort	Enrollment	Objective Response (Rate)	Result
NSCLC	20	8 (42%)	Preliminary activity observed
Cholangiocarcinoma	8	1 (12%)	Interpret with caution due to low numbers
ECD/LCH*	18	6 (43%)	Preliminary activity observed
Anaplastic thyroid cancer*	7	2 (29%)	Interpret with caution due to low numbers
Breast cancer	N/A	N/A	Closed due to insufficient accrual
Ovarian cancer	N/A	N/A	Insufficient number of patients for analysis
Multiple myeloma	5	N/A	Insufficient number of patients for analysis
Colorectal cancer (monotherapy)	10	0 (0%)	Monotherapy not effective
CRC (cetuximab combo)*	27	1 (4%)	Phase II study in BRAF-mutant CRC started 11/2014 testing irinotecan+cetuximab with and without vemurafenib.
All others	27	N/A	Largest group of patients (13) had primary brain tumors
*Cohort added based on adaptive statistical analysis of the "all others" cohort.
Sources: Company reports and abstracts, clinicaltrials.gov

Roche subsidiary Genentech Inc. has mounted another histology-independent basket trial called "My Pathway." The Phase IIa trial will treat patients with advanced cancers that have no available beneficial therapy if they have a mutation targeted by one of four of the company's marketed targeted oncologics (see chart).

"My Pathway," more prosaically known as Phase IIa protocol ML28897, has a target enrollment of 500 patients, according to clinicaltrials.gov. The trial kicked off in April 2014 and is expected to run through August 2019.

Genentech's "My Pathway" Study (Protocol ML28897)
A Phase IIa protocol enrolling patients with actionable mutations who have no available beneficial therapy.
Actionable Mutation	Treatment
BRAF	Zelboraf (vemurafenib)
HER2	Herceptin (trastuzumab)/Perjeta (pertuzumab)
EGFR	Tarceva (erlotinib)
Hedgehog pathway-relevant mutation	Erivedge (vismodegib)

Milestones In Basket Trials: Roche's VE-BASKET And 'My Pathway'

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