TreeTopp
TreeTopp tested whether the HER-family blocker varlitinib added to capecitabine helps bile duct and gallbladder cancer after first-line chemotherapy. It did not: response, progression and survival were the same, and the planned phase 3 part was abandoned. A small gallbladder subgroup hinted at slower progression but the finding was not conclusive.
Overview
TreeTopp (NCT03093870) was a global, double-blind, randomised, placebo-controlled phase 2 (part 1 of a planned phase 2/3) in patients with unresectable or metastatic biliary tract cancer, including gallbladder and ampullary cancer, after one prior gemcitabine-containing line. Patients received varlitinib 300 mg or placebo twice daily with capecitabine 1,000 mg/m² twice daily on days 1 to 14 of 21-day cycles. Of 127 treated patients (64 varlitinib, 63 placebo), objective response by independent central review was 9.4 versus 4.8 percent (odds ratio 2.28, p 0.42), median progression-free survival 2.83 versus 2.79 months (hazard ratio 0.90, 95 percent confidence interval 0.60 to 1.37) and overall survival 7.8 versus 7.5 months (hazard ratio 1.11, 0.69 to 1.79). Grade 3 or worse treatment-emergent adverse events occurred in 65.6 versus 58.7 percent. In subgroup analysis varlitinib appeared to prolong progression-free survival in women (4.1 versus 2.8 months, hazard ratio 0.59) and in gallbladder cancer (2.9 versus 1.6 months, hazard ratio 0.55, 0.26 to 1.19). The trial ended varlitinib development in biliary cancer and is the clearest failure of unselected pan-HER inhibition in the disease, in contrast to HER2-selected antibody therapy.
- 9.4 vs 4.8 out of 100 had their tumour shrink with Varlitinib + capecitabine compared with Placebo + capecitabine; 4.6 more per 100.
- Roughly one extra person helped for every 22 treated. That is a rough figure taken from the two percentages, not a guarantee for any one person.
- The p-value (0.42) means the difference could plausibly be due to chance.
- A response rate counts how many people had their tumours shrink by a set amount; shrinking is encouraging but does not by itself show that people live longer or feel better.
- Median 2.8 vs 2.8 months with Varlitinib + capecitabine compared with Placebo + capecitabine; about 0 months longer for half the group.
- A median is a midpoint: half the people did better than this and half did worse, so it is not a prediction for any one person.
- Put another way, the treated group had about 10 percent lower chance of the event at any given time (hazard ratio 0.9, likely range 0.6 to 1.37).
- The likely range for the hazard ratio crosses 1, so the difference could be due to chance.
- This is a surrogate endpoint: it measures the cancer being controlled or absent on scans and tests, which often, but not always, translates into living longer.
- Median 7.8 vs 7.5 months with Varlitinib + capecitabine compared with Placebo + capecitabine; about 0.3 months longer for half the group.
- A median is a midpoint: half the people did better than this and half did worse, so it is not a prediction for any one person.
- Put another way, the treated group had about 11 percent higher chance of the event at any given time (hazard ratio 1.11, likely range 0.69 to 1.79).
- The likely range for the hazard ratio crosses 1, so the difference could be due to chance.
- Overall survival counts deaths from any cause, so it is the most direct measure of whether a treatment helps people live longer.
- Median 2.9 vs 1.6 months with Varlitinib + capecitabine compared with Placebo + capecitabine; about 1.3 months longer for half the group.
- A median is a midpoint: half the people did better than this and half did worse, so it is not a prediction for any one person.
- Put another way, the treated group had about 45 percent lower chance of the event at any given time (hazard ratio 0.55, likely range 0.26 to 1.19).
- The likely range for the hazard ratio crosses 1, so the difference could be due to chance.
- This is a surrogate endpoint: it measures the cancer being controlled or absent on scans and tests, which often, but not always, translates into living longer.
- These results apply to the people the trial enrolled: Second-line advanced biliary tract cancer after one gemcitabine-containing line: capecitabine with varlitinib or placebo, double-blind randomised (part 1 of a planned phase 2/3). People in a different situation may not see the same effect.
Numbers are from the trial as recorded here; see the source links in the table below. This is orientation, not medical advice: ask your team how closely the trial population matches you.
151 enrolled.
| Endpoint | Arm | n | Value | HR (95% CI) | p | Source |
|---|---|---|---|---|---|---|
| Objective response rate (independent central review)primary | Varlitinib + capecitabine | 64 | 9.4% | - | 0.42 | link |
| Placebo + capecitabine | 63 | 4.8% | ||||
| Progression-free survivalprimary | Varlitinib + capecitabine | 64 | 2.83 months | 0.9 (0.6 to 1.37) | 0.63 | link |
| Placebo + capecitabine | 63 | 2.79 months | ||||
| Overall survival | Varlitinib + capecitabine | 64 | 7.8 months | 1.11 (0.69 to 1.79) | 0.66 | link |
| Placebo + capecitabine | 63 | 7.5 months | ||||
| Progression-free survival, gallbladder cancer subgroup | Varlitinib + capecitabine | - | 2.9 months | 0.55 (0.26 to 1.19) | - | link |
| Placebo + capecitabine | - | 1.6 months |
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