There is evidence of synergism between vinorelbine and trastuzumab, in preclinical studies of several HER-2 over-expressing breast cancer cell lines.r Data for single agent vinorelbine efficacy in both the IV and oral setting is contained in a large array of phase II trials with comparable efficacies, first line PFS being 5.0 - 7.1 months for the oral formulation compared to 3.0 - 9.0 months for IV treatment.rrr Equivalent activity of oral and IV formulations has been reported in a randomised comparison in lung cancer patientsr in keeping with the indirect comparative data from breast cancer studies.
Further to this, phase II trials in metastatic breast cancer have consistently demonstrated marked efficacy and encouraging tolerability for the trastuzumab - IV vinorelbine combination, which has achieved overall response rates (ORRs) ranging from 40–85%, complete response (CR) rates from 3–15%, partial response (PR) rates from 40–75% and PFS of 9–12 months, and good tolerability. Patients receiving the trastuzumab-vinorelbine combination as first-line therapy typically had the highest ORRs (51–86%), but ORRs of 50–60% are also reported in patients who had received previous adjuvant chemotherapy.r
Considering comparison of IV vinorelbine with trastuzumab to other chemotherapy-based regimens, two prospective trials have evaluated trastuzumab with IV vinorelbine head-to head against other chemotherapy partners. The first-line phase III HERNATA (HERceptin plus NAvelbine or TAxotere) study reported equal efficacy with numerically superior time to progression and OS for vinorelbine.r The first-line phase III trial, the TRAstuzumab and VInorelbine Or TAxane (TRAVIOTA) study, again found comparable efficacy between trastuzumab and vinorelbine versus trastuzumab and the investigators’ choice of taxane, again with numerically superior results in favour of vinorelbine: ORR 51% vs 40%; and median time to progression 8.5 vs 6.0 months.r
Clinical trial evidence for oral vinorelbine in combination with trastuzumab in HER-2 positive metastatic breast cancer comes from a number of single institution or national phase II trials and a retrospective analysis. The expert reference panel supported publication of this protocol on the basis of the information summarised below:
Source |
Study & year published |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase II trials |
Chan et al 2013 r |
Yes |
No |
Vinorelbine (PO) 60 mg/m2 day 1 and 8, q21 days. Dose escalation to 80 mg/m2 from cycle 2.
Standard dose trastuzumab given weekly.
Study also included capecitabine 1000 mg/m2 BD on day 1 to 14 |
|
Farhat et al. 2016 r |
Yes |
No |
Vinorelbine (PO) 60 mg/m2 day 1,8 and 15, q21 days. Dose escalation to 80 mg/m2 from cycle 2.
Standard dose trastuzumab three weekly or weekly |
|
Heinemann et al. 2011 r |
Yes |
No |
Vinorelbine (IV) 25 mg/m2 d1 and vinorelbine (PO) 60 mg/m2 day 8, and 15, q21 days.
Standard dose trastuzumab three weekly |
|
Bartsch et al. 2006 r |
Yes |
Yes
(but no dose escalation) |
- |
Retrospective analysis |
Bergen et al. 2014 r |
Yes |
Yes
(but no dose escalation) |
In this study trastuzumab could be given weekly or three weekly |
Guidelines |
Date published/revised |
Supports use |
Is the dose and regiment consistent with the protocol |
Comments |
NCCN |
V 2. 2017r |
- |
- |
NCCN only mentions combination of IV vinorelbine with trastuzumab |
CCO |
2016 |
- |
- |
Protocol is for IV vinorelbine with trastuzumab |
BCCA |
2016 |
- |
- |
Protocol is for IV vinorelbine with trastuzumab |
ESMO |
Cardoso et al. 2016r |
- |
- |
Does not specify whether IV or oral vinorelbine |
Efficacy
The efficacy of the oral formulation of vinorelbine with trastuzumab specifically, is shown for three published cohorts in the table below.
Study |
Type |
N |
Line |
RR |
PFS
(months) |
OS
(months) |
Farhat et al. 2016r |
Phase II |
26 |
First line |
56% |
6.7 |
27.9 |
Bartsch et al. 2006r |
Phase II |
21 |
Any |
53% |
10.0 |
NR |
Bergen et al. 2014r |
Retrospective analysis |
40 |
First line |
62% |
9.0 |
59.0 |
A phase II study in 26 patients gave oral vinorelbine at 60 mg/m2 on day 1, 8 and 15 for the first cycle, stepping up to 80 mg/m2 after the first cycle. ORR was 56% including 12% CRs and clinical benefit rate of 88%. Median PFS was 6.7 months and median OS was 27.9 months.r
A second series of 21 patients gave 60 mg/m2 without dose escalation and with vinorelbine only on days 1 and 8 of a 21 day cycle. ORR was a comparable 53% and median PFS was 10.0 months.r
The third cohort formed part of a study comparing the efficacies of vinorelbine or docetaxel in combination with trastuzumab. Similar results for ORR and PFS between the two arms were seen, but trastuzumab and oral vinorelbine was associated with a significantly greater median OS than trastuzumab and taxane therapy (59 vs 49 months; p=0.033). In addition, duration of brain metastasis-free survival was significantly greater in the oral vinorelbine group than the taxane group (69 vs 51 months; p=0.032).r
Kaplan-Meier estimates for Progression-free survival (Fig.1) and Overall survival (Fig.2)r
© Breast Care 2014
Toxicity
Although the toxicity of oral vinorelbine is broadly comparable with the IV formulation some notable differences exist. This is best observed in the direct randomised comparison in NSC lung cancer.r Here both thrombocytopenia and grade 3-4 neutropenia were more common for the IV formulation. This was at the expense of more nausea and diarrhoea for oral vinorelbine in contrast to a higher rate of constipation with IV treatment.
Comparable toxicity profiles are seen for three studies of oral vinorelbine with IV trastuzumab.rrr No significant cardiac events are reported in any of these cohorts.
Comparison of oral and IV vinorelbine toxicities given as a single agent in NSCLC
Toxicityr |
Oral vinorelbine |
IV vinorelbine |
Any grade |
Grade 3/4 |
Any grade |
Grade 3/4 |
Neutropenia |
63 |
46 |
89 |
62 |
Thrombocytopenia |
8 |
0 |
14 |
0 |
Nausea |
83 |
11 |
46 |
0 |
Diarrhoea |
40 |
3 |
16 |
0 |
Constipation |
11 |
3 |
24 |
3 |
Neurosensory |
11 |
0 |
14 |
0 |
This combination also proved more tolerable than docetaxel-based trastuzumab treatment with fewer patients in the oral vinorelbine than taxane group required dosage reductions because of treatment-related toxicity in the above mentioned retrospective comparison (15.0% vs 30.6%).r This is in keeping with the comparisons of IV vinorelbine to taxane-based therapy. In the HERNATA trial, significantly more treatment-related grade 3 to 4 events were seen with taxane than vinorelbine (81% vs 51%; p<0.0001).r This included febrile neutropenia (36.0% vs 10.1%), leucopenia (40.3% vs 21.0%), infection (25.1% vs 13.0%), fever (4.3% vs 0%), neuropathy (30.9% vs 3.6%), nail changes (7.9% vs 0.7%) and oedema (6.5% vs 0%) were reported with docetaxel compared with vinorelbine. Treatment discontinuation owing to toxicity was more frequent with docetaxel (20.1%) than with vinorelbine (6.5%). For the TRAVIOTA study, both treatment regimens were generally well tolerated, with similar rates of neurological and gastrointestinal toxicity.r
Finally, considering patient preference, and giving further support to the tolerability of oral vinorelbine, a study in lung cancer combined vinorelbine and carboplatin administered two cycles with oral then two cycles with IV vinorelbine or vice versa. 32 of 43 patients preferred the oral formulation citing less toxicity and greater convenience.r