Trastuzumab Plus Lapatinib Show Promise For HER2-Positive Colorectal Cancer

Patients with heavily pretreated, metastatic HER2-positive colorectal cancer may respond to trastuzumab plus lapatinib

medwireNews: The combination of trastuzumab and lapatinib is both active and well tolerated in patients with HER2-positive, metastatic, treatment-refractory colorectal cancer, suggest findings from the proof-of-concept HERACLES trial.

“The results of this study could change the day-to-day clinical care management of patients with advanced HER2-positive colorectal cancer”, say Silvia Marsoni, from Istituto di Candiolo in Italy, and co-authors in The Lancet Oncology.

“Our findings could lead to the use of trastuzumab and lapatinib in earlier lines of treatment, with a possibility of chemotherapy-free regimens, for patients with HER2-positive tumours”, they believe.

The phase II trial included 27 patients whose tumours were HER2-positive and wild-type for KRAS exon 2, and had at least one measurable lesion. The participants had progressed during or within 6 months of receiving a standard of care treatment, including regimens with the epidermal growth factor receptor (EGFR) inhibitors, cetuximab or panitumumab.

After a median of 94 weeks, eight (30%) patients had achieved an objective response by RECIST v1.1 criteria, including one complete response and seven partial responses. Twelve patients had stable disease, eight of whom did not experience progression for at least 16 weeks.

Two patients experienced disease progression before the 8-week radiological assessment but 84% of the 25 patients assessed at this point showed tumour shrinkage, the investigators observe.

In all, 59% of the group achieved disease control for at least 16 weeks and the median progression-free survival (PFS) was 21 weeks. Median overall survival was 46 weeks, with 45% of the 27 patients alive at 1 year.

Diarrhoea, rash, fatigue, paronychia and conjunctivitis were the most common side effects, reported in 78%, 48%, 48%, 33% and 19% of the patients, respectively. Six (22%) of the patients experienced grade 3 side effects, namely fatigue (n=4), skin rash (n=1) and elevated bilirubin (n=1), but there were no grade 4 or 5 events or drug-related serious events.

Of note, all but one of the patients who achieved an objective response had a HER2 score of 3+ on immunohistochemistry whereas just 10 of the 17 patients with stable disease or progression had a 3+ score.

And further analysis showed that objective response was significantly more likely in patients with a HER2 gene copy number above 9.45 than those with a lower number, at 44% versus 0%. Median PFS was also higher, at 29 versus 16 weeks.

“Our results show that HER2 amplification is a clinically relevant genetic alteration in metastatic colorectal cancer”, conclude Silvia Marsoni et al.

“This alteration can be screened for with established diagnostic tools, can be acted on at the therapeutic level, and occurs in 3–5% of patients with KRAS codon 12/13 wild-type metastatic colorectal cancer, similar to that of other genetic alterations for which licensed drugs are effective (eg, in lung cancer).”

Describing the results as “extraordinary” for a group of heavily pretreated patients, the author of an accompanying comment said that, combined with findings from the MyPathway basket trial of colorectal cancer patients with a druggable target, the data “define a new standard of routine therapy” for HER2-positive patients.

Hans-Joachim Schmoll, from Martin-Luther-Universität Halle-Wittenberg in Germany, now questions the optimal treatment combination and timing of treatments targeting HER2 and EGFR in colorectal cancer patients and where best to focus future research.

“While this anti-HER2 strategy could be adopted for routine salvage therapy and is being investigated in earlier lines, ongoing research is also investigating targeting of HER3 and the combined inhibition of EGFR and HER2–4”, he writes, noting that HER3 is expressed in up to three-quarters of colorectal tumours.

References

Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol 2016; 20 April. DOI: http://dx.doi.org/10.1016/S1470-2045(16)00150-9

Schmoll H-J. Targeting HER2: precision oncology for colorectal cancer. Lancet Oncol 2016; 20 April. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30039-0

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