Neratinib versus Tucatinib

Some see neratinib as a drug with little benefit but a lot of side effects. However, with recent data updates, this perception seems to be changing. In combination with other agents, neratinib might have its place beyond extended adjuvant therapy. Tucatinib, another selective oral HER2 TKI is currently also studied in combination with other agents and data updates also have been encouraging. The perception seems to be that tucatinib is superior in terms of efficacy but mainly also in terms of safety due to neratinib’s issues with diarrhea. There’s no head to head comparison between the two agents (and there probably never will be). Despite the different study settings and the early nature of the data, here’s the attempt to compare the two:

There have been two recent tucatinib studies released. One studied the drug in combination with capecitabine and/or trastuzumab in advanced HER2+ MBC with and without brain mets. This study produced encouraging results and suggest a synergistic effect mainly with capecitabine alone (ORR 83%, PFS=7.1 months, n=6) or as triple therapy together with trastuzumab (ORR 61%, PFS=7.8, n=23) while the combination with trastuzumab alone did not show equally good results (OR 40%, PFS=5.5, n=15). A second Phase 1b study in combination with TDM-1 also produced encouraging results with a 48% ORR and 8.2 months PFS (N=57).

Puma also tested the combination neratinib + capecitabine in a phase II trial in third line metastatic HER+ patients with an ORR of 64% and PFS of around 9.3 months. Puma is currently testing this combination versus a lapatinib combination in a randomized phase III trial which should read out later this year (NALA trial). The NSABP FB-10 trial also tested TDM-1 in combination with neratinib.  Latest results from this trial were reported at ASCO 18. The study enrolled patients who had previously been treated with chemotherapy and the combination of trastuzumab and pertuzumab. For the 20 patients who were evaluable for efficacy, the ORR was 64% with 3 patients experiencing a complete response. Finally, neratinib is also being tested in combination with Paclitaxel in the NEfERET-T trial in first line metastatic breast cancer, with or without brain metastases. Here, paclitaxel-neratinib produced a 12.9 months PFS with an ORR of 74.8%

Most women on neratinib suffer from more or less severe forms of diarrhea. Grade 3 diarrhea rates in the ExteNET trials were as high as 40%. Diarrhea mainly occurs at the beginning of the therapy and rates of incidence drop rather quickly to around 20% after five weeks on the drug. Puma is currently running the Control trial, where different prophylaxis regimens are tested in order to figure out the optimal diarrhea management strategy. Preliminary data shows that a combination of loperamide and colestipol can reduce initial grade 3 diarrhea down to around 11% with rates falling to single digit after the first week. Final results of the Control trial are due later this year but all in all it seems that diarrhea should become a manageable side effect of neratinib.

Tucatinib diarrhea rates are more favorable. In the phase I dose escalation study, only 22% of patients suffered from any grade diarrhea. In the combination trial with capecitabine and trastuzumab, there were no cases of grade 3 diarrheas, while rates of grade 1-2 were at around 30-40%.

Other side effects
In the tucatinib phase I dose escalation study, grade 3 AEs were reported in 42% of patients; those occurring in >1 patient were anemia and cellulitis (3 patients each, 6%) and abdominal pain, hypokalemia, increased ALT, increased AST, musculoskeletal chest pain and vomiting (3 patients each, 4%). In the tucatinib/TDM-1 study, drug related toxic reactions that were grade 3 and above included thrombocytopenia (7 patients; 14%) and hepatic transaminitis (6 patients; 12%). The trastuzumab/capecitabine combination study reported one grade 4 cerebral edema. In this study 80% of patients had increased AST levels and 63% had increased ALT levels. Grade 3 AST and ALT increases were at 5% each. Overall 34 (57%) of patients required dose interruption and in 28 of these cases, tucatinib was reinitiated. Nine of these patients continued with a reduced dose.

For neratinib, the most common grade 3 adverse events in the ExteNET trial were nausea and abdominal pain with 2% each and vomiting with 3%. 9% of patients had elevated ALT levels with grade 3 events at 1% and AST was increased in 7% with 0.5% grade 3 events. In the Neratinib TDM-1 combination study treatment-related grade 3 toxicities included diarrhea (19%), thrombocytopenia (15%), nausea (11%), and ALT elevation (4%). In the phase 2 neratinib/ capecitabine combination study, the most common grade 3 events next to diarrhea were hypokalemia (16%), fatigue (11%) as well as vomiting and nausea with 8%.

Due to small study sizes, it is not yet clear which of the two drugs is better in terms of efficacy. But there is no evidence that tucatinib is superior. At the margin, neratinib even seems to produce a bit more durable results than tucatinib. In terms of side effects, the diarrhea issue of neratinib is well known and Puma is addressing it with an optimal support regimen. Looking at the ExteNET data, neratinib does not seem to produce any other worrying side effects.

While not fully absent, GI effects of Tucatinib are more benign. The single cerebral edema case in the combination study is not conclusive. Where tucatinib is clearly inferior to neratinib is hepatotoxicity. Especially in combination with other agents, there seems to be a clear liver toxicity signal.

While Puma’s NALA trial should read out later this year, we will have to wait for the HER2climb phase III tucatinib study until late 2020. These two data sets will allow for a more accurate comparison.