The ASCO Post issue of June 25, 2017, did an excellent job of summarizing the results and controversy generated by the initial results of the APHINITY trial, reported at the 2017 ASCO Annual Meeting and published simultaneously online in The New England Journal of Medicine.1 With a median follow-up of about 45 months, adding 1 year of pertuzumab (Perjeta) to 1 year of trastuzumab (Herceptin) plus standard chemotherapy improved invasive disease–free survival among those entered with positive axillary nodes from 90.2% to 92.0% at 3 years and 86.7% to 89.9% at 4 years. Node-negative patients did very well in this trial regardless of whether they received pertuzumab, as they did with 12 weeks of paclitaxel and 1 year of trastuzumab in a 400-patient phase II experience,2 so most everyone concludes they do not need pertuzumab. No survival benefit is even hinted at in the first 4 years of APHINITY, and toxicity was relatively mild and manageable, with 9% experiencing severe diarrhea only during the period pertuzumab was given during chemotherapy and little excess cardiac toxicity.
The ASCO Post reported discussions emphasizing that the benefit is small and the drug very expensive (about $100,000 for 1 year of pertuzumab), the follow-up is short, and the endpoint inappropriate. William Sikov, MD, of the Alpert Medical School of Brown University Providence, wrote: “The study will never demonstrate a survival advantage” from our investment of $100,000 per patient, most of whom would do well without pertuzumab.
Overall Survival Is Correct Endpoint
If one is in the conservative majority of oncologists who give adjuvant systemic therapy to prevent distant metastases and resulting death from breast cancer, not local recurrences or contralateral new breast primaries, then the correct endpoint is overall survival, with distant disease–free survival as the usual surrogate, since distant metastases are the engine of mortality for breast cancer patients. Distant disease incidence for the entire 4,804 patients in APHINITY was improved by 27 events from 139 events for the placebo group to 112 for pertuzumab (slightly different figures are given in the online appendix Figure S4). The hazard ratio was 0.82, and the difference was not statistically significant (P = .101).
A small delay in distant metastases (not yet significant) may not improve overall survival if the pertuzumab benefit in survival after distant metastases is lost because resistance developed on adjuvant pertuzumab.— Steven E. Vogl, MD
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The proper interpretation of these data is that distant events may be delayed or prevented by adding pertuzumab, but so far this benefit is not statistically significant, nor has a significant improvement in distant disease–free survival been reported (there will be some deaths without prior distant disease, usually not due to the breast cancer itself). One can guess (based on the published data) that the distant disease incidence benefit for those with positive nodes is about 2.0% at 4 years, multiplying the 62% of invasive recurrences that were distant events by the 3.2% overall invasive disease benefit). This is a small benefit.
Distant Disease Incidence: Poor Overall Survival Surrogate for Pertuzumab!
A further consideration gives one pause when considering a recommendation for adjuvant pertuzumab. The use of distant disease–free survival as a surrogate endpoint for overall survival assumes that survival after distant recurrence will not be impaired by the intervention. Pertuzumab has the unusual distinction of extending median survival in women with metastatic disease by about 16 months when given with trastuzumab and docetaxel—from 41 to 57 months.3 If this benefit is lost because the breast cancer was rendered resistant by 1 year of pertuzumab exposure, then pertuzumab adjuvant therapy is much less attractive.
We have no data regarding whether pertuzumab adds benefit in the treatment of metastatic HER2-positive breast cancer after failure of prior pertuzumab-containing chemotherapy or after 1 year of adjuvant pertuzumab. The first author of the APHINITY paper, Gunter von Minckwitz, MD, PhD, assumes it does because trastuzumab still improves outcomes after prior trastuzumab,4 but there are not even animal or in vitro data to support the assumption that this applies to pertuzumab.
The arguments for recommending adjuvant pertuzumab are weak…until we have a significant and impressive benefit in overall survival.— Steven E. Vogl, MD
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It pays to carefully analyze the numbers from the 10-year report of the combined analysis of N9831 and B-31 by Edith Perez, MD, to see how this works out.5 The mortality rate at 10 years in women given doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab (ACTH) was 16%. About 11.7% had deaths definitely attributed to breast cancer, presumably the result of about 13.4% of women developing distant metastases (calculated crudely by multiplying the incidence of disease-free survival events by the percentage of disease-free survival events caused by distant or local plus distant first events). If pertuzumab further reduces distant events, with a hazard ratio of 0.82, they should go down to about 11.0%. This 11% of distant relapse will have a median survival of 40 months from the time of distant relapse if their cancers are totally pertuzumab-resistant, whereas the 13.4 % relapsing without 1 prior year of pertuzumab would have a median survival after relapse of 56 months. Modeling the outcome at various time points is complex and beyond my abilities, but some of the gains from reducing distant relapses with adjuvant pertuzumab will be lost, because survival after relapse will be so much shorter if pertuzumab fails to prolong survival after relapse.
Improved therapy for metastatic disease in the near future compared with the time during which CLEOPATRA was conducted will also play a role. As therapy for metastatic disease improves with drugs such as ado-trastuzumab emtansine (Kadcyla; formerly known as T-DM1) and perhaps better tyrosine kinase inhibitors (of which neratinib [Nerlynx] might prove to be one), then the survival benefit from delaying or preventing distant relapse by giving an initial year of pertuzumab may be delayed, making an overall survival benefit more difficult to establish in the eventual final analysis of APHINITY.
Closing Thoughts on Adjuvant Pertuzumab
The results of adjuvant ACTH for node-positive women with HER2-positive breast cancers in N9831 and B-31 are very good, with relatively low rates of distant metastases at 10 years. So far, pertuzumab has not improved overall survival at all, nor has it reduced distant relapses to a statistically significant extent. Any survival benefit from pertuzumab in this regard may be lost if adjuvant pertuzumab exposure means pertuzumab does not prolong survival after diagnosis of metastases. Although pertuzumab seems safe, we really have data only for 4 years of follow-up, and major toxicities may yet be identified. This is important because more than 86% of women given ACTH alone will not develop distant metastases by 10 years with ACTH alone and so cannot benefit in terms of distant disease–free or overall survival from added pertuzumab.
Although pertuzumab seems safe, we really have data only for 4 years of follow-up, and major toxicities may yet be identified.— Steven E. Vogl, MD
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Except in situations of extraordinary risk (HER2-positive cancer that is locally advanced or with massive matted axillary nodes), the arguments for recommending adjuvant pertuzumab are weak, and those for investing the huge resources demanded to pay for it are even weaker, until we have a significant and impressive benefit in overall survival.■
DISCLOSURE: Dr. Vogl reported no conflicts of interest.
Dr. Vogl, an oncologist who works in a private office, is affiliated with Montefiore Medical Center in New York City and White Plains Hospital.
REFERENCES
1. von Minckwitz G, Procter M, de Azambuja E, et al: Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med 377:122-131, 2017.
2. Tolaney SM, Barry WT, Dang CT, et al: Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 372:134-141, 2015.
3. Swain SM, Baselga J, Kim SB, et al: Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372:724-734, 2015.
4. von Minckwitz G, du Bois A, Schmidt M, et al: Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: A German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol 27:1999-2006, 2009.
5. Perez EA, Romond EH, Suman VJ, et al: Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: Planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol 32:3744-3752, 2014.
