This is a tumor class we don’t write about that often but it bears remembering that there remains significant unmet need in an indication often touted as an example of victory over cancer. For those patients encountering resistance to therapy, metastases or breast cancers subtypes with few new options (e.g. triple negative breast cancer, TNBC) victory can seem far away.
There was a flurry of interesting papers over the last few weeks that I think give a peek behind the curtain at progress and frustrations in the ongoing evolution of breast cancer care. This post assumes some baseline knowledge of breast cancer therapy and application to specific oncogenic signatures.
As many readers will know, HER2-directed therapy has transformed care for patients carrying elevated levels of the growth factor receptor HER2 aka EGFR2. About 20% of breast cancer patients are HER2+ or become HER2+ as a mechanism of resistance to other therapies). This is an aggressive breast cancer subtype that has yielded to HER-2 targeting agents such as the small molecule inhibitor lapatinib that blocks EGFR and EGFR2 signaling, trastuzumab, an antibody that specifically kills EGFR2 positive cells, and T-DM1, an antibody-drug conjugate (ADC) consisting of trastuzumab bound to a cytotoxic “payload”. Lapatinib (Tykerbtm) is made by GlaxoSmithKline (GSK), trastuzumab by Roche/Genentech (Herceptintm) and T-DM1 (Kadcylatm) by Roche in collaboration with Immunogen. A second anti-EGFR2 antibody, pertuzumab (Perjetatm, Roche/Genentech) binds a different epitope than trastuzumab and is approved in combination with that antibody.
Although some patients experience long-term remission with HER2-directed therapeutics, relapse is a common problem. There are various mechanisms of relapse, and PI3K activation is a common one (first identified in 2009 by multiple groups). PI3K signals through AKT to mTOR to drive expression of numerous pro-growth and pro-survival genes, making this a known oncogenic pathway, indeed it is a known oncogenic pathway in breast cancer.
Recently Loibl et al. (http://jco.ascopubs.org/content/32/29/3212) reported that activating mutations in the PIK3CA gene that encodes for the PI3K alpha subunit were associated with poor response to initial HER2-directed therapy, that is, not in the relapse setting. This means we are seeing the impact of the activation of both the EGFR2 and PI3K pathways in these patients. Of the breast cancer patients examined, 21.4% harbored a PIK3CA mutation. Detection of a PIK3CA mutation was associated with a lower Complete Response (CR) rate in a cohort of nearly 300 EGFR–positive tumors. The CR rate was 11.3% with a PIK3CA mutation compared with 27.5% without the mutation. Worse yet, in patients with PIK3CA mutation, the CR rates were 16%, 24.3%, and 17.4% with lapatinib, trastuzumab, and the combination, respectively, compared to 18.2%, 33%, and 37.1%, respectively in patients not carrying the mutation. The difference in CR rates was significant (P = .017). Fortunately, multiple drugs targeting different parts of this pathway have been developed, and it is of course possible to combine these inhibitors with anti-HER2 therapies in patients with defined PIK3CA activating mutations. Indeed one such study of the mTOR inhibitor everolimus (Afinitortm, Novartis) in combination with trastuzumab showed an increase in progression-free survival, although there was considerable toxicity associated with the regimen (Andre et al. 2014). Many other trials with more selective inhibitors of the pathway are underway targeting PI3K rather than mTOR, and may give a better efficacy/toxicity profile. However most of these trials are in the relapse setting rather than the first-line setting, and results may not be as effective once relapse has occurred. One take home from the Loibl et al. is that HER2+ breast cancer patients should be screened for PIK3CA activating mutations so that combination therapy can be initiated earlier in the therapy cycle.
Saura et al. (link) reported early phase clinical results of a new pan-EGFR inhibitor for HER2+ breast cancer. Neratinib, developed by Pfizer and Puma Biotechnology, was tested in combination with chemotherapy. This study presents the results of the multinational, open-label, phase I/II trial in patients with HER2-positive metastatic breast cancer, and is most notable for defining the maximum tolerated dose (MTD) of 240 mg per day (with the chemotherapeutic capecitabine). The most common drug-related adverse event was diarrhea (in 88% of patients), severe enough to cause dose interruptions or dose reductions in some patients. In July of this year Puma announced interim results of a Phase III trail of neratinib versus placebo after adjuvant treatment with trastuzumab in women with early stage HER2-positive breast cancer. The ExteNET trial enrolled over 2,800 patients with early-stage HER2-positive breast cancer who had undergone surgery and adjuvant treatment with trastuzumab, and were then randomized to receive extended adjuvant treatment with either neratinib or placebo for a period of one year. The primary endpoint of the Phase III trial was disease free survival (DFS). Neratinib therapy resulted in a 33% improvement in DFS (versus placebo, p = 0.0046). There was also a 37% improvement in DFS including ductal carcinoma in situ versus placebo (this was the secondary endpoint).
Neratinib has had tolerability issues due to the grade 3 or higher diarrhea, and we will have to see if this is enough to limit its use outside the clinical trial setting. However, the drug’s efficacy is very promising, and the toxicity may be manageable. It is unclear where the companies will present the full results of this Phase III trial, although the upcoming San Antonio Breast Cancer Congress is one likely venue.
A quick look at Puma’s stock (NASDAQ: PBYI) over the last year shows the impact this data set had in July:
The stock jumped on large volume in July and has held steady even through the recent downturn. I think we can expect little movement until the full Phase 3 results are presented. While we are likely to see more detailed DFS data from the Phase 3 study, significant upside would be possible if an impact on overall survival (OS) was demonstrated – but that is a very high hurdle in this patient population.
Notably, ongoing clinical trials of neratinib include TNBC and lung cancer (NSCLC) (both in combination with chemotherapy) and renal cancer (RCC) in combination with cetuximab (anti-EGFR antibody, Erbituxtm, from BristolMyersSquibb). Preliminary NSCLC data were presented at the ESMO conference last month. If the new indications are impacted positively by this therapy, we can expect further value in PBYI shares.
Lets turn to a late phase disappointment in metastatic breast cancer. An antibody to a different growth factor receptor, VEGFR2, failed to shown clinical benefit in the first-line setting when added to docetaxel chemotherapy. Mackey et al (link2) reported that ramucirumab (Cyramzatm, Eli Lilly), a human antibody that binds VEGFR2 receptor-2 and blocks ligand-stimulated activation, had no impact in a Phase 3 trial of 1,144 patients with HER2–negative breast cancer who had not received cytotoxic chemotherapy in the advanced setting. The primary end point was progression-free survival (PFS) and the secondary endpoint was OS. HER2-negative breast cancer is less aggressive than HER2-positive breast cancer and can be controlled with debulking and chemotherapy if it has not advanced to extensive lymph node involvement (TNBC is a further, and very aggressive, subset). Eli Lilly is also testing icrucumab, an anti-VEGFR1 in a similar setting.
Several studies have focused on the predictive value of tumor-infiltrating lymphocyte (TIL) status in breast cancer settings. Nabholtz et al (TIL-1 link) studies the therapeutic utility of panitumumab combined with anthracycline-taxane-based chemotherapy in patients with operable, stage II-III, TNBC. The CR rate for combination therapy was ~55% compared to ~47% with chemotherpy alone. Poor response to therapy was associated with high EGFR expression and low cytokeratin 8/18 expression. A positive response to therapy was correlated with a high density of CD8+ TILs, suggesting that interrupting growth factor receptor signaling allowed a productive immune response to the tumor to take place.
Loi et al. (TIL-2 link) reported that TIL status was a useful marker for both TNBC and HER2+ patients treated with trastuzumab. In TNBC, TIL numbers correlated with metastatic recurrance of disease. In HER2+ breast cancer, TIL numbers were associated with better response to trastuzumab therapy.
These two latter studies suggest that immunotherapy will play a significant role in the treatment of diverse breast cancers. Early attempts here include the CD3 x HER2 bispecific antibodies, ipilimumab treatment, nivolumab treatment and many others. That’s a story for another time.