This week I'm snowed under with work, so was unable to attend the ECCO/ESMO conference, but have been following the key updates on Twitter and via press releases. Here are a few snippets of data I found interesting and some analysis/commentary:
1) Bayer announced some updated Phase II data with Nexavar (sorafenib) in breast cancer.
They found that when combined with Roche's capecitabine, it makes a significant difference to the time women live without their disease worsening.
Pfizer's Sutent (sunitinib) also had positive Phase II data in breast cancer in the past, before concluding that the Phase III data was unlikely to show a significant effect. We should therefore probably wait for the phase III sorafenib data before getting over excited.
2) The PI3K pathway might be as a factor in poor response or resistance to HER2-inhibitors such as trastuzumab.
"Of the 8,000 genes tested, we found that only knock down of PTEN conferred resistance to Trastuzumab. Decreased PTEN expression results in hyper activation of the PI3K pathway. Significantly, activating mutations in the gene encoding the p110a catalytic subunit of PI3K (PIK3CA) have been identified in some 25% of primary breast cancers potentially mimicking the effects of PTEN loss. Indeed, overexpression of the breast cancer-derived mutant PIK3CA (H1047R) also conferred resistance to Trastuzumab in cell culture. These findings are consistent with a major role of the PI3K pathway in the development of resistance to trastuzumab."
It makes sense to consider a) predict whether patients are likely to respond to therapy upfront and b) consider multiple therapies to overcome the development of resistance.
3) Impact of microsatellite instability (MSI) positivity and the presence of KRAS and BRAF mutations on colon carcinoma patients.
It has been observed in the past that stage III colon carcinoma patients with the BRAFV600E mutation had a significantly worse prognosis, based on the results of a study that aimed to assess the impact of microsatellite instability (MSI) positivity and the presence of KRAS and BRAF mutations on colon carcinoma patients.
The current study reported on 258 patients with stage III colon cancer who were treated with surgery followed by a 5-fluorouracil-based adjuvant therapy. KRAS mutations in codons 12 and 13 were determined by PCR followed by direct sequencing, and MSI status was determined by typing the BAT 26 marker (positive in 99% of MSI-positive white patients). It was concluded that tumor mutational status should be determined to predict survival more accurately in patients with colon carcinoma.
We will probably hear more about BRAF as a predictive marker in CRC, in addition to the KRAS mutation that was all the rage at ASCO earlier this year. Predicting responses to therapy is one thing, but the real need for patients going forward, is to find new therapies that will overcome the resistance induced by these mutations.
4) Is Iressa (gefitinib) making a comeback in NSCLC?
Two interesting abstracts (O9002 and O9003) demonstrated that analysis of four phase III trials comparing gefitinib monotherapy (250 mg orally per day) versus chemotherapy (docetaxel alone or carboplatin/docetaxel) produced marked efficacy of gefitinib in NSCLC patients with EGFR mutations. The benefits of gefitinib in prolonging progression-free survival (PFS) were even greater in Asians with mutations than in non-Asians with mutations.
It is good sense that EGFR testing should be performed in NSCLC patients in order to select for therapy and ensure that those most likely to respond are treated. There is little point in giving a drug to patients who are unlikely to respond, so the value of biomarkers is clearly demonstrated in this setting.
5) Bayer's shows activity in renal cell carcinoma
In addition to sorafenib, Bayer also have an oral multikinase inhibitor, regorafenib (BAY 73-4506), in development, which produced disease regression or stabilization in 81% of patients in 1st-line treatment of patients with metastatic or unresectable RCC
"Of 48 patients evaluable for efficacy, preliminary data indicate a partial response (PR) in 33% (23% confirmed PR) and stable disease in 46% of patients."
Renal cell carcinoma is fast becoming a) a useful tumour type for testing proof of concept for new drugs in development, but that also means that b) that the market is becoming very competitive for such a small indication. I'm not sure what Bayer would usefully gain by having two such products on the market in the same tumour type, since it potentially cannibalises their sorafenib market share.
6) Amgen's motesanib (AMG-706), a VEGF inhibitor looks active in metastatic breast cancer
"Motesanib in combination with P (paclitaxel) or D (docetaxel) appears to be tolerable and shows evidence of antitumor activity in pts with advanced breast cancer. Coadministration with either P or D had no major effect on motesanib PK."
I've been following this agent for a little while as it started cropping up in searches for clinical trials in multiple tumor types. It appears to target VEGF, KIT and PDGF. Poster PD-5029 is a dose finding study, so the emphasis is on adverse events and tolerability rather than efficacy, but 28-29% response rates this early are interesting at this stage. This is one agent I'll be following more closely as more results are published in the future.
There are probably some other interesting abstracts out there, but those are the ones that caught my eye in the news this week. Anyone who saw some other data is welcome to mention or discuss them in the comments below!