Good news this morning as Roche announced that their Hedgehog (Hh) inhibitor licensed from Curis, GDC-0449 (now known as vismodegib), has been submitted to the FDA for the treatment of advanced basal cell carcinoma (BCC) in patients for whom surgery is not appropriate.

The filing is based on phase II data from the ERIVANCE (BCC/SHH4476g) phase II trial that was reported earlier this year at the American Association of Cancer Research (AACR) meeting. The pivotal trial was a single arm study with the design based on discussions with the FDA, since there are no approved therapies for this setting. In other words, these are refractory patients with advanced disease.

For those interested in the previous data and history, the AACR plenary presentation was previously reviewed and discussed here on PSB, as was the phase I vismodegib data and the evolving Hedgehog market segment.

I first came across this compound several years ago at the Rodman And Renshaw conference in 2009, when Curis presented the initial data and concept – very promising even then – although the CEO was a bit clueless on the market size and opportunity in the Q+A at that time, so it’s been an interesting ride to watch.

The submitted data is based on overall response rate (ORR), the primary endpoint of the trial, which is typical with accelerated review filings based on phase II data in patients who have no other treatment options.  Certainly, the interim data presented at AACR by Dr Ervin Epstein showed some truly stunning responses in some patients that caused some gasps in the audience around me.

The final ORR announced by Roche was 43% patients with locally advanced BCC (laBCC) and 30% in patients with metastatic BCC (mBCC).  At the AACR meeting, I don’t recall the PFS being reached at that time, but Roche/Genentech noted in their press release that:

“The median duration of progression-free survival (PFS) by independent review for both metastatic and locally advanced BCC patients was 9.5 months.

That’s pretty good news for patients, methinks!  The side effect profile was similar to that presented at AACR (ie no new surprises) and characteristic of Hh inhibitors:

“The most common drug-related adverse events were muscle spasms, hair loss, altered taste sensation, weight loss, fatigue, nausea, decreased appetite and diarrhea. Serious adverse events (SAEs) were observed in 26 patients (25 percent).”

The Roche press release also went on to describe the SAEs more more detail:

“Four patients (4 percent) had SAEs that were considered to be related to vismodegib, including one case each of: blocked bile flow from the liver (cholestasis), dehydration with loss of consciousness (syncope), pneumonia accompanied by an inability of the heart to pump enough blood (cardiac failure) and a sudden arterial blockage in the lung (pulmonary embolism).  Fatal events were reported in seven patients (7 percent).”

Overall, with these kind of side effects, the drug is more suitable for advanced patients as tolerability (including dysgeusia) will be an issue for patients diagnosed earlier, so vismodegib is unlikely to replace surgery in the long run. That said, it does represent an advance for patients in whom surgery is no longer an option.

The early data suggested that resistance to vismodegib might become an issue after 6 months in some patients, but other patients clearly did better than that, which is reflected in the updated PFS data of 9.5 months.  No doubt researchers are already working on the understanding the mechanisms of resistance as exemplified by de Sauvage’s group at Genentech see Metcalfe and de Sauvage (2011) and Dijkgraaf et al., (2011) for examples, which will hopefully lead us to new trials with logical combinations in the near future.

Conclusions:

The big question on everyone’s mind is probably will the FDA accept the filing after summarily sending back the T-DM1 submission with a refusal to file letter?

My educated guess is yes, based on the fact that these patients are clearly refractory to surgery, AND no treatment options exist or are currently approved. That’s a rather different situation from advanced breast cancer, where many many treatment options exist and we don’t know how many of the patients in the T-DM1 trial were truly receiving the drug as salvage therapy.

Based on the clear cut data I saw presented at AACR, I’m expecting that the vismodegib filing will be accepted by FDA and receive a fairly rapid approval.  If approved, vismodegib will offer the first proof of concept for the role of Hedgehog and Smoothened inhibition in the treatment of cancer.

References:

rb2 large gray Roche files vismodegib for basal cell carcinoma with FDAMetcalfe, C., & de Sauvage, F. (2011). Hedgehog Fights Back: Mechanisms of Acquired Resistance against Smoothened Antagonists Cancer Research, 71 (15), 5057-5061 DOI: 10.1158/0008-5472.CAN-11-0923

Dijkgraaf GJ, Alicke B, Weinmann L, Januario T, West K, Modrusan Z, Burdick D, Goldsmith R, Robarge K, Sutherlin D, Scales SJ, Gould SE, Yauch RL, & de Sauvage FJ (2011). Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance. Cancer research, 71 (2), 435-44 PMID: 21123452