Pivotal study designs revealed

Having completed just one phase 1 study of its key project, the anti-EGFR x TGF-β fusion protein ficerafusp alfa, Bicara Therapeutics is launching a pivotal trial in first-line head and neck cancer.

Fortifi-HN01, as it will be known, is one of three key phase 3 studies newly listed on clinicaltrials.gov, the other two involving Gilead's Trodelvy moving into small-cell lung cancer, and Roche's divarasib into front-line NSCLC. For Bicara speed is of the essence, given comparisons against Merus's petosemtamab, and the design of ficerafusp's phase 3 trial had been eagerly awaited since both projects yielded promising response rates in early trials last year.

In November Bicara said it had "aligned with the FDA on the design" of Fortifi-HN01, but it's only now that the clinicaltrials.gov entry is up that this has been made public. As expected Fortifi-HN01 won't involve HPV-positive patients, with the study's entry mandating that subjects with oropharyngeal squamous cell carcinoma must be HPV negative.

Unlike petosemtamab, an anti-EGFR x LGR5 bispecific MAb, ficerafusp's phase 1 activity in HPV-positive head and neck cancer was underwhelming, and Bicara had earlier indicated further development of ficerafusp specifically in HPV-negative disease.

Like the phase 1 trial, the new pivotal study, which formally begun in December, combines ficerafusp with Merck & Co's Keytruda, and focuses on PD-L1-positive patients; overall survival and ORR are the key primary endpoints.

The ORR number to beat is around 15-19%, according to anecdotal data from Keytruda's Keynote-048 trial, which showed a median OS benefit of 13 months in all patients. The OS result hasn't been split out by HPV status, but Keytruda is known to perform relatively badly in HPV-negatives.

Recent key phase 3 study initiations

Source: OncologyPipeline.

Also keenly awaited were the designs of Gilead's Evoke-SCLC-04 study of the anti-TROP2 ADC Trodelvy, and Roche's Krascendo-2 trial of the KRAS G12C inhibitor divarasib. Both pivotal tests had been trailed by the companies before their initiation, which according to clinicaltrials.gov is due in April and May respectively.

Trodelvy's move into SCLC followed the drug's discontinuation in second-line NSCLC, resulting in Gilead writing off $1.8bn of the value of its $21bn acquisition of Trodelvy's originator, Immunomedics. 

Like the phase 2 Tropics-03 study, Evoke-SCLC-04 will enrol patients who have relapsed after chemo; Evoke-SCLC-04 subjects might also have failed on PD-(L)1 therapy, but don't have to have done so. Tropics-03 mandated progression on chemo as well as PD-(L)1, and showed ORR of 42%, median PFS of 4.4 months and median OS of 14 months. 

Trodelvy has a small but growing niche in its approved breast cancer settings. In the phase 3 SCLC trial it will be compared against topotecan on ORR and OS co-primary endpoints.

Meanwhile, divarasib represents Roche's expected entry into KRAS G12C, and last year saw the start of its first pivotal trial, Krascendo-1, in which the molecule is going head to head against the approved KRAS G12C drugs Lumakras or Krazati in second-line NSCLC.

At the time Roche also promised another pivotal trial, in the first-line NSCLC setting, and this has now materialised in the form of Krascendo-2. The new study will combine divarasib with Keytruda but without chemo, in G12C-mutated NSCLC that has non-squamous histology, and test co-primary endpoints of PFS and OS versus Keytruda plus pemetrexed and platinum.