Table 4:

FDA Benefit: Risk Analysis

Dimension	Evidence and Uncertainties	Conclusions and Reasons
Analysis of Condition	Each year, an estimated 8,000 people in the United States are diagnosed with bile duct cancer and the 5-year survival for intrahepatic bile duct cancer is 9%. FGFR2 fusions are present in an estimated 13-14% of patients with iCCA. Patients with FGFR rearrangements appear to have a longer median overall survival compared to those with iCCA lacking a FGFR rearrangement.	Cholangiocarcinoma is a serious and life-threatening illness and there is no satisfactory available therapy for the treatment of cholangiocarcinoma with a FGFR2 gene fusion or other rearrangement that has received at least one prior line of treatment.
Current Treatment Options	Current treatment options for patients with CCA are limited, and at the time of pemigatinib approval, there were no approved treatments for the treatment of patients with CCA in the second-line setting, irrespective of whether the tumor harbors an FGFR2 gene fusion or rearrangement.	There is an unmet medical need for new effective treatments for patients with cholangiocarcinoma with a FGFR2 gene fusion or other rearrangement who have received at least one prior line of treatment.
Benefit	FIGHT-202 demonstrated a clinically meaningful and durable ORR in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with a FGFR2 gene fusion or other rearrangement. The estimated ORR was 36% (95% confidence interval [CI]: 27%, 45%). At the time of the analysis, the median DOR was 9.1 months; 24 of the 38 (63%) responders had a DOR lasting at least 6 months and 7 (18%) responders had a DOR of at least 12 months.	The magnitude and duration of responses observed in patients with cholangiocarcinoma with a FGFR2 gene fusion who received prior treatment was large, and reasonably likely to predict clinical benefit. The submitted evidence meets the statutory evidentiary standard for accelerated approval. Incyte has agreed to a postmarketing requirement to submit data from a randomized trial to verify and confirm the clinical benefit of pemigatinib in patients with FGFR2 fusion/rearrangement-positive cholangiocarcinoma.
Risk and Risk Management	The most common adverse reactions occurring with an incidence ≥ 20% were hyperphosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye, dry mouth, decreased appetite, vomiting, arthralgia, abdominal pain, hypophosphatemia, back pain, and dry skin. Ocular toxicity and hyperphosphatemia are important risks of pemigatinib.	The observed safety profile is acceptable when assessed in the context of the treatment of a life-threatening disease. Most of the adverse reactions to pemigatinib were manageable with supportive care and dose modification as needed. The significant and potentially serious adverse reactions of hyperphosphatemia and ocular toxicity are adequately addressed in the Warnings and Precautions section and the dose modification recommendations included in product labeling.