New FDA Approvals: ASCO Session Reviews Uses and Adverse Effects

What should doctors expect if they prescribe nirogacestat for desmoid tumors? What about fruquintinib for metastatic colorectal cancer (mCRC)?

Nirogacestat, marketed as Ogsiveo (Springworks Therapeutics), and fruquintinib, marketed as Fruzaqla (Takeda Pharmaceuticals), were among the therapies featured in the annual session on newly approved drugs, which took place on the first day of the American Society of Clinical Oncology (ASCO) annual meeting.

Mrinal M. Gounder, MD | Image credit: MSKCC

Mrinal M. Gounder, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, offered an overview of desmoid tumors, which are fibrous growths that emerge in connective tissue, typically in young adults. The tumors can appear in many areas of the body but most often are found in the abdomen. The experience can be extremely painful and isolating for patients, Gounder said, and he encouraged clinicians to help patients find support groups.

“Since very few patients die of this disease, it’s very important to evaluate whether a drug actually improves their quality of life,” Gounder said. Sometimes tumors spontaneously regress for reasons not well understood.

Enter nirogacestat, approved November 27, 2023.¹ This oral gamma secretase inhibitor is the first systemic treatment approved specifically for desmoid tumors, based on a phase 3 study that evaluated patients whose tumors had progressed within 12 months of screening. Results showed significant improvement in progression free survival (PFS) compared with placebo, with a hazard ratio (HR) of 0.29.1

“It was highly statistically significant,” Gounder said. There were PFS benefits among many subgroups, including patients with prior chemotherapy. The study showed responses in the placebo arm as well, “reinforcing that an initial period of observation is appropriate in a selected group of patients with this disease.”

Giving patients nirogacestat means managing adverse effects, including diarrhea, nausea, and fatigue that are associated with the drug class. Some patients experience a rash or a post-nasal drip. In the study, Gounder said, 42% of patients had dose reductions and 20% discontinued treatment.

A more serious adverse event, “is ovarian toxicity, which was observed in 75% of women of childbearing potential,” Gounder said. “As I mentioned before, most of the population that [develops] desmoid tumors are really young people in their 20s and 30s,” and there is “a slight preponderance for women.”

He described ovarian toxicity as a decrease in several specific female reproductive hormone levels; thus, female patients should have baseline levels recorded before treatment. Gounder also refers female patients to a fertility preservation specialist. On the plus side, “What's important is that the majority of patients 78% patient had resolution of this ovarian toxicity.”

“This drug is effective in first or subsequent lines of therapy,” Gounder said. Diarrhea, skin, nasal congestion are transitory, and can be addressed by temporarily holding the drug or adjusting the dose “as necessary to maintain the quality of life of these patients. And ovarian toxicities genuinely have been reversible.”

Fruquintinib for mCRC

Cathy Eng, MD, FACP, FASCO | Image credit: VUMC

Cathy Eng, MD, FACP, FASCO, professor of medicine, hematology, and oncology and codirector GI Oncology and coleader, GI Cancer Research Program at Vanderbilt-Ingram Cancer Center, reviewed the approval for fruquintinib, which came on November 8, 2023.² This inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, is approved for third-line treatment or beyond for patients with mCRC who have received prior treatment with fluoropyrimidine‑, oxaliplatin‑, and irinotecan‑based chemotherapy, an anti‑VEGF therapy, and, if RAS wild‑type and medically appropriate, an anti-EGFR therapy.

Fruquintinib addressed a significant medical need in mCRC. “As many of you know, for our surgically unresectable patients, the 5-year survival for these patients is 15%,” said Eng, who was the co-senior author for FRESCO-2, 1 of 2 trials that led to the approval.² The primary endpoint for FRESCO-2 was overall survival (OS), which had an HR of 0.66; the median OS for fruquintinib was 7.4 months, compared with 4.8 months for placebo. FRESCO, conducted in China, had a similar HR of 0.65; in this trial, Eng said, OS was 9.3 months for fruquintinib and 6.57 months for placebo. PFS for FRESCO-2, the key secondary endpoint, was 3.7 months for fruquintinib vs 1.8 months for placebo, for a difference of 1.9 months, Eng said during the session.²

“The mechanism of action for this selective inhibitor of VEGF inhibitors impacts angiogenesis,” which affects tumor growth, she said. Common side effects include hypertension—which is a class effect—anemia, and hand and foot skin reactions.

“In China, they noted a fairly high incidence of hypertension [at] grade 3 for about 21% of patients and hand-foot skin reaction in about 11% of patients,” Eng said. The hypertension incidence was not as high in FRESCO-2; about 14% of patients reported it, and a smaller share of patients had anemia and skin reactions. Said Eng, “24% of patients required dose reductions—similar to FRESCO.”

“We also looked at health-related quality of life,” she said, and time to deterioration was either in favor of fruquintinib or equivalent, “but no worse.”

Real-world experience. “How do we apply this to the patient population?” Eng asked. She shared a case of a 56-yearold woman with surgically unresectable MSI stable mCRC, who had been previously treated with FOLFOX plus bevacizumab. No clinical trial was available.

The patient “informs me she travels for work and would like some increased convenience,” Eng displayed information for different treatment options, adding, “I show you this data here not for cross trial comparisons per se, but really to look at the toxicities of therapy that may potentially occur with your patient, because this is what we do in real life.”

For Eng’s patient, fruquintinib offered a choice that would be least disruptive. The patient did experience some discomfort in her thumb and her foot,; she delayed treatment for a week, but resumed therapy with no residual issues. “After much discussion, we offer shared decision making and she opted not to decrease her dose—she feels rather well,” with CT scans set for next month.

Belzutifan in Advanced Renal Cell Carcinoma

Eric Jonasch, MD, of The University of Texas MD Anderson Cancer Center, discussed belzutifan, approved as Welifreg on December 14, 2023, in renal cell carcinoma (RCC).³ This oral drug, a HIF-2α inhibitor, is administered once a day and was previously approved for patients with Von Hippel-Landau (VHL) disease-associated RCC.

Eric Jonasch, MD | Image credit: MD Anderson

As Jonasch explained, belzutifan is approved for patients with RCC after progression on an immune checkpoint inhibitor and a tyrosine kinase inhibitor. Results from the phase 3 trial showed that “tumor reduction or stabilization occurred in about two-thirds of individuals,” and compared with everolimus, there was an improved response rate duration of response.

“We do see that this drug has not only novel mechanism of action, but novel-ish side effects, including anemia, hypoxia, and fatigue,” he said. Recommendations, which include monthly monitoring of hemoglobin, self-monitoring of oxygen saturation and appropriate dose adjustments and interventions, ‘are going to optimize the quality of life for these individuals receiving this therapy.”

Jonasch outlined belzutifan’s mechanism of action in detail, explaining the activity of HIF-2α especially if there is deficiency in VHL; the “unbridled” levels of HIF-2α must then be reined in to prevent the growth of VHL-associated tumors. Belzutifan blocks HIF-2α from interacting with other proteins that would allow tumor growth..

He outlined a case of a 64-year-old woman with metastatic clear cell RCC who developed metastatic disease 18 months after nephrectomy. Two separate lines of treatment, including immunotherapy, produced initial improvement, followed by progression in the form of lung lesions.

“How do you treat? Looking at the [National Comprehensive Cancer Network] guidelines, we have a little bit of a conundrum here. And for those who are familiar with the NCCN guidelines for renal cell carcinoma in subsequent lines of therapy, we don't have preferred agents we have other recommended because there are few trials that really have been done in this setting of post [immuno-oncology] most of the registrational studies have been both been done post TKI [tyrosine kinase inhibitors]. So, we're tempering our enthusiasm somewhat for the agents.”

What of the patient? She noticed a change in her oxygen saturation, which went from baseline mid-90s to high 80s. With a dose reduction to 80 mg, her oxygen saturatioin goes back to above 90%.

Understanding progress with this therapy can be challenging. “Unlike TKI is where we see most of the benefit occurring in the first 1 or 2 scans, we see a linear continuous improvement and those individuals who do have a decrease in the disease size. At this point in time her hemoglobin has dropped below 10, and after discussion with the patient about the risks and benefits of either not doing anything, dose reducing transfusions, or giving exogenous erythropoietin, she chooses to receive a darbepoetin (alfa) injection.”

The patient had a partial response at the next restaging.

Although it’s not specific, Jonasch said, “I would not recommend you use this for non-clear cell RCC after progression on an [immune checkpoint inhibitor] and a TKI on tumor reduction. Stabilization occurred in about two-thirds of individuals, and we do see that if a response occurs, it's fairly durable.”

References

1. FDA approves nirogacestat for desmoid tumors. FDA newsroom. Updated November 28, 2023. Accessed June 1, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nirogacestat-desmoid-tumors
2. FDA DISCO burst edition: FDA approval of Fruzaqla (fruquintinib) in adult patients with metastatic colorectal cancer. FDA newsroom. January 5, 2024. Accessed June 1, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-fruzaqla-fruquintinib-adult-patients-metastatic-colorectal
3. FDA approves belzutifan in advanced renal cell carcinoma. FDA newsroom. Updated December 14, 2023. Accessed June 1, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-advanced-renal-cell-carcinoma