Nine years after selling Medivation to Pfizer for $14 billion, David Hung, M.D., is going toe to toe with the New York drugmaker and two other pharma giants in a lung cancer field.
Hung’s Nuvation Bio has won FDA approval for Ibtrozi, or taletrectinib, to treat patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC). With the nod, Ibtrozi will go up against existing medicines from Pfizer, Bristol Myers Squibb and Roche.
ROS1 is a well-established subset of NSCLC. As it stands, Roche’s Rozlytrek is largely duking it out with BMS’ Augtyro, while Pfizer’s first-generation tyrosine kinase inhibitor (TKI) Xalkori gradually falls out of favor.
However, ROS1 NSCLC has not been viewed as a major market opportunity, with combined Rozlytrek and Augtyro sales reaching roughly $200 million in 2024 despite their additional uses in NTRK gene fusion-positive solid tumors.
But Hung believes Ibtrozi boasts a unique profile that could allow the next-generation TKI to reach new heights. For their part, analysts at Jefferies see potential for the Nuvation drug to become a blockbuster.
ROS1-positive NSCLC sometimes has a high degree of brain metastases. But Pfizer’s Xalkori doesn’t even penetrate the blood-brain barrier to address that issue, Hung explained in an interview with Fierce Pharma.
Before Ibtrozi, Augtyro had demonstrated the best tumor response and disease progression data. But the BMS drug comes with some central nervous system side effects such as dizziness and cognitive impairment that have affected its dosing and adoption.
By comparison, Ibtrozi’s label does not come with any CNS safety warnings, which Hung attributed to Ibtrozi’s increased selectivity for ROS1 over TRKb, a neurotrophic receptor.
Importantly though, Ibtrozi’s label does include a warning of QTc interval prolongation—an abnormal heart rhythm problem—that Augtyro doesn’t have.
In terms of efficacy, Ibtrozi showed its power in two single-arm studies, Trust-I in China and Trust-II globally. Among ROS1-positive TKI-naïve patients, Ibtrozi mounted response rates of 90% and 85% in the two trials, respectively. The numbers were 52% and 62% in TKI-pretreated patients between the two studies.
The median duration of response was not reached or not included in the drug's label because of short follow-up times in the TKI-naïve patients. In TKI-experienced patients, the median duration of response was 13.2 months in Trust-I and not displayed for Trust-II, given a shorter follow-up in the study.
Previously, a pooled analysis of the two studies using an earlier data cut linked Ibtrozi to a 44.2-month median duration of response and 45.6 months of median progression-free survival (PFS) in TKI-naïve patients. For TKI-pretreated patients, the pooled figures were 16.6 months for median duration of response and 9.7 months for median PFS.
Those data look competitive compared with those posted by BMS’ Augtyro, which has shown a median progression-free survival of 35.7 months in TKI-naïve patients and nine months in second-line patients.
Besides, among 24 second-line patients who also had measurable CNS metastases, intracranial responses were recorded in 15 (63%) individuals who took Ibtrozi, according to the pooled analysis. Hung argued that data point is important because CNS is the most common site of progression in ROS1 NSCLC.
Although Ibtrozi maintains activity in the second line, Hung argued that doctors should still use the drug right upfront in the first-line setting.
“If you would wait for progression, all drugs become less effective,” Hung said. “When patients have progressed and with brain metastases, you’re putting a patient in a very difficult position.”
Besides efficacy and tolerability issues, Hung spotlighted one logistical challenge that has played a major role in stymieing the growth of the ROS1 market.
After being diagnosed with NSCLC, patients have typically been put on a PD-1 and chemotherapy while their tumor samples are assessed for genetic mutations. In many cases, rather than switching to a ROS inhibitor, the patient may choose to stay on the PD-1/chemo regimen when their tests come back ROS-positive two to three weeks later, Hung explained.
Hung blamed that practice on the previous National Comprehensive Cancer Network (NCCN) guidelines, which recommended both PD-1/chemo maintenance and switching to a TKI as viable options for patients who’ve already started on an immune checkpoint regimen.
All of that changed in January, when the NCCN updated its guidelines and now deems immunotherapy contraindicated in ROS1-positive NSCLC. Hung believes that change marks a tailwind going into Ibtrozi’s launch.
About 3,000 new ROS1-positive NSCLC cases are diagnosed in the U.S. each year, according to Nuvation’s estimate.
In a November note, Jefferies analysts predicted that Ibtrozi could reach more than $1 billion in peak sales, largely thanks to its long revenue tail if patients are progression-free for about four years and the drug is well tolerated to support long-term use.
Nuvation obtained rights to Ibtrozi outside of China, Japan and Korea just last year from its all-stock acquisition of AnHeart Therapeutics, which itself got the TKI from Daiichi Sankyo.