HER2 exon 20 inserted mutation lung cancer (NSCLC) innovative drug! Pan-HER tyrosine kinase inhibitor poziotinib has suffered a major regulatory setback, and Luye Pharmaceutical has the rights in China!

Nov.
25, 2022 /Biovalley BIOON/ -- Spectrum Pharma is a biopharmaceutical company
focused on novel targeted oncology therapies.
Recently, the company announced that the U.
S.
Food and Drug Administration (FDA) has issued a full response letter (CRL) to the new drug application (NDA)
for the novel targeted cancer drug poziotinib (poziotinib, HM781-36B).
The NDA seeks approval for poziotinib: a novel, oral, irreversible EGFR family receptor-blocking pan-HER inhibitor for the treatment of previously treated patients
with locally advanced or metastatic non-small cell lung cancer (NSCLC) carrying HER2 exon 20 insertion mutations (Ex20ins).
Previously, the FDA has granted poziotinib Fast Track Designation (FTD).

HER2 exon 20 insertion mutations (Ex20ins) are a rare subtype that accounts for about 2-4%
of NSCLC.
There is no approved treatment
for non-small cell lung cancer (NSCLC) carrying HER2 exon 20 insertion mutations, either treatment-naive or previously treated.

Poziotinib is developed by Hanmi Pharma, with Luye Pharma owning the rights to the Chinese market and Spectrum owning the rights
outside of China and South Korea.
poziotinib is a novel oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that inhibits EGFR and tyrosine kinase activity of HER2 and HER4, thereby inhibiting the proliferation
of tumor cells expressing these receptors.
Mutation or overexpression/amplification of EGFR family receptors is associated with many different types of cancer, including non-small cell lung cancer (NSCLC), breast cancer, and gastric cancer
.

The FDA issued a CRL indicating that the agency cannot approve poziotinib
in its current NDA form.
According to the CRL, the company had to generate additional data, including a randomized controlled study
.
The FDA's decision came as no surprise, as the agency's Oncology Drug Advisory Committee (ODAC) voted 9-4 in September that the benefits of poziotinib did not outweigh its risks
.

As a result of this regulatory setback in the U.
S.
, Spectrum has decided to immediately deprioritize the poziotinib project and accelerate cost reductions, including cutting R&D-related personnel by 75%.

Based on the expected cost savings from the restructuring, Spectrum believes the company will be able to generate the working capital needed to support its strategic alignment
through 2024.
The company will focus on driving the growth
of its recently launched commercial drug, Rolvedon (eflapegrastim-xnst).

Rolvedon is the first novel long-acting granulocyte colony-stimulating factor (LA-GCSF) approved by the US FDA in September 2022: it is a "whitening" drug for the treatment of febrile neutropenia and reduce the incidence of
infection in adult patients with non-myeloid malignancies who are receiving myelosuppressive anticancer drugs.
Rolvedon has been listed in the U.
S.
in October 2022 with an estimated market opportunity of approximately $2 billion
.

Tom Riga, President and CEO of Spectrum, said, "While we are not surprised by CRL due to the approval recommendation made by ODAC in September this year, we are disappointed
.
We have had many interactions with the FDA since ODAC, and after careful consideration, we made the strategic decision
to immediately deprioritize the poziotinib project.
We remain convinced that poziotinib may be a meaningful treatment option
for patients with this rare type of lung cancer who have failed treatment with other therapies.
At the same time, we are committed to exploring potential strategic alternatives to poziotinib, including partnerships and business development opportunities, and identifying the best path
forward to support patients.
”

Pozitinib chemical structure (Image source: selleck.
cn)

poziotinib (positinib) is a pan-HER tyrosine kinase inhibitor that irreversibly blocks signaling at all HER family tyrosine kinase receptors, including HER1 (erbB1; EGFR）、HER2（erbB2）、HER4（erbB4）
。 For HER receptors carrying exon 20 insertion mutations, preclinical trials have shown that poziotinib inhibits it dozens of times
more than existing tyrosine kinase inhibitors.

In the US, poziotinib NDA is based on the results of cohort 2 of
the multi-cohort open-label Phase 2 ZENITH20 study (NCT03066206).
Cohort 2 enrolled previously treated patients with locally advanced or metastatic NSCLC carrying HER2 exon 20 insertion mutations, and a total of 90 patients were enrolled in the cohort who were treated
with poziotinib at a once-daily dose of 16 mg.

Intention-to-treat (ITT) analysis showed a confirmed objective response rate (ORR) of 27.
8% (95% CI: 18.
9-38.
2), with 18.
9% of observed lower values exceeding the prespecified lower
limit of 17%.
The median duration of response (DOR) was 5.
1 months and the median progression-free survival (PFS) was 5.
5 months
.
In this group of patients, 87% experienced drug discontinuation, 11 patients (12%) were permanently discontinued due to adverse events, and 13 patients (14%) experienced serious adverse events
related to treatment.

Previously, Spectrum held a successful pre-NDA meeting with the FDA, culminating in an agreement
to submit a poziotinib NDA.
During the meeting, Spectrum and the FDA confirmed that Cohort 2 data can be used as a basis for
NDA submissions.
(Biovalley Bioon.
com)

Spectrum Pharmaceuticals Receives Complete Response Letter from U.
S.
Food and Drug Administration for Poziotinib; Reaffirms Focus on the Commercialization of ROLVEDON™ (eflapegrastim-xnst) injection