Spectrum Pharmaceuticals Submits New Drug Application for Poziotinib for metastatic NSCLC with HER2 exon 20 insertion mutations.

 

                  

Spectrum Pharmaceuticals, a biopharmaceutical company focused on novel and targeted oncology therapies,  announced that it has submitted its New Drug Application (NDA) for poziotinib to the U.S. Food and Drug Administration (FDA) for use in patients with previously treated locally advanced or metastatic non-small cell lung cancer (NSCLC) with HER2 exon 20 insertion mutations. The NDA submission is based on the positive results of Cohort 2 from the ZENITH20 clinical trial, which assessed the safety and efficacy of poziotinib. The product has received Fast Track designation and there is currently no treatment specifically approved by the FDA for this indication.

“The NDA submission for poziotinib marks an important step in achieving a first treatment for patients with HER2 exon 20 insertion mutations in lung cancer,” said Joe Turgeon, President and CEO of Spectrum Pharmaceuticals. “I want to thank the patients, investigators and our internal staff who have passionately worked to achieve this important milestone in an area of high unmet medical need.”

ZENITH20 Cohort 2 Clinical Results Summary

Results for Cohort 2 of the ZENITH20 clinical trial have been published in the Journal of Clinical Oncology (November 29, 2021), and can be accessed by clicking here.

Cohort 2 enrolled 90 patients who received an oral once daily dose of 16 mg of poziotinib. The intent-to-treat analysis demonstrated a confirmed objective response rate (ORR) of 27.8% (95% Confidence Interval (CI), 18.9%-38.2%). The observed lower bound of 18.9% exceeded the pre-specified lower bound of 17%. The median duration of response was 5.1 months and the median progression free survival was 5.5 months. In this cohort, 87% of patients had drug interruptions with 11 patients (12%) permanently discontinuing due to adverse events. 13 patients (14%) had treatment-related serious adverse events. As previously announced, the company had a successful pre-NDA meeting with the FDA which resulted in an agreement to submit an NDA for poziotinib. During the meeting, Spectrum confirmed with the FDA that Cohort 2 data could serve as the basis of an NDA submission. The company will continue to work with the FDA as appropriate, while the agency conducts its review.

About the ZENITH20 Clinical Trial

The ZENITH20 study consists of seven cohorts of NSCLC patients. Cohorts 1 (EGFR) and 2 (HER2) in previously treated NSCLC patients with exon 20 mutations and Cohort 3 (EGFR) in first-line patients have completed enrollment. Cohort 4 (HER2) in first-line NSCLC patients with exon 20 mutations is still enrolling patients. Cohorts 1- 4 are each independently powered for a pre-specified statistical hypothesis and the primary endpoint is objective response rate (ORR). Cohort 5 includes previously treated or treatment-naïve NSCLC patients with EGFR or HER2 exon 20 insertion mutations. Cohort 6 includes NSCLC patients with classical EGFR mutations who progressed while on treatment with first-line osimertinib and developed an additional EGFR mutation. Cohort 7 includes NSCLC patients with a variety of less common mutations in EGFR or HER2 exons 18-21 or the extracellular or transmembrane domains

 https://en.wikipedia.org/wiki/Poziotinib 

Combined drug treatment for lung cancer and secondary tumors

In continuation of my update on alectinib, erlotinib and  osimertinib

 

                                                                   alectinib

                                                    

                                                                     erlotinib

                                                  

                                                                             Osimertinib

Researchers at Kanazawa University report in the Journal of Thoracic Oncology a promising novel approach for a combined treatment of the most common type of lung cancer and associated secondary cancers in the central nervous system. The approach lies in combining two cancer drugs, with one compensating for a resistance side effect of the other.

In 20 to 40% of patients with cancer, metastasis (the development of secondary tumors) in the central nervous system (CNS) occurs. CNS metastasis impacts negatively on a patient's quality of life, and is associated with a poor health prognosis. In a form of cancer known as ALK-rearranged non-small-cell lung cancer (NSCLC), CNS metastasis is known to persist when drugs targeting primary tumors are used. Now, Seiji Yano from Kanazawa University and colleagues have investigated the origins for the resistence to such drugs, and tested a new therapeutic strategy on a mouse model.

The researchers looked at the drug alectinib. Although used in standard treatments for advanced ALK-rearranged NSCLC, approximately 20 to 30% of patients treated with alectinib develop CNS metastasis, which is attributed to acquired resistance to the drug.

By treating mice first injected with tumor cells with alectinib daily for 16 weeks, the scientists obtained a mouse model displaying alectinib resistance. By biochemical analyses of the mouse brains, Yano and colleagues were able to link the resistance to the activation of a protein known as epidermal growth factor receptor (EGFR). This activation is, in turn, a result of an increase in production of amphiregulin (AREG), a protein that binds to EGFR and in doing so 'activates' it.

Based on this insight, the researchers tested the effect of administering drugs used for inhibiting the action of EGFR in combination with alectinib treatment. The experiments showed that a combination treatment of alctinib with either erlotinib or osimertinib—two existing EGFR-inibiting drugs—prevented the progression of CNS metastasis, controlling the condition for over 30 days.

The scientists conclude that the combined use of alectinib and EGFR-inhibitors could overcome alectinib resistance in the mouse model of leptomeningeal carcinomatosis (LMC), a particular type of CNS metastasis. Quoting Yano and colleagues: "Our findings may provide rationale for clinical trials to investigate the effects of novel therapies dual-targeting ALK and EGFR in ALK-rearranged NSCLC with alectinib-resistant LMC."

Non-small-cell lung cancer

Non-small-cell lung carcinoma (NSCLC) and small-cell lung carcinoma (SCLC) are the two types of lung cancer. 85% of all lung cancers are of the NSCLC type. NSCLCs are less sensitive to chemotherapy than SCLCs, making drug treatment of the highest importance.

Alectinib is a drug used for treating NSCLC, with good efficiency. However, 20-30% of patients taking the drug develop secondary cancer in the central nervous system (CNS), which is associated with an acquired resistance to alectinib. Seiji Yano from Kanazawa University and colleagues have now made progress towards a novel therapy against this resistance: a combination of alectinib with other drugs.

Epidermal growth factor receptor inhibitors

The drugs that Yano and colleagues tested in combination with alectinib on a mouse model were of a type known as epidermal growth factor receptor (EGFR) inhibitors, including osimertinib and erlotinib. Both are being used as medication for treating NSCLC. The former was approved in 2017 as cancer treatment by the U.S. Food and Drug Administration and the European Commission. Yano and colleagues obtained results showing that EGFR inhibitors counteract resistance to alectinib and have therefore potential in novel therapies for NSCLC and secondary cancers in the CNS.

https://medicalxpress.com/news/2017-11-osimertinib-progression-free-survival-asian-egfr-mutated.html

FDA Approves Tagrisso (osimertinib) as First-Line Treatment for EGFR-Mutated Non-Small Cell Lung Cancer

In continuation of my update on Osimertinib, AstraZeneca,announced that the US Food and Drug Administration (FDA) has approved Tagrisso (osimertinib) for the 1st-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) mutations (exon 19 deletions or exon 21 L858R mutations), as detected by an FDA-approved test. The approval is based on results from the Phase III FLAURA trial, which were presented at the European Society of Medical Oncology 2017 Congress and published in the New England Journal of Medicine.

Dave Fredrickson, Executive Vice President, Head of the Oncology Business Unit at AstraZeneca, said: “Today’s FDA approval of Tagrisso in the 1st-line setting is an exciting milestone for patients and our company. Tagrisso delivered unprecedented median progression-free survival data across all pre-specified patient subgroups, including patients with or without CNS metastases, and could prolong the lives of more patients without their tumors growing or spreading.”

Dr. Suresh S. Ramalingam, Principal Investigator of the FLAURA trial, from Winship Cancer Institute of Emory University, Atlanta, said: “The approval of osimertinib (Tagrisso) in the 1st-line setting represents a major advance in the treatment of patients with EGFR mutations and a significant change in the treatment paradigm. Osimertinib (Tagrisso) provides robust improvements in progression-free survival with no unexpected safety signals compared to the previous generation of EGFR inhibitors.”

The FLAURA trial compared Tagrisso to current 1st-line EGFR tyrosine kinase inhibitors (TKIs), erlotinib or gefitinib, in previously untreated patients with locally advanced or metastatic EGFR-mutated (EGFRm) NSCLC. Tagrisso met the primary endpoint of progression-free survival (PFS) (see table below). PFS results with Tagrisso were consistent across all pre-specified patient subgroups, including in patients with or without central nervous system (CNS) metastases. Overall survival data were not mature at the time of the final PFS analysis.

*Confirmed responses

Safety data for Tagrisso in the FLAURA trial were in line with those observed in prior clinical trials. Tagrisso was generally well tolerated, with Grade 3 or higher adverse events (AEs) occurring in 34% of patients taking Tagrisso and 45% in the comparator arm. The most common adverse reactions (≥20%) in patients treated with Tagrisso were diarrhea (58%), rash (58%), dry skin (36%), nail toxicity (35%), stomatitis (29%), fatigue (21%) and decreased appetite (20%).

In the US, Tagrisso is already approved for the 2nd-line treatment of patients with metastatic EGFRm NSCLC, whose disease has progressed on or after a 1st-line EGFR-TKI therapy and who have developed the secondary T790M mutation, as detected by an FDA-approved test. In 2017, Tagrisso was granted Breakthrough Therapy and Priority Review designations by the US FDA in the 1st-line treatment setting. Tagrisso is under regulatory review in the European Union and Japan for use in the 1st-line treatment setting with regulatory decisions anticipated in the second half of 2018.

Tagrisso received its first approval for 1st-line use based on the FLAURA data in Brazil in patients with metastatic EGFRm NSCLC on April 16, 2018.

FDA Approves Tagrisso (osimertinib) as First-Line Treatment for EGFR-Mutated Non-Small Cell Lung Cancer

Trial shows apple allergen as effective treatment option for birch pollen-related apple allergy

In continuation of my update on Osimertinib

Osimertinib improves progression-free survival compared to standard first line therapy in Asian patients with EGFR-mutated non-small-cell lung cancer (NSCLC), according to the Asian subset analysis of the FLAURA trial presented at the ESMO Asia 2017 Congress, sumultaneously published in The New England Journal of Medicine.

EGFR mutations occur in 30-40% of NSCLC in Asian populations compared to 10-15% in Western populations. The phase III FLAURA trial compared osimertinib, a third generation EGFR-tyrosine kinase inhibitor (TKI), to standard of care EGFR-TKIs (erlotinib or gefitinib) as first line therapy in NSCLC patients with EGFR mutations. A total of 556 patients from Asia, Europe, and North America were randomized 1:1 to treatment with osimertinib or standard of care. Osimertinib improved progression-free survival by 54%.

This subset analysis included the 322 Asian patients in the FLAURA trial, of whom 46 were Chinese, 120 were Japanese, and 156 were from other parts of Asia.

The median progression-free survival was 16.5 months with osimertinib compared to 11.0 months for the standard therapy, with a hazard ratio of 0.54 (95% confidence interval, 0.41-0.72; p<0.0001).

The median duration of response was two-fold higher for patients treated with osimertinib (17.6 months) compared to standard of care (8.7 months). The overall response rate was 80% with osimertinib compared to 75% with standard of care treatment. Median overall survival was not reached. The incidence of grade 3 or higher toxicities was lower for osimertinib (40%) than the standard treatment (48%).

Lead author Professor Byoung Chul Cho, Yonsei Cancer Center, Seoul, Korea, said: "As in the overall trial population, osimertinib provided a significant progression-free survival benefit in Asian patients with EGFR-mutated NSCLC. Asian patients had similar toxicities with osimertinib as the overall FLAURA population. Osimertinib should be the preferred first line treatment for EGFR-mutant NSCLC in Asia."

Commenting on the findings Professor James CH Yang, Chairman, Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei City, Taiwan, said: "The results of this subset analysis are quite compatible with the findings in the overall population presented at the ESMO 2017 Congress in Madrid. We can therefore conclude that osimertinib can be considered as the standard of care for the first line treatment of Asian advanced NSCLC patients with EGFR mutations."

"The proportion of patients having adverse events that caused them to stop taking osimertinib was similar in the overall (13%) and Asian (15%) populations," added Yang. "We tend to think osimertinib is a well tolerated drug so these discontinuation rates were surprisingly high and need further investigation."

Yang continued: "Although there was no statistical difference between the hazard ratios for progression-free survival, it was numerically lower in non-Asians (0.34) compared to Asians (0.54). There is an ongoing debate as to whether Asian and non-Asian patients with EGFR mutations have distinct responses to EGFR-TKIs. This might be due to variations in clinical practice rather than biology. A meta-analysis of all relevant studies could shed light on this issue."

"It will also be important to know whether Asian and non-Asian patients in the FLAURA trial with brain metastases had similar outcomes," said Yang.

Trial shows apple allergen as effective treatment option for birch pollen-related apple allergy

AstraZeneca reports new Phase I extended follow-up data on osimertinib in NSCLC patients at ELCC 2016

AstraZeneca today reported new Phase I extended follow-up data on osimertinib in both first- and second-line treatment of patients with non-small cell lung cancer (NSCLC), at the European Lung Cancer Conference (ELCC) 2016. Late-breaker presentations reinforced the efficacy and safety profile for osimertinib previously seen in the AURA clinical trials programme.

osimertinib

Phase I data from the AURA trial on osimertinib investigated as first-line treatment in 60 patients (pooled 80mg and 160mg dose cohorts) with epidermal growth factor receptor (EGFR) mutation-positive advanced NSCLC showed an objective response rate (ORR, a measurement of tumour shrinkage) of 77% (95% confidence interval (CI): 64%-87%) and a progression-free survival (PFS) of 19.3 months, with 55% of patients remaining progression-free at 18 months (95% CI: 41%-67%).1 Median duration of response (DoR) was non-calculable (NC) (95% CI: 12.5 months to NC) at the time of data cut off, with 53% of patients continuing to respond at 18 months (95% CI: 36%-67%).1 Of the 60 first-line patients, five had tumours also harbouring the T790M mutation at diagnosis (known as de novo patients) and all five of these patients showed durable responses. The most common adverse events were rash (78% overall; 2% ≥Grade 3), diarrhoea (73% overall; 3% ≥Grade 3), dry skin (58% overall; 0 ≥Grade 3) and paronychia (50% overall; 3% ≥Grade 3). All of the Grade 3 or above events in these categories occurred at the 160mg dose.

Klaus Edvardsen, Vice President, Clinical Oncology and Interim Head of Oncology, Global Medicines Development at AstraZeneca said:

In a Phase I study with osimertinib as first-line therapy in EGFR-mutation positive NSCLC, we are seeing consistently durable responses. In many cases, responses continue for at least 18 months including in a small group of patients with the T790M mutation detectable at diagnosis. The ongoing Phase III FLAURA trial will further characterise the potential of osimertinib 80mg in the first-line EGFRm setting.

AstraZeneca reports new Phase I extended follow-up data on osimertinib in NSCLC patients at ELCC 2016: AstraZeneca today reported new Phase I extended follow-up data on osimertinib in both first- and second-line treatment of patients with non-small cell lung cancer (NSCLC), at the European Lung Cancer Conference (ELCC) 2016. Late-breaker presentations reinforced the efficacy and safety profile for osimertinib previously seen in the AURA clinical trials programme.

IASLC lauds FDA approval of alectinib for lung cancer treatment

The International Association for the Study of Lung Cancer (IASLC) is once again gratified to see the approval of a new second-generation lung cancer treatment that can help many patients in their battle against the disease. Lung cancer patients got another round of hope with the FDA's rapid progression of lung cancer drug approvals - this time for alectinib (Alecensa, Roche/Genenetech) for patients with advanced (metastatic) ALK-positive non-small cell lung cancer (NSCLC) if their disease deteriorated after treatment with another therapy called crizotinib (Xalkori, Pfizer). Patients who could not tolerate treatment with crizotinib also qualify for use of alectinib.

Lung cancer is the leading cause of cancer deaths around the world, responsible for claiming more lives than prostate, colon and breast cancer combined. Medications that target the individual characteristics of a patient's disease continue to create new options and hope for those with lung cancer. For example, tumor cells in about 5 percent of lung cancer patients with NSCLC contain the ALK (anaplastic lymphoma kinase) genetic mutation. In patients with metastatic cancer, the disease spreads to new part of the body. For ALK-positive NSCLC metastatic patients, the disease often spreads to the brain.

Many ALK-positive patients benefit from treatments called ALK inhibitors, such as crizotinib which blocks the activity of the ALK protein and can prevent NSCLC cells from growing and spreading. Alectinib is an oral medication that performs similarly. Patients can also develop resistance to ALK inhibitors such as crizotinib, so alectinib gives health professionals a new option to continue to extend their patients' life span. The FDA previously approved ceritinib (Novartis) in the same treatment setting.

"These types of medications that take advantage of a patient's specific genetic mutations are the future of lung cancer treatments and these treatments create a blueprint of how we can turn some cancers into a chronic disease and eventually create a cure," said Fred R. Hirsch, MD, PhD, Professor of Medicine and Pathology at the University of Colorado Cancer Center and School of Medicine and CEO of the IASLC.

Alectinib is the fifth lung cancer treatment approved by the FDA since early October. The others include:

Necitumumab in combination with standard chemotherapy to treat patients with advanced squamous NSCLC who did not previously received systemic therapy;

Two immunotherapy treatments: nivolumab and pembrolizumab;

And osimertinib, a 3rd-generation EGFR TKI.

IASLC lauds FDA approval of alectinib for lung cancer treatment