FDA Approves Cosela (trilaciclib) to Decrease the Incidence of Chemotherapy-Induced Myelosuppression

G1 Therapeutics, Inc. (Nasdaq: GTHX), a commercial-stage oncology company, announced   the U.S. Food and Drug Administration (FDA)   approval of  Cosela (trilaciclib) for injection to decrease the incidence of chemotherapy-induced myelosuppression in adult patients when administered prior to a platinum/etoposide-containing regimen or topotecan-containing regimen for extensive-stage small cell lung cancer (ES-SCLC). It is the first and only therapy designed to help protect bone marrow (myeloprotection) when administered prior to treatment with chemotherapy. Cosela is expected to be commercially available through G1’s specialty distributor partner network in early March.

“The approval of trilaciclib (Cosela) is an important advance in the treatment of patients with extensive-stage small cell lung cancer receiving chemotherapy,” said Dr. Jeffrey Crawford, Geller Professor for Research in Cancer in the Department of Medicine and Duke Cancer Institute. “The most serious and life-threatening side effect of chemotherapy is myelosuppression, or damage to the bone marrow, resulting in reduced white blood cells, red blood cells and platelets. Chemotherapy-induced myelosuppression may lead to increased risks of infection, severe anemia, and/or bleeding. These complications impact patients’ quality of life and may also result in chemotherapy dose reductions and delays. To date, approaches have included the use of growth factor agents to accelerate blood cell recovery after the bone marrow injury has occurred, along with antibiotics and transfusions as needed. By contrast, trilaciclib provides the first proactive approach to myelosuppression through a unique mechanism of action that helps protect the bone marrow from damage by chemotherapy. In clinical trials, the addition of trilaciclib to extensive-stage small cell lung cancer chemotherapy treatment regimens reduced myelosuppression and improved clinical outcomes. The good news is that these benefits of trilaciclib will now be available for our patients in clinical practice.”

Chemotherapy is an effective and important weapon against cancer. However, chemotherapy does not differentiate between healthy cells and cancer cells. It kills both, including important hematopoietic stem and progenitor cells (HSPCs) in the bone marrow that produce white blood cells (immune cells that help fight infection), red blood cells (cells that carry oxygen from the lungs to the tissues), and platelets (cells that prevent bleeding from cancer, surgeries, chronic diseases, and injuries). This chemotherapy-induced bone marrow damage, known as myelosuppression, can lead to increased risk of infection, anemia, thrombocytopenia, and other complications. Myeloprotection is a novel approach of protecting HSPCs in the bone marrow from chemotherapy-induced damage. This approach can help reduce some chemotherapy-related toxicity, making chemotherapy safer and more tolerable, while also reducing the need for reactive rescue interventions.

“Chemotherapy is the most effective and widely used approach to treating people diagnosed with extensive-stage small cell lung cancer; however, standard of care chemotherapy regimens are highly myelosuppressive and can lead to costly hospitalizations and rescue interventions,” said Jack Bailey, Chief Executive Officer at G1 Therapeutics. “Cosela will help change the chemotherapy experience for people who are battling ES-SCLC. G1 is proud to deliver Cosela to patients and their families as the first and only therapy to help protect against chemotherapy-induced myelosuppression.”

Cosela is administered intravenously as a 30-minute infusion within four hours prior to the start of chemotherapy and is the first FDA-approved therapy that helps provide proactive, multilineage protection from chemotherapy-induced myelosuppression. The approval of Cosela is based on data from three randomized, placebo-controlled trials that showed patients receiving Cosela prior to the start of chemotherapy had clinically meaningful and statistically significant reduction in the duration and severity of neutropenia. Data also showed a positive impact on red blood cell transfusions and other myeloprotective measures. The trials evaluated Cosela in combination with carboplatin/etoposide (+/- the immunotherapy atezolizumab) and topotecan chemotherapy regimens. Approximately 90% of all patients with ES-SCLC will receive at least one of these regimens during the course of their treatment.

The majority of adverse reactions reported with Cosela were mild to moderate in severity. The most common adverse reactions (≥10%) were fatigue, hypocalcemia, hypokalemia, hypophosphatemia, aspartate aminotransferase increased, headache, and pneumonia. Serious adverse reactions occurred in 30% of patients receiving Cosela. Serious adverse reactions reported in >3% of patients who received Cosela included respiratory failure, hemorrhage, and thrombosis. Grade 3/4 hematological adverse reactions occurring in patients treated with Cosela and placebo included neutropenia (32% and 69%), febrile neutropenia (3% and 9%), anemia (16% and 34%), thrombocytopenia (18% and 33%), and leukopenia (4% and 17%), respectively.

“Quite often, people diagnosed with extensive-stage small cell lung cancer rely on chemotherapy to not only extend their lives, but also to acutely alleviate their symptoms,” said Bonnie J. Addario, lung cancer survivor, co-founder and board chair of the Go2 Foundation for Lung Cancer. “Unfortunately, the vast majority will experience chemotherapy-induced side effects, resulting in dose delays and reductions, and increased utilization of healthcare services. G1 shares our organization’s goal to improve the quality of life of those diagnosed with lung cancer and to transform survivorship among people living with this insidious disease. We are thrilled to see new advancements that can help improve the lives of those living with small cell lung cancer.”

Approximately 30,000 small cell lung cancer patients are treated in the United States annually. G1 is committed to helping patients with extensive-stage small cell lung cancer in the U.S. gain access to treatment with Cosela. For more information on access and affordability programs, patients and providers should call the G1toOne support center at 833-G1toONE (833-418-6663) from 8:00 a.m. to 8:00 p.m. Eastern time.

G1 received Breakthrough Therapy Designation from the FDA in 2019 based on positive data in small cell lung cancer patients from three randomized Phase 2 clinical trials. As is common with breakthrough-designated products that receive priority review, G1 will conduct certain post-marketing activities, including in vitro drug-drug interaction and metabolism studies, and a clinical trial to assess impact of trilaciclib on disease progression or survival in patients with ES-SCLC with chemotherapy-induced myelosuppression treated with a platinum/etoposide-containing or topotecan-containing regimen with at least a two year follow up. G1 intends to initiate the post-approval clinical trial in 2022.

Cosela (trilaciclib) Co-Promotion Agreement with Boehringer Ingelheim

In June 2020, G1 announced a three-year co-promotion agreement with Boehringer Ingelheim for Cosela in small cell lung cancer in the U.S. and Puerto Rico. G1 will lead marketing, market access and medical engagement initiatives for Cosela. The Boehringer Ingelheim oncology commercial team, well-established in lung cancer, will lead sales force engagement initiatives. G1 will book revenue and retain development and commercialization rights to Cosela and pay Boehringer Ingelheim a promotional fee based on net sales. The three-year agreement does not extend to additional indications that G1 is evaluating for trilaciclib. Press release details of the G1/ Boehringer Ingelheim agreement can be found here.

Ref : https://en.wikipedia.org/wiki/Trilaciclib

One-Cycle BE500P Seems Safe for High-Risk Early Testicular Cancer

 

Bleomycin                                                                             etoposide

Cisplatin

In continuation of my update on etoposide and cisplatin

For high-risk stage 1 nonseminoma germ cell tumors of the testis (NSGCTT), one cycle of adjuvant bleomycin, etoposide (500 mg/m²), and cisplatin (BE500P) is safe, resulting in a two-year malignant recurrence (MR) rate of 1.3 percent, similar to that reported for two cycles of BE360P, according to a study published online Jan. 1 in European Urology.

Michael Cullen, M.D., from the University Hospitals Birmingham NHS Foundation Trust in the United Kingdom, and colleagues compared recurrence rates for one cycle of BE500P to recurrence rates for two cycles of BE360P among 246 patients with vascular invasion-positive stage 1 NSGCTT or combined seminoma + NSGCTT registered in a single-arm prospective study.

Patients were followed for a median of 49 months. Ten patients with increasing tumor markers were excluded at baseline. The researchers found that four patients had MR at six, seven, 13, and 27 months; all were treated with secondary chemotherapy, and at five years, three remained recurrence-free. The rate of two-year MR was 1.3 percent (95 percent confidence interval, 0.3 to 3.7 percent). Nonmalignant recurrences developed in three patients who had localized differentiated teratoma; after surgery, they were rendered disease-free. In 6.8 percent of patients, grade 3 to 4 febrile neutropenia occurred.

"Our study has found strong evidence to suggest that testicular cancer chemotherapy can be safely reduced from two cycles to just one -- making their treatment shorter, kinder, and cheaper," a coauthor said in a statement.

https://www.europeanurology.com/article/S0302-2838(19)30895-4/fulltext
https://en.wikipedia.org/wiki/Bleomycin
https://en.wikipedia.org/wiki/Etoposide
https://en.wikipedia.org/wiki/Cisplatin

Amrubicin promise for etoposide-naïve SCLC patients

Patients with chemotherapy-refractory small-cell lung cancer (SCLC) may benefit from treatment with the topoisomerase II inhibitor amrubicin, research from Japan suggests.

The 82 patients enrolled in the open-label, single-arm Japan Clinical Oncology Group Study JCOG0901 trial received amrubicin 40 mg/m2 for 3 days on a 21-day cycle, for a median of four cycles. All patients had already experienced no response, or progression, following treatment with at least one platinum-based regimen, with 51.2% previously treated with etoposide and 57.3% with irinotecan.

The overall response rate, defined as an independently assessed complete or partial response, was highly significant, at 32.9%, compared with a null hypothesis threshold of 10.0% or below. Median progression-free survival was 3.5 months and overall survival was 8.9 months, with over a third (35.7%) of patients alive 1 year later.

And amrubicin showed particular promise for patients who had not previously received etoposide, another type of topoisomere II inhibitor, say Haruyasu Murakami (Shizuoka Cancer Center) and colleagues.

Etoposide-naïve patients achieved an objective response rate of 45.0%, compared with 21.4% for those previously treated with the agent, a significant difference.

Both median progression-free survival and overall survival were also significantly higher in etoposide-naïve than pretreated patients, at 5.1 versus 2.9 months and 13.1 versus 7.9 months, respectively.

The reduced benefit of amrubicin found in patients previously treated with etoposide may be due to downregulation of topoisomerase II following the initial treatment, Murakami et al suggest in Lung Cancer.

Amrubicin promise for etoposide-naïve SCLC patients

Podophyllotoxin in American Mayapple ?

A common plant called American mayapple (see the picture) may soon offer an alternative to an Asian cousin that's been harvested almost to extinction because of its anti-cancer properties. The near-extinct Asian plant, Podophyllyum emodi, produces podophyllotoxin (see the structure), a compound used in manufacturing etoposide, the active ingredient in a drug used for treating lung and testicular cancer. Podophyllyum emodi is a cousin of the common mayapple, sometimes considered a weed, found in the United States.

Podophyllotoxin and its derivatives are used in several commercially available pharmaceutical products such as the anticancer drugs etoposide, teniposide, and etopophos, which are used in the treatment of small-cell lung cancer, lymphoblastic leukemia, testicular cancer, and brain tumors. Podophyllotixin derivatives are also used for the treatment of psoriasis and malaria, and some are being tested for the treatment of rheumatoid arthritis. Currently, podophyllotoxin is produced commercially using the roots and rhizomes of Indian mayapple, an endangered species harvested from the wild in India, Pakistan, Nepal, and China.

Now the researchers from the US, found that mayapple colonies in the eastern part of the United States can be used for the development of high podophyllotoxin cultivars, which could subsequently provide the base for commercial production of podophyllotoxin in the United States.

Ref : http://hortsci.ashspublications.org/cgi/content/abstract/44/2/349