FDA OKs Bavencio as first-line bladder cancer therapy

Bavencio, or avelumab, Pfizer and Merck's immunotherapy, was approved by the FDA as a maintenance treatment for patients who have locally advanced or metastatic bladder cancer whose disease didn't progress after undergoing first-line platinum-containing chemotherapy.

Avelumab is already approved in bladder cancer patients whose disease has progressed following chemotherapy. Bavencio has been approved for maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma that has not progressed with first-line platinum containing chemotherapy. Avelumab is indicated for the treatment of metastatic Merkel cell carcinoma (MCC).

BAVENCIO® (avelumab) is the FIRST and ONLY FDA-approved human anti-PD-L1 immunotherapy with DUAL ENGAGEMENT of both the adaptive and innate immune systems. BAVENCIO has been shown to release the suppression of the T cell-mediated antitumor immune response by blocking the interaction of PD-L1 with PD-1 receptors in preclinical models. BAVENCIO has also been shown to induce NK cell-mediated direct tumor cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.

https://pharmaphorum.com/news/fda-approves-pfizer-merck-kgaas-bavencio-in-first-line-bladder-cancer/

{Avelumab is currently being studied as a therapy for HER2+ MBC in the Aviator clinical trial.}

https://clinicaltrials.gov/ct2/show/NCT03414658

EMA speeds review of AZ, Daiichi Sankyo HER2 drug Enhertu

The European Medicines Agency will fast-track its review of AstraZeneca and Daiichi Sankyo's HER2-positive breast cancer candidate Enhertu, or trastuzumab deruxtecan. The FDA approved the antibody drug conjugate as a treatment for metastatic HER2-positive disease in December.

http://www.pmlive.com/pharma_news/ema_fast-tracks_review_of_azdaiichi_sankyos_her2_drug_1344455

ASCO develops guideline for management of men with breast cancer

Research has led to major improvements in breast cancer diagnosis, treatment and survival. However, men with breast cancer represent only 1% of the U.S. breast cancer population and have not been emphasized in this research.

"Nearly all clinical trial participants have been women," Michael J. Hassett, MD, MPH, medical oncologist at Dana-Farber Cancer Institute and lead author of ASCO's guideline on management of male breast cancer, said in an interview with Healio. "When so few men have been included in the trials, it's hard to draw conclusions about how to treat men vs. women. Considering that more than 95% of breast cancers in men are hormone receptor positive, some have suggested that men and women with breast cancer should be treated differently."

https://www.healio.com/news/hematology-oncology/20200708/asco-develops-guideline-for-management-of-men-with-breast-cancer?utm_source=selligent&utm_medium=email&utm_campaign=news&m_bt=6155829948217

A novel HER2-targeted antibody-drug conjugate offers the possibility of clinical dosing at trastuzumab-equivalent exposure levels

Molecular Cancer Therapeutics

Trastuzumab and the related antibody-drug conjugate (ADC), ado-trastuzumab emtansine (T-DM1), both target HER2-overexpressing cells. Together, these drugs have treatment indications in both early-stage and metastatic settings for HER2+ breast cancer. T-DM1 retains the antibody functionalities of trastuzumab and adds the potency of a cytotoxic maytansine payload. Interestingly, in the clinic, T-DM1 cannot always replace the use of trastuzumab plus chemotherapy administered together as single agents. We hypothesize that this failure may be due in part to the limited systemic exposure achieved by T-DM1 relative to trastuzumab because of toxicity-related dosing constraints on the ADC. We have developed a trastuzumab-based ADC site-specifically conjugated to maytansine through a noncleavable linker. This construct, termed CAT-01-106, has a drug-to-antibody ratio (DAR) of 1.8, approximately half the average DAR of T-DM1, which comprises a mixture of antibodies variously conjugated with DARs ranging from 0-8. The high DAR species present in T-DM1 contribute to its toxicity and limit its clinical dose. CAT-01-106 showed superior in vivo efficacy compared to T-DM1 at equal payload dosing and was equally or better tolerated compared to T-DM1 at equal payload dosing up to 120 mg/kg in Sprague-Dawley rats and 60 mg/kg in cynomolgus monkeys. CAT-01-106 also showed improved pharmacokinetics in rats relative to T-DM1, with 40% higher ADC exposure levels. Together, the data suggest that CAT-01-106 may be sufficiently tolerable to enable clinical dosing at trastuzumab-equivalent exposure levels, combining the functions of both the antibody and the payload in one drug and potentially improving patient outcomes.

https://www.meta.org/papers/a-novel-her2targeted-a...

DOI: 10.1158/1535-7163.mct-20-0190

Antibody-drug conjugates in breast cancer: the chemotherapy of the future?

Current Opinion in Oncology

Abstract

Antibody-drug conjugates (ADCs) represent an interesting new class of anticancer agents, capable of exploiting the specificity of monoclonal antibodies toward cellular-antigens for a targeted release of potent cytotoxic drugs, with a potential increased activity and reduced toxicity compared with traditional chemotherapies. The aim of this article is to review the efficacy and safety of ADCs in breast cancer. Following the approval of T-DM1 both in early and advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer, novel anti-HER2 ADCs have been investigated. Some of these compounds, such as the recently FDA-approved trastuzumab deruxtecan, have shown relevant activity in T-DM1-pretreated patients, possibly thanks to the so-called bystander effect, namely the ability to exert cytotoxic activity also against antigen-negative cells. Such feature allows to overcome the HER2 intratumoral heterogeneity in breast cancer and could explain in the preliminary activity demonstrated also in HER2-low breast cancers. However, several ADCs targeting other cancer-associated antigens than HER2 are under development, representing a promising strategy for the treatment of triple-negative tumors, exemplified by the encouraging results of sacituzumab govitecan. ADCs are innovative and effective therapeutic drugs in breast cancer. Research efforts are ongoing to identify novel targets and combination with other treatment modalities, particularly with immunotherapy, to further improve patients' outcomes.

https://www.meta.org/papers/antibodydrug-conjugate...

DOI: 10.1097/cco.0000000000000656

T-DM1 in Patients With HER2-Positive Metastatic Breast Cancer and Brain Metastases

Annals of Oncology

This exploratory final analysis of a phase IIIb trial was designed to evaluate the benefit of trastuzumab emtansine (T-DM1) for patients with HER2-positive breast cancer and brain metastases. Reduction in the sum of major diameters of brain metastases >30% occurred in 42.9% of patients. Significant intracranial responses were observed among 49.3% of those who had not received brain metastasis–directed radiotherapy.T-DM1 has good activity in this population, and further study is warranted.

CONCLUSION: This exploratory analysis of patients with HER2-positive MBC and BM enrolled in a prospective clinical trial shows that T-DM1 is active and well-tolerated in this population. T-DM1 should be explored further in this setting.

https://www.practiceupdate.com/C/103466/56?elsca1=emc_enews_topic-alert

https://www.annalsofoncology.org/article/S0923-7534(20)39930-0/fulltext#

DOI:https://doi.org/10.1016/j.annonc.2020.06.020

Gussy: Thanks for sharing that - it does sound interesting.

For others who want highlights:

Larotrectinib is an oral drug that received accelerated breakthrough status after it displayed remarkable success in treating adult and pediatric cancers that currently have no satisfactory alternative treatments or have progressed following treatment. This is the second ever FDA-approved drug that treats cancers based on a certain genetic trait, regardless of the patient's age or cancer type, and it is the first drug to ever treat cancers that contain the specific NTRK gene that is present in several common forms of adult cancer and many forms of rare pediatric cancers. NTRK fusions are rare, but can occur in salivary gland, lung, breast, and thyroid cancers, as well as soft tissue sarcoma – and prior to this week's FDA approval, there had been no treatment for many of the cancers that frequently expressed this mutation.

Here is the FDA announcement: https://www.fda.gov/news-events/press-announcements/fda-approves-oncology-drug-targets-key-genetic-driver-cancer-rather-specific-type-tumor

Yes. Looks like Foundation One screens for it.

Here is their list:

https://assets.ctfassets.net/w98cd481qyp0/YqqKHaqQmFeqc5ueQk48w/0a34fcdaa3a71dbe460cdcb01cebe8ad/F1CDx_Technical_Specifications_072020.pdf

I also found all 3 NTRK alterations on the Strata Oncology test list - so it appears that Strata tests for these alterations as well.

Addendum: These tests generally recommend drugs that treat cancer with the genomic finding. So it would be interesting to hear whether this drug is now being recommended. I looked at my results from Strata but, since I did not have any of these alterations, I didn't get any associated recommendations. Strata (in theory) tells you drugs in clinical trial for the alteration, but... that part did not appear to be a perfect process. I know of one drug off the top of my head that was in stage 3 trials at the time my test was run but was left off the list of clinical trial drugs (DS-8201a AKA Enhertu). In fact, they did not recommend any clinical trial drugs. In fairness, Strata was still in clinical trial phase at that point so maybe they had not fully implemented that function yet.