ASCO: Emerging targeted therapies show signs of clinical activity across multiple cancer types

Julia Pitts tried all the standard treatment options with her local physicians after she was diagnosed with metastatic uterine cancer in 2015. When they were no longer effective, she decided to seek out clinical trial options at MD Anderson.

Her cancer had mutations in the KRAS gene, which made her a candidate for an investigational targeted therapy called sotorasib, or AMG 510, which blocks the mutant KRAS protein. After roughly one year on the treatment, she’s seen her tumor shrink twice and remained stable over her last three scans, all with minimal side effects.

“I was at the end of my rope when the chemotherapy and radiation therapy stopped working, and I never thought I’d be where I am now,” says Pitts. “After being on this trial, I’ve been able to continue my normal life, back to gardening and walking. People actually look at me and can’t tell I have cancer. It’s been a life changing experience for me.”

Targeted therapies are designed to take advantage of certain vulnerabilities within cancer cells, selectively attacking the Achille’s heel of the tumor in order to provide more effective treatments for patients in need while. Often these rely on specific genetic mutations in the cancer, requiring genomic testing in order to identify patients that may benefit.  

Studies presented at the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting by MD Anderson researchers showcase early results from several targeted therapies with evidence of clinical activity in treating patients with certain mutations across a variety of cancer types.

KRAS inhibitor sotorasib appears well-tolerated with modest clinical activity for patients with KRAS G12C mutations (abstract 4018, 3511)

KRAS mutations are among the most common across cancer, and a particular mutation known as KRAS G12C is associated with poor outcomes in patients. This mutation is found in roughly 13% of all non-small cell lung cancers, up to 3% of colorectal cancers and a variety of other solid tumor types. There are no approved targeted therapies available for targeting KRAS mutations.

Sotorasib is currently under investigation in the CodeBreak 100 Phase I/II trial, and updated results from patients with colorectal cancer and other solid tumors were shared in two presentations. David Hong, M.D., professor of Investigational Cancer Therapeutics, is senior author of Abstract 4018 and presenting author of Abstract 3511.

In 42 patients with advanced colorectal cancers, treatment with sotorasib resulted in an overall response rate of 7.1% and a disease control rate of 76.2%. In other non-lung cancers, sotorasib achieved a partial response in three of 22 patients, with stable disease in 13 patients. Across both studies, treatment appeared to be well-tolerated, with manageable side effects consistent with earlier reports of this medication.

Hong explained that while these are modest effects, the clinical activity provides proof of concept for continued research, including possible combination approaches.

Full information on co-authors and disclosures for these studies is available here and here.

RET inhibitor selperactinib shows anti-tumor activity in brain metastases of patients with RET fusion-positive lung cancer (Abstract 9516)

RET fusions occur when the chromosome containing the RET gene breaks apart and joins with a gene on a different chromosome, creating a fusion protein. These RET fusions drive cancer progression across multiple cancer types, most commonly in lung and thyroid cancers.

Selpercatinib, a targeted RET inhibitor, recently was approved by the Food and Drug Administration for treating patients with RET fusion-positive lung cancers and medullary thyroid cancers based on data from the Phase I/II LIBRETTO-001 clinical trial.

Vivek Subbiah, M.D., associate professor of Investigational Cancer Therapeutics, leads this trial at MD Anderson and presented data on the activity of selpercatinib, or LOXO-292, in brain metastases from RET fusion-positive lung cancers

Presented data showed that among 22 patients with measurable brain metastases, 82% (18) of patients achieved objective responses including complete responses in 23% (5) and partial responses in 59% (13). These data indicate that selpercatinib is capable of generating strong responses in intracranial lesions consistent with those seen in primary lung cancers, explains Subbiah.

Full information on co-authors and disclosures for these studies is available here.

PI3K inhibitor copanlisib achieves partial responses in advanced cancers with PIK3CA mutations (Abstract 3506)

The PI3K protein is an important signaling molecule in the normal cell that regulates a variety of cellular processes, including growth and survival. The PIK3CA gene encodes that catalytic portion of this protein, and mutations in these gene are commonly found in several cancer types, including liver, breast, colon, ovarian, gastric, brain and lung cancers.

Copanlisib is a class 1 pan-PI3K inhibitor with activity against both the alpha and delta isoforms of the protein. It is being evaluated as part of the NCI-MATCH platform clinical trial for patients with advanced cancers harboring PIK3CA mutations. Data from the copanlisib arm was presented by Senthil Damodaran, M.D., Ph.D., assistant professor of Breast Medical Oncology.

In 28 patients available for analysis, most common cancer types were gynecologic, gastrointestinal and genitourinary. Copanlisib achieved an overall response in three patients (11%) and a clinical benefit rate, indicating tumor shrinkage or stable disease, of 32%. Six patients had stable disease for more than six months on treatment. Toxicities reported were consistent with those previously reported for targeting the PI3K pathway.

Copanlisib showed meaningful clinical activity in select tumors with PIK3CA mutations in a group of patients that were heavily pre-treated, explains Damodaran. He notes the toxicity profile was favorable overall, thus suggesting further study is warranted to evaluate copanlisib as an option to target the PI3K pathway, either alone or in combination approaches.

Full information on co-authors and disclosures for these studies is available here.