How Four Decades of Research Led to an Important Advance in Lung Cancer

Three photos of Karen Milich: one with her grandson, one of her with her sons, and one of her alone

Clockwise, from upper left: Karen with her grandson, Giles, at Walt Disney World in July 2019, just before she started the trial for sotorasib; Karen at her son Zachary’s wedding in Georgia in October 2020; Karen with her sons Matthew (left) and Zachary Feiden in Washington, DC, in September 2020.

Update: On May 28, 2021, the US Food and Drug Administration granted accelerated approval to sotorasib (LumakrasTM) for the treatment of advanced non-small cell lung cancer driven by the KRAS-G12C mutation in patients who have already received at least one other treatment. The approval was based on the clinical trials co-led by Memorial Sloan Kettering medical oncologist Bob Li.

Karen Milich got the surprise call at 7:30 on a Saturday night. It was Bob Li, her medical oncologist at Memorial Sloan Kettering, telling her that he had obtained a slot for her on a clinical trial of a brand-new experimental drug called sotorasib (AMG 510). “Dr. Li was so excited, and his excitement made me cry,” remembers Karen, who at that time had been living with advanced lung cancer for nearly a year and whose disease was continuing to spread despite other treatments.

She got up the next day, rented a car, and — together with her sister, brother-in-law, and nephew — drove 20 hours from her home in Florida to New York City. She arrived at Dr. Li’s office at 11:00 on Tuesday morning. About a week later, she started taking the drug.

That was August 2019. Since that time, Karen’s cancer has melted away. “I wake up every morning and take my AMG, just like other people take a daily aspirin,” says Karen, who previously had received chemotherapy, radiation, and immunotherapy. “I don’t feel any side effects from it at all.”

A Small Pill with a Big Story

Sotorasib looks like any other pill, but it represents a breakthrough in cancer science. In fact, the US Food and Drug Administration officially granted it a Breakthrough Therapy designation in December 2020. This means the drug has demonstrated substantial improvement over standard treatment and may be close to receiving approval for use beyond clinical trials.

A targeted therapy, sotorasib blocks a cancer-causing protein that results from a mutation in a gene called KRAS (pronounced “kay-rass”). KRAS, initially discovered in 1982 by scientists at the National Cancer Institute and multiple other academic centers, was one of the first cancer genes ever found. Mutations in KRAS and two related genes, HRAS and NRAS, are found in about 20% of all cancers.

[Karen's story is] a testament to what a milestone this is, to be able to target this protein that was previously considered to be really bad news.
Bob T. Li medical oncologist

Yet despite decades of research, scientists kept hitting roadblocks. That’s because the protein’s smooth, round shape lacked notches or grooves where drugs could attach. The mutant protein eventually was given a label by scientists: undruggable.

In the early 2000s, molecular testing for lung cancer started becoming commonplace. If doctors found certain mutations in patients’ tumors, they could prescribe drugs to go after those mutations. Finding a KRAS mutation in a tumor was like drawing the short straw: It meant that the promising targeted therapies that were being developed for other cancer genes would not work.

Looking for Better Treatments

When Karen was first diagnosed in the fall of 2018, receiving a drug to target her KRAS mutation was not an option. She initially was given chemotherapy and radiation at MSK Westchester.

After staying with her mother-in-law in New York for several months while receiving treatment, Karen was ready to return to her home in Florida. Dr. Li arranged for her see a doctor at the Miami Cancer Institute, where she received an immunotherapy drug. (The Miami Cancer Institute is a member of the MSK Cancer Alliance.)

Her cancer continued to grow. It spread to the peritoneum, which is the lining of the abdomen. At that point, she felt like she was running out of options. That’s when she learned she may be a candidate for the sotorasib trial.

Leading the Way in Lab Research

The trial came about thanks to years of hard work, much of it done at MSK. In a paper published in Science in 2016, MSK physician-scientists Piro Lito and Neal Rosen showed how it was possible to target KRAS in cancer cells. Their research built on early molecules that were originally developed by Kevan Shokat at University of California, San Francisco. These compounds inhibit the most common form of mutated KRAS in lung cancer called KRAS-G12C, which is found in about one in eight non-small cell lung cancers — including Karen’s.

Dr. Lito is a member of MSK’s Human Oncology and Pathogenesis Program and also is taking care of patients on the sotorasib trial. He’s played a key role in the development of these inhibitors, including a study published in Nature in early 2020 that showed on the molecular level why so many patients develop resistance to sotorasib and similar drugs as well as ways to overcome it.

“The clinical trials for KRAS inhibitors represent the efforts of many institutions,” Dr. Lito says. “But what really sets MSK apart in this area is the combination of preclinical and clinical development focused on understanding how these drugs work and the best way to administer them to patients.”  

What really sets MSK apart … is the combination of preclinical and clinical development focused on understanding how these drugs work and the best way to administer them to patients.
Piro Lito physician-scientist

A Milestone for People with Lung Cancer

Today, scans show no sign of cancer in Karen’s lungs or anywhere else. In addition, liquid biopsies show no evidence of the cancer-causing mutation in her blood. Although many other patients in the trial eventually developed resistance to sotorasib, Karen has not. But if she does, MSK has additional trials under way that combine sotorasib with other drugs to overcome that resistance, based largely on Dr. Lito and Dr. Li’s research. MSK is also participating in trials of other drugs that target KRAS-G12C, currently led by medical oncologists Gregory Riely and Kathryn Arbour.

“Karen’s got a remarkable story, but she’s not the only one,” says Dr. Li, who is a member of MSK’s Early Drug Development Service, which focuses on early-stage clinical trials. “It’s a testament to what a milestone this is, to be able to target this protein that was previously considered to be really bad news.”

Karen, now 59, still lives in Florida, but since she started on the trial, she’s been staying in the New York City area. Because of her cancer diagnosis and the COVID-19 pandemic, she’s had to step back from her job as a restaurant manager. But that’s given her more time to spend with her 7-year-old grandson, Giles, who she calls “the apple of my eye and the love of my life.” This summer, they’ll be spending the entire month of July together, which has become a family tradition. “I’m thankful to God every day for Dr. Li, Sloan Kettering, and the trial,” Karen says. “They’re all incredible.”

She adds: “I’m also thankful for my whole family who supported me throughout treatment, especially my two sons.”

Dr. Li has served as an uncompensated advisor to Amgen, Genentech, Boehringer Ingelheim, Lilly, AstraZeneca, Daiichi Sankyo, and has received consulting fees from Guardant Health and Hengrui Therapeutics. He has received research grants to his institution from Amgen, Genentech, AstraZeneca, Daiichi Sankyo, Lilly, Illumina, GRAIL, Guardant Health, Hengrui Therapeutics, MORE Health, and Bolt Biotherapeutics. He has received academic travel support from Resolution Bioscience, MORE Health, and Jiangsu Hengrui Medicine. He is an inventor on two institutional patents at MSK (US62/685,057 and US62/514,661) and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. Dr. Lito has served as a scientific advisor to Revolution Medicines and Black Diamond Therapeutics, and he has received grants to his institution from Amgen, Mirati, Revolution Medicines, Boehringer Ingelheim, and Vitrac Pharmaceuticals.