Dozens of investigators from Memorial Sloan Kettering Cancer Center (MSK) shared their research at the 2022 American Association for Cancer Research (AACR) annual meeting, held April 8 to 13 in New Orleans. The studies presented included:
- A clinical trial that looked at the long-term benefits of a targeted lung cancer drug.
- Lab research that suggested statins may boost the effectiveness of a targeted breast cancer drug.
- Findings validating a new molecular diagnostic tool for blood cancers.
Two-Year Data for Sotorasib, a Novel Targeted Drug for Lung Cancer
Sotorasib (Lumakras™) is a targeted lung cancer drug that was designed to treat non-small cell lung cancers driven by a mutation called KRAS-G12C. At this year’s AACR meeting, a multicenter team of investigators presented two years’ worth of follow-up data for CodeBreaK100, the clinical trial that led to sotorasib’s accelerated approval by the U.S. Food and Drug Administration in May 2021. CodeBreaK100 was co-led by MSK lung cancer expert Bob Li, who is senior author of the new study.
At the meeting, the researchers not only reported the longest-ever survival and safety data for a KRAS-G12C inhibitor but also the genomic profiles of the tumors. In the future, this information could be used to help predict which patients are most likely to benefit long-term from treatment with sotorasib.
The trial enrolled 174 people with non-small cell lung cancer driven by the KRAS-G12C mutation. Most had already received treatment with chemotherapy, immunotherapy, or both, and had stopped responding. All of them had disease that had spread beyond the lung.
For all patients in the trial, the response rate was 41%, which was measured by substantial shrinkage of their tumors. The average time that it took for the cancer to begin advancing again was 6.3 months, and the average time that patients lived after starting treatment with sotorasib was 12.5 months, with just over half of patients living at least a year. The most significant result is that nearly one-third of patients continue to survive after two years.
For those patients who initially respond to sotorasib but later develop resistance to it, research is ongoing at MSK and other centers looking at combination therapies that further extend the length of time that patients continue to do well.
The most common side effects from sotorasib were diarrhea, nausea, and changes in liver enzymes. Most of these side effects were not severe. Even for the patients who remained on the drug for two years or longer, the side effects did not get worse.
The investigators looked at the genomic differences in the tumors, including whether the tumors made a protein called PD-L1. They found that tumors with any measurable level of PD-L1 responded to sotorasib, including those with low or negative levels. This is significant because patients with low or negative levels of PD-L1 usually do not respond to immunotherapy drugs called checkpoint inhibitors that target PD-1 or PD-L1. The findings suggest that those with low or negative levels of this protein might do better if they are treated with sotorasib instead.
“The development of sotorasib and other KRAS-G12C inhibitors required a monumental effort on the part of the physicians and scientists who worked on it,” Dr. Li says. “For decades, mutations in the KRAS gene, which are implicated in many different kinds of cancer, were considered to be undruggable. This drug has become a good treatment option for patients with advanced disease, with some people deriving long-term benefit.”
The latest results from CodeBreaK100 were presented at AACR by thoracic oncologist Grace Dy of Roswell Park Comprehensive Cancer Center in Buffalo.
This clinical trial was funded by Amgen. Dr. Li has served as an uncompensated advisor and consultant to Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Genentech, and Lilly. He has received research grants to his institution from Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Hengrui USA, and Lilly. He has received academic travel support from Jiangsu Hengrui Medicine and MORE Health. He is an inventor on two institutional patents at MSK (US62/685,057, US62/514,661) and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. Dr. Li is supported by the Memorial Sloan Kettering Cancer Center Support Grant P30 CA008748 from the National Institutes of Health.
Combining a Breast Cancer Drug With Statins
Bo Liu, a senior research scientist in the lab of MSK physician-scientist Sarat Chandarlapaty, presented research that suggested cholesterol-lowering medications called statins may improve the effectiveness of a class of targeted breast cancer drugs. The breast cancer drug the team studied was TDM-1 (also known as ado-trastuzumab emtansine, or Kadcyla®), a so-called antibody-drug conjugate (ADC).
TDM-1 contains two parts: first, an antibody that seeks out HER2 (a protein that’s found on the surface of some cancer cells) and second, a payload of chemotherapy. The antibody delivers the chemotherapy directly into the cancer cells, mostly sparing healthy tissue. TDM-1 has been shown to be effective in treating breast and stomach cancers with high levels of HER2, but unfortunately many patients develop resistance to it. Researchers are looking for ways to make it more effective and longer lasting.
To look for drugs that might boost the power of TDM-1 and other ADCs, Drs. Liu and Chandarlapaty collaborated with MSK scientist Jason Lewis, who had identified that cholesterol-lowering medicines, statins, can change the way HER2 is present on the cell surface. Dr. Liu, having developed a cell-based test to carefully track cellular uptake on TDM-1, tested the effect of combining it with a statin and found that the statin helped drive the TDM-1 into the cancer cell and enhance its anti-cancer efficacy.
The investigators found combining statins with TDM-1 destroyed HER2-positive breast cancer cells not only in the test tube but also in mouse models. Once they confirmed this synergistic effect in the lab, the research team decided to retrospectively look at clinical records, to determine whether patients receiving TDM-1 who were also being treated with statins had a better response to their cancer treatment.
In an analysis of 164 patients, 21 of whom were taking statins at the same time, the cholesterol-reducing medications did appear to improve outcomes: For patients taking statins and TDM-1 together, progression-free survival (the time it takes for cancer to advance) was 14 months, compared with 5.4 months for patients taking TDM-1 alone.
“We are not able to draw statistically significant conclusions because of the small number of patients,” Dr. Liu explains. “We are now pursuing analysis for larger groups of patients to evaluate the clinical benefit of statin therapy. We are also working with cell lines and mouse models to deepen our understanding of the mechanisms by which statins enhance the activity of ADCs and to evaluate the safety of this combination treatment.”
This research was supported by National Institutes of Health grant R01 249666 and the Breast Cancer Research Foundation. Dr. Chandarlapaty has relationships with or financial interests in the Breast Cancer Research Foundation, Eli Lilly and Company, the Global Breast Cancer Conference, the National Comprehensive Cancer Network, Novartis, Paige.AI Inc., Sanofi US Services Inc., and the Seoul Breast Cancer Symposium.
Using Cell-Free DNA Tests To Analyze Certain Blood Cancers
In a poster session, a team led by test development manager Sara DiNapoli and molecular pathologist Maria E. Arcila presented the first, preliminary validation data for MSK-ACCESS™ Heme, a new blood test developed at MSK for the molecular diagnosis of certain blood cancers. MSK-ACCESS Heme works through the analysis of cell-free (cf) DNA in the blood plasma.
The test extends previous efforts for the development and implementation of MSK-ACCESS™ (Analysis of Circulating cfDNA to Evaluate Somatic Status), which has been used at MSK since 2019 to provide genomic profiling and disease monitoring for solid tumors. “We tend to think of hematologic malignancies as cancers that circulate in the blood, but there are many that do not actually circulate,” Dr. Arcila explains. “For these cancers, tumor biopsies for initial diagnostic profiling and for subsequent disease monitoring may be very challenging. Cell-free DNA provides an alternate and less-invasive way for us to assess these tumors.”
MSK-ACCESS Heme detects alterations in 117 genes that have been linked to hematologic malignancies. By narrowing the content to key genes, the team is able to provide higher sensitivity, which is required for detection of genetic alterations in circulating tumor DNA.
In the AACR presentation, the investigators reported how the new MSK-ACCESS Heme test performed on 53 validation samples — 26 normal and 27 with known genetic variants. MSK-ACCESS Heme successfully detected 100% of the genetic variants that were present in the samples, including those at relatively low concentration (down to 0.5% frequency).
Dr. DiNapoli says that her team is preparing to submit data to the New York State Department of Health, which could approve MSK-ACCESS Heme for clinical use as early as later this year with an intended initial use in lymphoma.
In addition to being easier for patients, Dr. Arcila notes, examining cell-free DNA in the blood can also provide a more complete picture of these cancers, which tend to be multifocal and very heterogeneous (meaning that not all cancer cells carry the same mutations). Accurate molecular diagnosis is important for matching patients with the best targeted therapies for their particular tumors. Also, because these blood tests can be performed often in a noninvasive fashion, they enable doctors to monitor how tumors may be changing in response to treatment and the potential development of resistance mechanisms.
In the future, there are plans to continue expanding MSK-ACCESS Heme to include other sources of cell-free DNA in body fluids and to encompass other hematologic cancers.
This study was supported by the Comprehensive Cancer Center Core Grant (P30 CA008748) at Memorial Sloan Kettering Cancer Center from the National Institutes of Health. Dr. Arcila has relationships with or financial interests in AstraZeneca, Biocartis US Inc., Bristol-Myers Squibb, Clinical Care Options, Invivoscribe, Janssen Global Services LLC, PeerView Institute for Medical Education (PVI), and Physicians’ Education Resource