Tumors With KRAS G12C Mutation Respond to Adagrasib and Using Toripalimab to Treat Stage III Lung Cancer: The ASCO Plenary Series

ASCO ® Plenary Series
April 19, 2023
Greg Guthrie, ASCO staff

The pace of progress in cancer research keeps getting faster and faster. However, the results of this research can take time to reach the medical community. The ASCO Plenary Series is a program developed by the American Society of Clinical Oncology (ASCO) to help speed the delivery of high-impact cancer research. In this series, cancer care providers gather online to learn about new, carefully selected research and discuss the study results with their colleagues.  

The April 2023 session in the ASCO Plenary Series features these studies:   

Adagrasib shows promise in treating advanced cancers with a KRAS G12C mutation

Who does this study affect: People with advanced tumors that contain a KRAS G12C mutation, including pancreatic cancer, biliary tract cancer, and other tumors.

What did this study find: A genetic change, or mutation, called KRAS G12C can be found in about 14% of non-small cell lung cancers and 4% of colorectal cancers. Percent is how many out of 100. Less commonly, this mutation can also be found in other tumors, including pancreatic cancer, biliary tract cancer (which includes bile duct cancer and gallbladder cancer), ovarian cancer, and other cancer types. This study focused on these less common tumor types, many of which have limited treatment options available for advanced stage disease.   

In the phase 1/2 KRYSTAL-1 clinical trial, researchers wanted to see if a targeted therapy medication called adagrasib (Krazati) would be effective at treating tumors with this specific mutation. When a treatment is used to target only a tumor’s specific genetic changes rather than the tumor’s location in the body, it is called a “tumor agnostic” treatment. Adagrasib is already approved by the U.S. Food and Drug Administration to treat advanced non-small cell lung cancer with a KRAS G12C mutation. The primary goals of a phase 1/2 clinical trial are to see if experimental treatments are safe to use in people and if they are effective. These phases do not compare the effectiveness of the experimental treatment against other treatments.

In this study, 63 people with tumors that had a KRAS G12C mutation were treated with adagrasib. The types of tumors included 21 pancreatic cancer, 12 biliary tract cancer, 9 appendix cancer, 5 ovarian cancer, 4 gastroesophageal junction or esophageal cancer, 4 unknown primary, 3 small bowel cancer, 3 uterine cancer, 1 breast cancer, and 1 glioblastoma. The median age of the participants was 65 years, which means that half of the patients were younger than 65 and the other half were older than 65. Many had previously received systemic therapy to treat the cancer.

The researchers were able to measure the effectiveness of adagrasib in 57 participants. They used the following measurements:

  • Objective response rate (ORR). The percentage of patients whose tumors responded to the treatment.

  • Disease control rate (DCR). The percentage of patients who had stable disease or a complete or partial response.

  • Duration of response (DOR). The amount of time from the start of a partial or complete response to when the disease begins growing and spreading again or causes death.

  • Progression-free survival (PFS). The amount of time that the cancer stopped growing and spreading.

  • Overall survival (OS). The amount of time that a patient is alive from the time a treatment is started.

In the 57 participants total, the ORR was 35%, DCR was 86%, DOR was about 5 months, PFS was nearly 7.4 months, and OS was 14 months. Among the 21 participants with pancreatic cancer, the ORR was about 33%, DCR was 81%, PFS was 5.4 months, and OS was 8 months. For the 12 participants with biliary tract cancer, the ORR was nearly 42%, DCR was about 92%, PFS was 8.6 months, and OS was 15.1 months.  

Adagrasib caused side effects in nearly all participants. Most common were nausea, diarrhea, fatigue, and vomiting. More serious side effects occurred in about 1 out of every 4 patients.

What does this mean for patients? Some tumors with the KRAS G12C mutation responded to adagrasib, providing a pathway for further study on treatment options for these advanced-stage diseases.

Our study demonstrates that adagrasib has clinical activity across a broad range of KRAS G12C-mutated tumors, including pancreatic and biliary tract cancers, and observed a response rate of 35% in patients who have no standard-of-care treatment available to them or have declined available therapies.

—   lead study author Shubham Pant, MD, MBBS
University of Texas MD Anderson Cancer Center
Houston, Texas

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Toripalimab plus chemotherapy is more effective than chemotherapy alone in stage III non-small cell lung cancer

Who does this study affect: People with stage III non-small cell lung cancer (NSCLC) that can be treated with surgery.

What did this study find: For people with stage III NSCLC who can undergo surgery, systemic treatment with chemotherapy, immunotherapy, or combined chemotherapy and radiation therapy may be given before the surgery. After surgery, additional systemic treatments may be given. In the phase 3 Neotorch clinical trial from China, the researchers wanted to see whether adding an immunotherapy medication called toripalimab (TuoYi) before and after surgery was more effective than using chemotherapy alone.

Toripalimab (TuoYi) targets the PD-1 protein expressed on immune cells. PD-1 interacts with another protein called PD-L1. PD-L1 helps cancer cells avoid the immune system, allowing them to grow. By blocking this interaction between the PD-1 and PD-L1 proteins, toripalimab boosts the body’s immune system and the ability to fight cancer. Toripalimab is not approved for use in the United States.  

This study included 404 participants with stage III NSCLC that can be treated with surgery and without mutations in the EGFR or ALK genes. The participants were divided evenly into 2 treatment groups. In the toripalimab group, the 202 patients received toripalimab plus chemotherapy for 3 cycles before surgery and 1 cycle after surgery. After surgery, the patients received toripalimab for 13 more cycles. In the chemotherapy plus placebo group, 202 patients received chemotherapy plus a placebo for 3 cycles before surgery and 1 cycle after surgery. After surgery, they received a placebo for 13 more cycles. (Learn more about placebos in cancer clinical trials.)

When the researchers analyzed the data, they had monitored the participants’ health for a median of 18.3 months (about 1.5 years). The researchers measured event-free survival (EFS) to compare the treatment groups. EFS is the amount of time after treatment ends that patients do not have their cancer come back or get worse. In this study, toripalimab plus chemotherapy improved EFS by 60%, compared with chemotherapy plus placebo. The median EFS for toripalimab was not reached. This means that when the data were analyzed, more than half of the people in the toripalimab group were still alive and had not had their cancer come back or get worse. For those in the chemotherapy plus placebo group, the EFS was about 15 months.

The researchers also measured the major pathologic response (MPR) rate, which is when there is 10% or less tumor cells left after treatment, and pathologic complete response (pCR) rate, which is when there are no signs of cancer in tissue samples removed after treatment. In the toripalimab group, the MPR rate was nearly 49% and the pCR rate was about 25%. In the chemotherapy plus placebo group, the MPR rate was about 8% and the pCR rate was 1%.

The rates of side effects were similar for both treatment groups. However, those in the toripalimab group did have more immune-related side effects.

What does this mean for patients? For people with stage III NSCLC that can be treated with surgery, adding toripalimab to chemotherapy is more effective than chemotherapy alone.

“These findings support establishing anti-PD-1 antibody treatment in combination with chemotherapy as the backbone regimen for patients with resectable NSCLC, which will change the clinical practice in the near future.”

—   lead study author Shun Lu, MD, PhD
Shanghai Jiao Tong University
Shanghai, China 

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