Targeted Drugs Suggested by Molecular Tumor Board Shrunk Tumors in Two-Thirds of Lung Cancer Patients

NEW YORK – A study evaluating the efficacy of molecular tumor board recommendations at the University Medical Center Groningen found that lung cancer patients' treating doctors were willing to take up the expert body's targeted therapy recommendations, and when they did, these treatments shrunk tumors in two-thirds of patients. 

The results of the retrospective analysis were published last week in JCO Precision Oncology. 

In recent years, targeted therapies directed towards specific driver mutations have become the standard of care in many cancers, especially non-small cell lung cancer. Expert bodies now recommend testing non-small cell lung cancer patients for EGFR mutations, BRAF V600 mutations, ALK and ROS1 rearrangements, and EGFR T790M resistance mutations, in order to ensure that they receive approved targeted drugs.

Next-generation sequencing and extensive molecular profiling sometimes can reveal more uncommon or unknown combinations of genomic alterations that have not been described in NSCLC but are reported in other malignancies. The rarity of these mutations makes it impractical to try to enroll patients in large drug trials. For that reason, cancer centers are increasingly convening multidisciplinary molecular tumor boards (MTBs) that can weigh the available evidence on rare driver mutations detected in cancer patients and recommend clinical trials, off-label, or investigational drugs that may potentially be beneficial. 

The study, led by Leon van Kempen from the University Medical Center Groningen, found that for NSCLC cases with complex molecular profiles, when patients' treating doctors took up the MTB's recommended targeted drugs outside of a clinical trial, patients had an objective response rate of 67 percent, with a median progression-free survival of 6.3 months and an overall survival of 10.4 months.

The molecular tumor board at UMCG comprised pulmonary oncologists, medical oncologists, pathologists, clinical scientists in molecular pathology, and structural biologists. Cases submitted to the MTB have typically undergone genomic profiling at the UMCG molecular pathology lab.

The board first considers available, approved, guideline-based targeted therapies. If none are available, the board then considers available clinical trials that the patient may be eligible for. If no trials are available, then the board considers off-label targeted therapies for which there is evidence of actionability against the mutation. The recommendations are noted in the hospital's medical record system and shared with the treating oncologist, who weighs factors like patient performance status before prescribing the treatment.

In this study, data from 110 genomically profiled NSCLC samples representing 106 patients were reviewed by the MTB (three patients were evaluated multiple times). The tumor board recommended targeted therapies in 59 cases, including 35 that had no prior systemic therapy and 24 with one or more prior therapies. Of the 59 cases, the MTB recommended 24 for clinical trials, with follow-up information available in 21. The MTB suggested on-label targeted therapies for 15 cases, with follow-up available in 10, and 20 cases were guided to an off-label treatment, with follow-up available in 16.

Out of the 21 patients who were recommended for a clinical trial, four were enrolled.

All patients recommended for on-label therapy received them, while 11 of the 16 patients recommended for off-label targeted therapy got them. In five patients who were recommended for off-label targeted therapy but didn't get them, this was because the treatment could not be prescribed due to the patient's poor performance score, the drug couldn't be obtained, or because the clinician and patient decided against it for other reasons.

Patients treated with an off-label targeted therapy all had at least one prior treatment. Recommendations included targeted therapies for uncommon resistance mechanisms to ALK or EGFR inhibitors. The MTB-recommended treatment in this group resulted in a partial response or complete response in six out of the 11 patients, and stable disease in one patient. Two patients progressed on treatment, and tumor response was not evaluable in the remaining two patients.

In this group, median progression-free survival was 4.8 months and median overall survival was 7 months. At the last check-in, three patients had an ongoing response, one patient switched to an alternative treatment due to progression, and seven patients died.

The authors wrote that the adherence rate for off-label cases of 69 percent in this study is high compared to rates reported by other molecular tumor boards, which range from 27 percent to 40 percent. They also wrote that the response rate of 55 percent to off-label drugs is high considering most cases were reviewed when they were progressing to multiple prior lines of therapy. Response rates for off-label therapy described by other molecular tumor boards tend to range from 13 percent to 30 percent.

"The higher response rate reported here could be due to strict on-target-only criterion for off-label targeted therapy recommendations. For example, in contrast to others, pathways downstream of KRAS were not considered actionable in cases of a KRAS mutation. In this example, the recommendation would then be standard nontargeted therapy," the authors wrote. "Furthermore, successful off-label therapy is not only determined by matching a drug to a genomic alteration but also by the healthcare infrastructure to support the treatment."

In the 10 patients that received on-label targeted therapy recommendations whose follow-up data was available, 80 percent had either a partial response or a complete response. Median progression-free survival in this group was 8.5 months and median overall survival was 12.1 months. At the last follow-up, one patient had an ongoing response, five patients had switched to another treatment due to progression, and four patients had died.