A new hope is on the horizon for patients with cancers that have historically had a poor outlook with conventional therapies.
Patients with metastatic head and neck cancer may have dramatically better odds of survival if the flood of new drugs under development deliver on their promise.
“There’s been an explosion of novel agents in head and neck cancer. It’s been an extremely exciting time,” medical oncologist Dr Trisha Wise-Draper told the audience at the 2022 American Society of Clinical Oncology conference in Chicago this month.
“Historically, we know that there’s been poor overall response rates to single agent chemotherapy after failure of first line therapy in head and neck cancer,” said Dr Wise-Draper, who is from the University of Cincinnati Medical Center.
“However, there have been many mutations and alterations that have been detected in head and neck cancer, especially in those with HPV-negative disease. Some of those may be targetable with novel agents.”
“Head and neck cancer patients have often been found to have impaired immune functions, but if they do have high T cell infiltration into their tumours, then they also have superior survival outcomes. [This suggests] if we can reverse immune dysfunction, that these patients would have better outcomes. Therefore, it’s important to be able to develop novel therapies in order to improve the current response rates to immunotherapy and other agents.”
Dr Wise-Draper outlined half a dozen of the most exciting novel agents and combinations, particularly those targeting alterations in signalling pathways.
“I think that’s where we’re failing the most right now, we are giving a lot of these agents to allcomers rather than selecting patients.”
Dr wise-draper, asco 2022
Tipifarnib was approved by the FDA last year as a breakthrough therapy for patients with recurrent or metastatic HRAS-mutant head and neck squamous cell carcinoma. The HRAS gene is mutated in 4-8% of head and neck SCCs, and this farnesylation inhibitor blocks the HRAS pathway.
Early results from an open label phase II trial found an overall response rate of 55% in patients with at least a 20% HRAS variant allele frequency, leading to progression free survival of about 5.6 months.
PI3K inhibitors have also been a target of research, because mutations are common in different mediators in this pathway, Dr Wise-Draper said. Patients taking buparlisib and paclitaxel had a slightly longer progression-free survival period, of 4.6 months, compared to those taking placebo and paclitaxel, with 3.5 months. A phase III study is now underway.
Growth factors are another target for development. In most of these cancers epidermal growth factor receptors (EGFR) are amplified, causing downstream signalling and proliferation, Dr Wise-Draper said.
While single agents such as the small molecule inhibitor afatinib or the recombinant chimeric antibody cetuximab only have overall response rates around 10-14%, these drugs can induce what’s known as antibody dependent cellular cytotoxicity, or ADCC. “[This] can be taken advantage of and can be combined with PD-1 inhibitors and induce a more robust immune response,” Dr Wise-Draper said.
Multiple phase II trials have now found “impressive” overall response rates of around 40-50% when patients were treated with a combination of EGFR and PD-1 inhibitors, such as pembrolizumab and cetuximab or avelumab and cetuximab.
PD-1 inhibitors have also been combined with VEGF inhibitors, such as in the lenvatinib and pembrolizumab phase II trial, with a “decent” overall response rate of 36%, and phase III trials are underway, Dr Wise-Draper said. VEGF inhibitors can potentially allow immune cell infiltration into the tumour, she explained.
Other immune checkpoint inhibitors, such as the B7-H3 antibody enoblituzumab, have been used with pembrolizumab with impressive early results and are in phase III trials now, Dr Wise-Draper said.
Researchers have also been investigating drugs that help natural killer cells overcome tumour cell defences with some success. Similarly, there’s some hope for modifying the tumour microenvironment to make it more toxic to cancer cells, but research is still in its very early stages, she said.
“We just have to wait for the phase III studies to confirm there are several promising approaches to overcome immunotherapy resistance as well, which we all know, with only a 20% response rate in metastatic head and neck cancer, is critically important,” Dr Wise-Draper said.
But personalised approaches were direly needed, she added. “I think that’s where we’re failing the most right now, is that we are giving a lot of these agents to allcomers rather than selecting patients. It’s not an easy task for any of us to answer, but I feel a personalised approach is the only way we’re going to make real headway in these patients and understand their individual defects.”
