Alrizomadlin may restore efficacy of PD-1 blockade in immunotherapy-resistant tumors
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Use of alrizomadlin with pembrolizumab appeared to restore the antitumor effects of the anti-PD-1 antibody among patients with melanoma resistant to or intolerant of immunotherapy, according to phase 2 study results.
The findings, presented during the virtual ASCO Annual Meeting, also showed early antitumor activity among patients with malignant peripheral nerve sheath tumor and liposarcoma. The combination of alrizomadlin (APG-115, Ascentage Pharma) and pembrolizumab (Keytruda, Merck) also appeared well-tolerated.
Alrizomadlin, a small-molecule MDM2-p53 antagonist, restores TP53 function and is a host immunomodulator and regulator of tumor immune escape mechanism, leading to enhanced T-cell mediated antitumor immunity. Preclinical models have shown synergy when used with PD-1 blockade.
“MDM2 is a common molecular alteration across a spectrum of malignancies,” Anthony W. Tolcher, MD, FRCPC, medical oncologist at Texas Oncology and co-founder and director of clinical research at NEXT Oncology, told Healio. “We started the conversation about combining MDM2 inhibition with pembrolizumab after Razelle Kurzrock, MD, and colleagues presented data showing that hyperprogression to PD-1 inhibitors was linked in a large retrospective database search to MDM2 amplification. This suggested that somehow MDM2 might convey resistance to immunotherapy or have a deleterious effect.
“Also, research evaluating whether MDM2 inhibitors somehow reprogrammed T cells showed reprogramming of STAT5 in T cells by MDM2 ultimately led to some antitumoral immune responses in preclinical models,” Tolcher added. “There may be multiple mechanisms by which this is working, which may be altered depending on the clinical setting.”
Researchers evaluated data of 102 adults (median age, 64 years; range, 23-89; 61.8% men) who had received a median two (range, 1-22) prior therapies.
The analysis included the following dose-expansion cohorts: 34 patients with immunotherapy-resistant melanoma; 15 patients with immunotherapy-resistant non-small cell lung cancer and 10 patients with STK11-mutated lung adenocarcinoma; 20 patients with solid tumors with mutated ATM and wild-type p53; 15 patients with MDM2-amplified and p53-wild type liposarcoma; 15 patients with immunotherapy-resistant urothelial carcinoma; and 10 patients with malignant peripheral nerve sheath tumor.
Patients received 150 mg APG-115 every other day along with 200 mg IV pembrolizumab on day 1 of a 21-day cycle.
Safety and overall response rate served as the study’s primary endpoints.
Overall, the combination appeared well-tolerated. Most adverse events were gastrointestinal in nature, including nausea, vomiting and diarrhea. Most grade 3 to grade 4 adverse events were hematologic, including thrombocytopenia, anemia and neutropenia, which Tolcher noted are class effects of MDM2 inhibitors.
Researchers observed the highest ORR, 24.1%, among patients with melanoma, which included one complete and six partial responses. Disease control rate for the melanoma cohort reached 55.2%.
When researchers closely evaluated the melanoma cohort, they identified ORRs of 14.3% among patients with uveal melanoma, 40% among patients with mucosal melanoma and 26.7% among patients with cutaneous melanoma.
“The response rate in the melanoma cohort of almost 25% is approaching the rate of those who have never seen pembrolizumab before,” Tolcher said. “We would expect to see responses among those with cutaneous melanoma, which tends to be more sensitive to PD-1 inhibitors, but for those patients who don’t respond, or who progress, there are very few options afterward that have meaningful benefit.
“There also were responses in uveal and mucosal melanoma, which are generally resistant to PD-1, so there seems to be some encouraging preliminary data in this cohort,” Tolcher added.
Although response rates were lower in the other cohorts, researchers noted these haven’t yet fully accrued. One partial response occurred in each of the NSCLC (6.7%), liposarcoma (6.2%), urothelial carcinoma (12.5%) and malignant peripheral nerve sheath tumor (16.7%) cohorts.
“It’s going to require more work to understand what it is about these patients who respond but, overall, these are very good data for a combination in an immunotherapy-resistant population,” Tolcher said. “Time will tell [how effective it is], and we have to do more work to define the optimal population and ultimately a phase 3 comparative study.”
Perspective
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Wafik S. El-Deiry, MD, PhD, FACP
Although cancer immunotherapy has been a major breakthrough in the field of oncology and has had a major impact on clinical outcomes, there are limitations. Only a minority of patients achieve a long-term survival benefit at 5 years. Also, a substantial percentage of patients do not respond to immunotherapy and, in fact, can display a phenomenon of hyperprogression where tumors grow faster than they were growing just before initiation of immune checkpoint blockade. The p53 tumor suppressor has some effects to suppress certain inflammatory responses, such as IL-6 production, that can dampen the response to immune checkpoint blockade.
Although p53 mutations are common in various human tumors, many tumors retain wild-type p53 genes. However, most tumors with wild-type p53 alleles do not have normal p53 signaling. Examples include cervical or head and neck cancers that express HPV E6 protein that targets p53 for degradation and soft tissue sarcomas and various other tumor types that either have MDM2 gene amplification or otherwise overexpress MDM2 or MDMX (MDM4). MDM2 is an E3 ubiquitin ligase that binds to the N-terminus of p53 and targets the protein for ubiquitin-mediated proteasomal degradation.
In tumors with wild-type p53 and MDM2 overexpression, it is possible to activate the p53 protein by use of DNA-damaging cytotoxic agents. Such agents activate checkpoint proteins such as ATM and Chk2 to phosphorylate the N-terminus of p53 so that it no longer binds to MDM2 and can therefore be stabilized and activated to cause tumor growth arrest or cell death. MDM2 inhibitors have been developed to restore p53 signaling in tumors with MDM2 amplification or overexpression, without the need to cause DNA damage or phosphorylate p53 by ATM. As such, ATM-mutated tumors may be particularly well-suited for treatment with MDM2 inhibitors in addition to the tumor types that have MDM2 amplification or overexpression. MDM2 inhibitors hold promise for treatment of soft tissue sarcomas and other tumors with MDM2 overexpression.
It is noteworthy that MDM2 and MDMX have been implicated in the phenomenon of hyperprogression following immune checkpoint blockade. As such, a promising strategy can employ MDM2 inhibitors to enhance response to immunotherapy in cases of hyperprogression or possibly enhance immunotherapy in otherwise resistant tumors by inhibiting immune-suppressive inflammatory molecules such as IL-6, and also by stimulating T-cell-mediated killing of tumor cells either alone or in combination with anti-PD-1 therapy.
Alrizomadlin appears to hold promise based on the clinical study with a small minority of patients experiencing partial responses. There is no description of cytokine analysis or analysis of immune cell activation state before or after therapy at this point but, surely, this would be expected in the future.
MDM2 inhibitor therapy can be associated with emergence of resistance through MDMX (MDM4), which has led the field toward the development of promising dual-targeting MDM2/MDMX inhibitors that may be the next-generation agents for combination with anti-PD-1 or other immune checkpoint blockers to boost T-cell activity and address hyperprogression or resistance to immune checkpoint blockade.
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Tolcher AW, et al. Abstract 2506. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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