MD Anderson at ESMO

ABSTRACTS: LBA71, 1088MO, 95MO, LBA48, 1082O, 1085O, LBA34, 243MO

The University of Texas MD Anderson Cancer Center’s Research Highlights provides a glimpse into recent basic, translational and clinical cancer research from MD Anderson experts.

This special edition features upcoming oral presentations by MD Anderson researchers at the 2023 European Society for Medical Oncology (ESMO) Congress focused on clinical advances across a variety of cancer types. Highlights include a combination strategy for EGFR-mutant metastatic lung cancer, updated results for a Phase II study on immunotherapy for skin cancer, a promising drug for bile duct cancer, pre-surgical treatment options for resectable melanoma, concurrent intrathecal and intravenous treatment for leptomeningeal disease, a triplet combination for melanoma brain metastases, promising results for an antibody drug conjugate targeting HER2, and the option to eliminate surgery for a subset of breast cancer patients. More information on ESMO content from MD Anderson can be found at MDAnderson.org/ESMO.

In addition to the studies summarized below, forthcoming press releases will feature the following late-breaking and oral presentations:

• Results from the Phase III CheckMate 77T study evaluating neoadjuvant nivolumab plus chemotherapy vs. neoadjuvant placebo plus chemotherapy followed by surgery and adjuvant nivolumab for untreated, resectable stage II-IIIB non-small cell lung cancer (Abstract LBA1)
• Results from the Phase III DUO-E trial for newly diagnosed advanced or recurrent endometrial cancer (Abstract LBA41)
• Results from the Phase III THOR study on erdafitinib vs. pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer (Abstract 2359O)
• Subgroups from the Phase III THOR study on erdafitinib vs. chemotherapy in patients with advanced or metastatic urothelial cancer with select FGFR alterations (Abstract 2362MO)

Combination treatment prolongs survival in patients with EGFR-mutant lung cancer (Abstract LBA71)  
Osimertinib, an EGFR inhibitor, is the current standard first-line treatment for patients with metastatic EGFR-mutant non-small cell lung cancer (NSCLC), yet there is a need to identify improved treatments to enhance its initial efficacy. In the randomized Phase II RAMOSE trial, researchers led by Xiuning Le, M.D., Ph.D., found combining osimertintib with ramucirumab, an anti-VEGF treatment, significantly prolonged progression-free survival (PFS). The median PFS was 24.8 months in the combination arm compared to 15.6 months for those who received osimertintib alone. The combination also demonstrated a favorable safety profile. This study suggests osimertinib plus ramucirumab should be considered as a first-line treatment option for patients with EGFR-mutant metastatic NSCLC. Le will present the updated findings on Oct. 21.

Pre-surgical immunotherapy improves patient outcomes in advanced operable cutaneous squamous cell carcinoma (Abstract 1088MO)
Patients with cutaneous squamous cell carcinoma (CSCC), the second most common form of skin cancer, typically present with early-stage disease that can be treated with surgery alone, though a subset with more advanced disease will require radiation in addition to surgery. In a one year follow-up to a multicenter Phase II study led by Neil D. Gross, M.D., neoadjuvant (pre-surgical) immunotherapy given to patients with advanced resectable CSCC demonstrated favorable survival outcomes with a median follow-up duration of 18.7 months. The study included 79 participants treated with neoadjuvant cemiplimab followed by curative-intent surgery. Based on treatment response, patients were offered up to 48 weeks of adjuvant cemiplimab, radiation therapy or observation only. Estimated 12-month event-free survival was 89%. Notably, none of the 40 patients with a pathological complete response (pCR) experienced recurrence. The results indicate that neoadjuvant cemiplimab followed by surgery is a viable treatment option for advanced, operable CSCC. A Phase III trial is planned to test this novel approach. Gross will present updated findings on Oct. 21.

Tinengotinib delivers promising efficacy in patients with advanced cholangiocarcinoma (Abstract 95MO)
Current FGFR inhibitor (FGFRi) therapies for patients with refractory or relapsed cholangiocarcinoma (CCA), or bile duct cancer, can lead to secondary FGFR2 mutations and treatment resistance. To address this, researchers led by Milind Javle, M.D., evaluated the efficacy and safety of tinengotinib, a next-generation FGFR2 inhibitor with unique target binding to overcome acquired resistance mutations. This Phase II trial enrolled patients who had received at least one prior line of chemotherapy, including those with prior FGFRi therapy. Among 58 evaluable patients, the overall response rate (ORR) was 20.7% and disease control rate (DCR) was 75.9%. Patients with FGFR2 kinase domain mutations had the best ORR at 50%. In patients with FGFR2 alterations who received prior FGFRi, the ORR was 34% and the DCR was 89.7%. For patients who acquired resistance to prior FGFRi treatment, the ORR was 38.1%. The findings suggest tinengotinib may have a potential role in treating CCA patients with FGFR2 fusions, including those with prior FGFRi treatment. These data are based on a limited patient population and need confirmation in a larger cohort. Researchers have launched the Phase III study of tinengotinib to further investigate this therapy. Javle will present the findings on Oct. 21.

Perioperative immunotherapy improves outcomes in patients with late-stage melanoma (Abstract LBA48)
Patients with advanced melanoma face a significant risk of relapse even after surgery. Adding immunotherapy to surgery is considered more effective than surgery alone. In the SWOG S1801 Phase II study, researchers led by Sapna Patel, M.D. demonstrated perioperative (pre- and post-surgery) immunotherapy resulted in better survival than adjuvant (post-operative) immunotherapy alone. A follow-up analysis found more than half of the participants who received perioperative immunotherapy had a major pathological response, meaning there was less than 10% remaining viable tumor after three doses of neoadjuvant (pre-operative) pembrolizumab. These data suggest perioperative pembrolizumab results in favorable tumor changes in a majority of patients. Patel will present the updated findings on Oct. 23. 

Intrathecal and intravenous immunotherapy improves survival in patients with leptomeningeal disease (Abstract 1082O)
Leptomeningeal disease (LMD) occurs when cancer cells from tumors migrate into the cerebrospinal fluid (CSF) and leptomeninges, part of the lining of the brain and spinal cord. LMD can be challenging to diagnose and treat, and patients face poor survival rates. A recent proof-of-concept study showed that intrathecal (IT) nivolumab, which is administered directly into the CSF, along with intravenous (IV) immunotherapy helped improve survival in patients with LMD. Building upon this, Isabella Glitza Oliva, M.D., Ph.D., and colleagues continued the combination therapy in an IT dose expansion study. The median overall survival (OS) was 30 weeks, with a landmark OS rate of 68%, 54% and 35% at 13, 26 and 52 weeks, respectively. This study demonstrates the safety and efficacy of this combination of IT and IV therapy among 50 patients treated, confirming its feasibility and supporting ongoing clinical evaluation to further improve outcomes in this underserved patient population. Glitza Oliva will present updated clinical outcomes on Oct. 23.

Triplet combination is safe and demonstrates clinical benefit in patients with refractory melanoma brain metastases (Abstract 1085O)
While many patients with melanoma brain metastases (MBM) respond well to immune checkpoint blockade, many fail to respond or subsequently develop resistance, leaving them with limited systemic treatment options and a poor prognosis. In this Phase II study, a research team led by Elizabeth Burton examined the safety and efficacy of atezolizumab, bevacizumab and cobimetinib in 20 patients with treatment refractory MBM. The intracranial (IC) response rate and IC benefit rate were 39% and 56%, respectively. Safety was consistent with expectations, with 18 patients experiencing treatment-related adverse events (TRAEs) and 7 (35%) experiencing grade 3/4 TRAEs. Although the median PFS was 2.7 months, the median OS was 9.3 months. Seven patients (55%) received treatment beyond progression, including stereotactic radiosurgery, after evaluation by MD Anderson’s multidisciplinary Brain Metastasis Clinic. These results, which highlight the tolerability of the combination, merit further clinical evaluation and underscore the importance of integrating multidisciplinary care into the evaluation of novel therapeutic strategies in this patient population. Burton will present updated findings on Oct. 23.

Primary analysis of Phase II data of trastuzumab deruxtecan continues to show promising signals (Abstract LBA34)
Trastuzumab deruxtecan (T-DXd), an antibody drug conjugate targeting HER2, has been approved for use in HER2-positive breast cancer, gastric cancer and HER2-mutant lung cancer. In the DESTINY-PanTumor02 study led by Funda Meric-Bernstam, M.D., T-DXd also showed potential as a treatment option in several other cancers, especially gynecological cancers. The objective response rate (ORR) across all patients was 37.1% with a duration of response of 11.3 months, but among patients with the highest levels of HER2 expression, ORR was 61.3% with a duration of 22.1 months. These data support the potential role of T-DXd as a tumor-agnostic therapy for patients with hard-to-treat HER2-expressing solid tumors that currently have limited treatment options. Interim data from this trial were presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. Meric-Bernstam will present the primary analysis on Oct. 23.

Eliminating surgery in select breast cancer patients shows low risk of cancer recurrence (Abstract 243MO)
Approximately 60% of early-stage triple-negative and HER2-positive breast cancers have a positive response to chemotherapy. An exceptional response to chemotherapy is a strong indicator of a favorable prognosis and can be accurately confirmed through a minimally invasive image-guided vacuum-assisted core biopsy (VACB). In a Phase II trial led by Henry Kuerer, M.D., Ph.D., 50 patients underwent a VACB after completing chemotherapy. Previous reports of this research showed no breast cancer recurrence within two years. VACB identified a complete absence of cancer in 31 patients and, over three years, there were no recurrences in the same breast. The three-year disease-free survival and overall survival rates were both 100%. This study suggests that, for carefully selected breast cancer patients, avoiding surgery carries a minimal risk of disease recurrence. Further investigation and clinical trials are essential to validate this approach. Kuerer will present the three-year findings on Oct. 23.

For patients with cholangiocarcinoma, or bile duct cancer, the first line of treatment often includes standard cancer treatments, such as surgery, chemotherapy and radiation therapy. However, in the last few years, oncologists have found that there may be a better option for patients whose cancer has a mutation in the fibroblast growth factor receptor (FGFR). 

FGFR inhibitors, in combination with standard treatments, have extended the lives of many with this disease. However, these drugs often stop working after six to eight months. 

“These drugs work very well for a while, but resistance is inevitable,” says gastrointestinal medical oncologist Milind Javle, M.D.

Now, a new type of FGFR inhibitor may allow patients to live longer without their disease progressing.

Javle will present Phase II clinical trial results at the 2023 European Society for Medical Oncology (ESMO) Congress.

The latest treatment for cholangiocarcinoma 

The drug being studied in the clinical trial, tinengotinib, is an example of a next-generation FGFR inhibitor because it binds to the FGFR2 in a unique way. 

This approach does seem to extend survival among patients, especially among those who initially responded to an FGFR inhibitor — the clinical trial showed a median progression-free survival of seven months. This means half the patients went longer without their cancer progressing, and half shorter. Even though seven months may not seem like a lot, it could be meaningful, Javle says, because in some cases, the patients can survive for years.  

The science behind how tinengotinib works 

FGFR inhibitors often stop working after a few months because the cancer acquires new genetic mutations — it essentially evolves — to become resistant to the medication. These cancer cells are then able to tolerate the original FGFR inhibitor.  

Tinengotinib, on the other hand, has a unique binding mechanism away from the ATP binding pocket that enables it to target even newly resistant cancer cells. It overcomes acquired resistance by targeting FGFR2 kinase domain mutations. Essentially, by inhibiting a number of different kinases (a particular type of enzyme important for cell growth), the drug targets the spread of the cancer cells with their acquired resistant mutations. 

These new treatments highlight the need to better understand each patient’s cancer genetics at different points in time.  

“Genomic profiling with next-generation sequencing is really important,” Javle says. “And because the cancer evolves, the genomic profiling of the tumor should be repeated after therapy to see if new changes have been acquired.” This can be done with a simple blood test called a liquid biopsy.  

Studying the safety and effectiveness of tinengotinib in patients 

In the clinical trial, there were three groups of patients: those for whom the FGFR inhibitor worked for some time then stopped working, those for whom the FGFR inhibitor never worked, and those whose cancer didn’t have any FGFR mutations. When beginning the study, 97% had stage IV disease. About half of the patients had already tried an FGFR inhibitor. 

One of the main things Phase II clinical trials consider is the drug's safety. Although drug-related adverse events occurred in more than 80% of patients, they were all manageable, and there were no deaths related to the drug. Most of these side effects were mild and went away after treatment ended.  

There was good news about the drug’s effectiveness as well: Overall, the response rate was about 20%, and the disease control rate was almost 75%. For patients who had previously tried an FGFR inhibitor, the response rate was 34%, and the disease control rate was 90%.  

“These are respectable figures for a disease for which there are no current options,” Javle says. “The study showed notable clinical benefit for cholangiocarcinoma patients with acquired resistance to prior FGFR inhibitors.”  

Future research seeks to provide more treatment options 

The next step is a worldwide randomized Phase III clinical trial, led by MD Anderson, which is already open for enrollment at some centers. This study will further evaluate tinengotinib in cholangiocarcinoma patients with alterations in FGFR2 and whose disease has progressed after receiving one of the first-generation FGFR inhibitors. 

“We are hoping that this work will lead to subsequent approval of therapeutic options for patients who have stopped responding to the first-line treatments,” Javle says.  

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ABSTRACT: LBA41

Immunotherapy with the anti-PD-L1 monoclonal antibody durvalumab improved progression-free survival (PFS) in patients with newly diagnosed advanced or recurrent endometrial cancer compared with chemotherapy alone, with further benefits gained from the addition of the PARP inhibitor olaparib in maintenance setting, according to researchers from The University of Texas MD Anderson Cancer Center. The findings, published today in the Journal of Clinical Oncology, were also presented at the 2023 European Society for Medical Oncology (ESMO) Congress.

Results of the Phase III DUO-E trial demonstrated that durvalumab plus chemotherapy followed by durvalumab plus olaparib reduced the risk of disease progression or death by 45% while adding durvalumab alone to chemotherapy achieved a 29% reduction compared to chemotherapy alone. Exploratory subgroup analyses by mismatch repair (MMR) status showed PFS benefits in both MMR-deficient (dMMR) and MMR-proficient (pMMR) disease.

"In cases of advanced or recurrent endometrial cancer, treatment choices are limited, as the cancer is typically unresponsive to hormonal therapy and requires chemotherapy," said global lead investigator Shannon Westin, M.D., professor of Gynecologic Oncology and Reproductive Medicine. "These findings showcase, for the first time, the potential of combining immunotherapy with a PARP inhibitor to deliver significant clinical improvements for these patients."

According to the American Cancer Society, endometrial cancer is the most common cancer of the female reproductive organs and, contrary to many other cancer types, incidence is on the rise. The five-year survival rate for advanced endometrial cancer is 20%, highlighting the need for treatment alternatives after current therapies are exhausted.

The DUO-E trial (GOG-3041/ENGOT-EN10) was conducted in 253 study locations across 22 countries, including the United States and locations across Europe, South America and Asia.

The trial randomized 718 patients with newly diagnosed stage III-IV or recurrent endometrial cancer to three treatment arms. In the control arm, patients received chemotherapy alone followed by a placebo. In arm two, patients received chemotherapy with durvalumab, followed by durvalumab maintenance and placebo. In arm three, patients received chemotherapy, durvalumab and olaparib maintenance. The primary endpoint was PFS.

The MMR status in endometrial cancer indicates if the normal DNA mismatch repair system is functioning correctly. MMR deficiency occurs in 20-40% of endometrial cancers and can influence treatment decisions and prognosis. Combining immunotherapy and chemotherapy has been effective in treating some patients with endometrial cancer, with more significant advantages observed in dMMR cases compared to those with pMMR.

Prespecified exploratory subgroup analyses by MMR status showed a PFS benefit of 58% in patients with dMMR disease in the durvalumab arm and 59% for those in the durvalumab plus olaparib arm, compared to the control arm. In the pMMR subgroups, PFS was improved by 23% in the durvalumab arm and 43% in the durvalumab plus olaparib arm compared to the control arm. An additional clinical benefit was observed when olaparib maintenance was added to durvalumab following durvalumab plus chemotherapy in the pMMR subgroup.

The safety profiles of the experimental arms were consistent with the known safety profiles of the individual agents. The trial analyses are ongoing. Although the overall survival data are not yet mature, a positive trend was observed.

“These findings may offer oncologists novel avenues to enhance outcomes for endometrial cancer patients,” Westin said. “We are encouraged by these responses and look forward to reviewing the long-term data from this trial and others.”

The trial was supported by AstraZeneca. Westin reports research support and consulting fees from AstraZeneca. A complete list of collaborating authors and disclosures can be found in the abstract here.

MADRID ― Compared with pre-surgical (neoadjuvant) chemotherapy alone, adding perioperative immunotherapy – given before and after surgery – significantly improved event-free survival (EFS) in patients with resectable early-stage non-small cell lung cancer (NSCLC). Results from the Phase III CheckMate 77T study were presented today at the 2023 European Society for Medical Oncology (ESMO) Congress by researchers from
The University of Texas MD Anderson Cancer Center.

At a median follow-up of 25.4 months, the median EFS with chemotherapy alone was 18.4 months, while the median had not yet been reached for patients receiving perioperative nivolumab, meaning EFS was prolonged significantly over the control group. These results correspond to a 42% reduction in risk of disease progression, recurrence, or death for those receiving the perioperative combination.

Patients who received the perioperative nivolumab-based regimen also saw significantly higher rates of pathological complete response (pCR), defined as no tumor remaining at surgery, compared with those who received chemotherapy alone (25.3% vs. 4.7%). Rates of major pathological response (MPR), less than or equal to 10% of viable tumor cells remaining at time of surgery, were also higher in patients who received perioperative immunotherapy (35.4% vs. 12.1%).

“This study builds on the standard-of-care neoadjuvant treatment and supports perioperative nivolumab as an effective approach that reduces the risk of lung cancer relapse,” said principal investigator Tina Cascone, M.D., Ph.D., associate professor of Thoracic/Head & Neck Medical Oncology. “These findings add to evidence that the perioperative immunotherapy path gives patients with operable lung cancer an opportunity to live longer without their cancer returning.”

Roughly 30% of patients diagnosed with NSCLC have operable disease, meaning their tumor can be removed by a surgical operation. While many of these patients can be potentially cured by surgery, more than half will experience cancer recurrence without additional therapy. Chemotherapy given either before or after surgery provides only a minimal survival benefit.

The randomized, double-blind CheckMate 77T trial, which began in 2019, included more than 450 NSCLC patients over the age of 18 from around the globe. Participants were randomized to treatment with either neoadjuvant nivolumab with chemotherapy followed by surgery and adjuvant nivolumab, or neoadjuvant chemotherapy and placebo followed by surgery and adjuvant placebo

The data showed no new safety signals with the perioperative nivolumab regimen and is consistent with the known safety profiles of individual agents. Grade 3-4 treatment-related side effects were observed in 32% and 25% of patients receiving the perioperative combination or control therapy, respectively. Surgery-related adverse events occurred in 12% of patients in both treatment arms.

These findings add to recent success seen with neoadjuvant nivolumab plus chemotherapy in NSCLC. In March 2022, the Phase III CheckMate 816 study led to FDA approval of nivolumab combined with platinum-based chemotherapy.

“I am enthusiastic about the initial findings of the study,” Cascone said. “Looking ahead, it will be critical to identify patient and disease characteristics that will tell us who can potentially be cured with neoadjuvant immunotherapy only and who will benefit from more intensified treatment strategies.”

The CheckMate 77T study was sponsored by Bristol Myers Squibb. A full list of co-authors and author disclosures can be found here.

ABSTRACTS: 2359O, 2362MO

Targeted treatment with the fibroblast growth factor receptor (FGFR) inhibitor erdafitinib improved responses and overall survival compared to standard chemotherapy for patients with metastatic urothelial cancers with FGFR alterations. Results from the Phase III THOR trial, led by researchers at The University of Texas MD Anderson Cancer Center, were reported at the 2023 European Society of Medical Oncology (ESMO) Congress.

"Metastatic urothelial cancer continues to challenge us with its absence of a cure, highlighting the need for innovative treatment approaches," said Arlene Siefker-Radtke, M.D., professor of Genitourinary Medical Oncology and senior investigator on the trial. "This ongoing study presents compelling evidence that erdafitinib could potentially serve as a valuable targeted treatment option for individuals with FGFR alterations."

Genetic changes in FGFR are present in approximately 20% of patients with metastatic bladder cancer and up to 35% of patients with other urothelial cancers, including renal pelvis and ureter cancers. In 2019, erdafitinib was approved by the Food and Drug Administration for advanced FGFR-altered urothelial cancer based on the results of a Phase II trial led by Siefker-Radtke. It was the first approved FGFR-targeted therapy and is the only approved FGFR-targeted option for advanced urothelial cancer.

The ongoing randomized THOR trial, conducted at 121 sites in 23 countries, evaluated the efficacy and safety of erdafitinib in patients with metastatic urothelial carcinoma and selected FGFR gene alterations. Patients were screened for the presence of FGFR gene alterations and assigned to two cohorts based on prior treatment with platinum-containing chemotherapy or immune checkpoint inhibitors.

Erdafitinib significantly improved overall survival relative to chemotherapy in patients with prior immunotherapy (Abstract 2362MO)

In the study's first cohort, published in the New England Journal of Medicine, 266 patients who had prior treatment with immune checkpoint inhibitors were randomized to receive either erdafitinib or chemotherapy. The median overall survival (OS) was 12.1 months and 7.8 months, respectively, corresponding to a 36% lower risk of death for those treated with erdafitinib. The OS benefit was seen across subgroups, including age, type of FGFR alteration, number of prior lines of treatment, visceral metastasis, location of the primary tumor and type of chemotherapy.

Further, erdafitinib achieved a median progression-free survival of 6 months compared to just 3 months for chemotherapy. Nearly half (46%) of patients treated with erdafitinib had an objective response, meaning their tumors shrank, while just 12% on the chemotherapy arm had an objective response. The data from this cohort was first presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.

Erdafitinib achieves similar outcomes compared to pembrolizumab in immunotherapy-naïve patients (Abstract 2359O)

In the second cohort, published in the Annals of Oncology, 351 patients who had not received prior immunotherapy were randomized to receive either erdafitinib or pembrolizumab (anti-PD-1). There was no statistically significant difference in OS between the treatment arms, as erdafitinib had similar survival compared to immunotherapy in patients who received prior pembrolizumab.

Erdafitinib did achieve a median progression-free survival of 4.4 months compared to 2.7 months for pembrolizumab. Further, 40% of patients treated with erdafitinib had an objective response, while just 21.6% on the pembrolizumab arm had an objective response. There was a shorter duration of response with erdafitinib (4.3 months) than with pembrolizumab (24.4 months).

“The data from this new cohort provides early evidence suggesting there may be important impacts from the sequence of treatments for an FGFR3-altered urothelial cancer,” Siefker-Radtke said. “Even though most primary FGFR-altered urothelial tumors are immunologically cold, it is possible that metastatic tumors may not share the same features. Perhaps these patients could benefit from combining erdafitinib with an immune checkpoint inhibitor.”

Treatment-related adverse events across both cohorts were manageable and consistent with the known safety profile of erdafitinib. The impact of erdafitinib on the OS of patients with metastatic urothelial carcinoma and FGFR alterations highlights the importance of conducting molecular tests to identify FGFR alterations in individuals with metastatic urothelial cancer.

Further work is necessary to understand the impact of combining and sequencing erdafitinib with a checkpoint inhibitor. There may be a role for erdafitinib in patients with visceral crisis where rapid response and symptom improvement is indicated, thanks to its higher response rate.

The trial was supported by Janssen Research & Development, LLC. Siefker-Radtke serves on the scientific advisory committee for Janssen. A complete list of collaborating authors and disclosures can be found in the abstracts.