The ESMO Congress is a globally influential oncology platform for clinicians, researchers, patient advocates and healthcare professionals from around the world. Once again this year, the latest ground-breaking data was disseminated, high-quality training was provided and excellent networking opportunities were created. The congress provides a venue for international perspectives to come together to shape the next generation of trials and management developments.
Immunotherapy, which enables the body’s own immune system to recognize and destroy cancer cells, improves long-term overall survival in patients with advanced melanoma, according to large international studies [1,3]. Researchers leading the longest follow-up study to date believe that immunotherapy offers a chance of cure in patients who respond to this treatment. Other clinical trials show improved long-term survival in women with difficult-to-treat early breast cancer (triple-negative breast cancer) and in patients with muscle-invasive bladder cancer when immunotherapy is given before and after surgery [3,4]. “The main message of all these studies is that immunotherapy continues to deliver on its promise and hope for long-term survival for many patients with different types of cancer,” said Dr. Alessandra Curioni-Fontecedro, Freiburg.
The results of a phase III trial of immunotherapy with an anti-programmed death (PD)-1-based therapy showed a sustained long-term survival benefit in patients with advanced melanoma [1]. After at least 10 years of follow-up, the median overall survival was 71.9 months in patients assigned to combined immunotherapy with nivolumab plus ipilimumab in the CheckMate-067 trial. Very few of the patients who initially responded well to anti-PD-1-based immunotherapy and in whom the disease did not progress for at least three years had died of melanoma after ten years (10-year survival rate for melanoma 96%). The researchers believe that there is now a chance of cure for patients who respond to these treatments.
Immunotherapy for TNBC
Immunotherapy has also been reported to improve overall survival rates in early-stage triple-negative breast cancer (TNBC) and muscle-invasive bladder cancer. Triple negative breast cancer is particularly difficult to treat as it does not have estrogen or progesterone receptors or elevated HER2 levels and therefore does not respond to commonly used breast cancer treatments. The results showed a statistically significant and clinically meaningful improvement in overall survival with immunotherapy plus chemotherapy before surgery and continued immunotherapy after surgery; the five-year overall survival rate was 86.6% in patients who received immunotherapy and 81.2% in the placebo group [3].
A similar improvement in overall survival with immunotherapy prior to surgery was observed in a study of patients with muscle-invasive bladder cancer [4]. In the phase III NIAGARA trial, patients were randomized to receive either immunotherapy with durvalumab plus chemotherapy prior to radical cystectomy, followed by continued immunotherapy, or chemotherapy alone prior to surgery. Patients treated with immunotherapy showed significantly longer event-free survival and overall survival compared to those who received chemotherapy alone. The researchers found that the administration of immunotherapy prior to surgery did not affect the ability to perform a radical cystectomy, which was completed in 88% of the immunotherapy group and 83% of the comparison group.
Therapy prospects for solid tumors
Genes encoding subunits of the SWI/SNF chromatin remodeling complex are among the most frequently mutated genes in cancer, occurring in 20-24% of all human cancers. The SWI/SNF complex contains one of two ATP-enzymatic subunits, SMARCA2 or SMARCA4, which function interchangeably. PRT3789 is a potent SMARCA2 degrader with >1000-fold selectivity for cancer cells with mutant SMARCA4 compared to wild-type cells. Researchers hypothesize that selective SMARCA2 degradation by synthetic lethality with PRT3789 will be an effective therapy for cancer with mutant SMARCA4. They conducted a phase I dose escalation study with refill cohorts added at active doses [5]. Patients with a solid tumor and a SMARCA4 mutation (loss of function or missense) were eligible. PRT3789 was administered intravenously weekly. The primary objectives were safety and determination of a recommended Phase 2 dose. As of March 7, 2024, 40 patients were enrolled (NSCLC [18], pancreas [5], breast [3], esophagus [2], other [12]); 55% have loss-of-function mutations. Dose escalation was performed in six levels from 24 to 212 mg, with two replenishment cohorts opened. No DLTs or study drug-related SAEs were reported. The most commonly reported adverse event, regardless of grade or association, was nausea. Dose-dependent increases in AUC were observed. Dose-dependent decreases in SMARCA2 levels were observed at all doses, with a trend toward increasing depth and duration with increasing doses; minimal effects on SMARCA4 levels were observed. The initial results suggest that PRT3789, a novel SMARCA2 degrader, appears to be well tolerated at the doses studied to date, exhibiting excellent pharmacodynamic activity and encouraging signs of antitumor activity even in early dose escalation. Dose escalation and top-up cohorts are still ongoing.
More time to live for SCAC patients?
Inoperable locally recurrent/metastatic squamous cell carcinoma of the anal canal (SCAC) is associated with suboptimal PFS and OS despite high initial response rates to platinum-based chemotherapy. Retifanlimab, an anti-PD-1 monoclonal antibody, has demonstrated antitumor activity in patients with advanced SCAC who responded to platinum-based chemotherapy. The POD1UM-303 study investigated the addition of retifanlimab to standard chemotherapy (SoC) in previously untreated locally recurrent/metastatic SCAC. The controlled double-blind phase III study involved treatment-naïve patients aged ≥18 years with unresectable, locally recurrent/metastatic SCAC; (neo)adjuvant/radiosensitizing chemotherapy and well-controlled HIV infection were eligible [6]. Patients were randomized in a 1:1 ratio to receive 6 cycles of standard-dose C-P plus placebo (P arm) or retifanlimab 500 mg q4w (R arm) for up to 1 year with the option to switch. The primary endpoint was progression-free survival (PFS) by blinded independent central review. Secondary endpoints were overall survival (OS, main endpoint), objective response rate (ORR), disease-free survival rate (DCR), duration of response (DOR), safety and pharmacokinetics.
A total of 308 patients were included; the median age was 62 years, 7% of patients were female, 87% were white, 4% were known to be HIV-positive and 36% had liver metastases. The study met its primary endpoint. Median progression-free survival was significantly higher in the R arm than in the P arm (9.30 vs. 7.39 months); a strong trend towards improved overall survival was observed, although the data are not yet mature. Overall, the addition of retifanlimab was tolerated and there were no new safety signals that could jeopardize or interrupt chemotherapy.
Fewer side effects with LA-NPC
Since intensity-modulated radiotherapy (IMRT) improves local control and chemotherapy administered before or after radiotherapy reduces the risk of distant failure, it was essential to investigate whether sequential chemoradiotherapy (SCRT) could serve as an alternative to the induction chemotherapy + concurrent chemoradiotherapy (IC+CCRT) protocol for patients with locally advanced nasopharyngeal carcinoma (LA-NPC). Therefore, an open-label, phase III non-inferiority clinical trial was conducted at six centers in China from January 2018 to September 2021 [7]. Patients aged 18 to 65 years who were diagnosed with stage T1-4N2-3 or T3-4N0-1 M0 NPC were randomly assigned (1:1) either two cycles of intraosseous chemotherapy with GP regimen (gemcitabine 1000 mg/m2 d1, cisplatin 25 mg/m2 d1-3, q21d) followed by IMRT and then two cycles of adjuvant chemotherapy (AC) with the same regimen or two cycles of IC with GP regimen followed by IMRT plus concomitant weekly cisplatin administration (30 mg/m2). The primary endpoint of the study was 3-year failure-free survival (FFS) with a non-inferiority margin of 10%.
A total of 420 patients were assigned to the SCRT or IC+CCRT group. After a median follow-up of 47.0 months, the 3-year FFS rate was 84.0% in the SCRT group compared to 79.8% in the IC+CCRT group, with an HR of 0.804 and an absolute difference of 4.2%. No significant differences were observed between the groups in terms of 3-year overall survival, locoregional control or distant metastasis-free survival. Compared to the IC+CCRT group, significantly fewer acute non-hematologic adverse events (AEs) of severity ≥3 occurred in the SCRT group due to the omission of concurrent chemotherapy. This included a reduction in acute mucositis (29.0% vs. 41.9%), nausea (9.5% vs. 18.1%) and vomiting (3.8% vs. 9.5%).
Source: ESMO Congress, September 13-17, 2024, Barcelona (Spain).
Literature:
- Larkin J, Chiarion Sileni V, Gaudy Marqueste C, et al: 10-y survival outcomes from the phase 3 CheckMate 067 trial of nivolumab plus ipilimumab in advanced melanoma. LBA43, Mini Oral Session on Sunday, September 15, 14:45-16:25, Oviedo Auditorium – Hall 3.
- Robert C, Carlino MS, McNeil C, et al: Pembrolizumab vs ipilimumab in advanced melanoma: 10-year follow-up of the phase 3 KEYNOTE-006 study. LBA44, Mini Oral Session on Sunday, September 15, 14:45-16:25, Oviedo Auditorium – Hall 3.
- Schmid P, Cortes J, Dent RA, et al: Neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for high-risk early-stage TNBC: overall survival results from the phase 3 KEYNOTE-522 study. LBA4, Presidential Symposium 2 on Sunday, September 15, 16:30-17:50, Barcelona Auditorium – Hall 2.
- Powles TB, van der Heijden MS, Galsky MD: A randomized phase 3 trial of neoadjuvant durvalumab plus chemotherapy followed by radical cystectomy and adjuvant durvalumab in muscle-invasive bladder cancer (NIAGARA). LBA5, Presidential Symposium 2 on Sunday, September 15, 16:30-17:50, Barcelona Auditorium – Hall 2.
- Guo R,Dowalti A, Dagogo-Jack I, et al: First clinical results from a phase I trial of PRT3789: A first-in-class intravenous SMARCA2 degrader, in patients with advanced solid tumors with a SMARCA4 mutation. 603O, Proffered Paper Session on Friday, September 13, 16:00-16:30, Santander Auditorium – Hall 5.
- Rao S, Samalin-Scalzi E, Evesque L, et al: POD1UM-303/InterAACT 2: Phase III study of retifanlimab with carboplatin-paclitaxel (c-p) in patients (Pts) with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC) not previously treated with systemic chemotherapy (Chemo). LBA2, Proffered Paper Session on Saturday, September 14, 16:52-17:04, Barcelona Auditorium – Hall 2.
- Hu C, Xue F, Ou D, et al: Sequential chemoradiotherapy versus induction chemotherapy plus concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma: A multicentre, open-label, non-inferiority, randomized, phase III trial. 847O, Proffered Paper Session on Sunday, September 15, 10:15-10:25, Valencia Auditorium – Hall 5.
InFo ONKOLOGIE & HÄMATOLOGIE 2024; 12(5): 22-23 (published on 24.10.24, ahead of print)
