Marco Donia’s Post

The impact of the order of treatment with checkpoint inhibitors or BRAF/MEK inhibitors on the development of brain metastases in patients with metastatic unresectable BRAF V600-mutant melanoma is unknown. The SECOMBIT trial examined the impact of the order of receipt of these treatments in such patients.      In this three-arm trial, we reviewed patients without brain metastases who received the BRAF/MEK inhibitors encorafenib and binimetinib until they had progressive disease followed by the immune checkpoint inhibitors ipilimumab and nivolumab (arm A); or treatment with ipilimumab and nivolumab until they had progressive disease followed by encorafenib and binimetinib (arm B); or treatment with encorafenib and binimetinib for 8 weeks followed by ipilimumab and nivolumab until they had progressive disease followed by retreatment with encorafenib arm binimetinib (arm C).     Brain metastases were discovered during the trial in 23/69 patients in arm A, 11/69 in arm B, and 9/68 in arm C. At a median follow-up of 56 months, the 60-month brain metastases–free survival rates were 56% for arm A, 80% for arm B (hazard ratio [HR] vs. A: 0.40, 95% confidence interval [CI] 0.23 to 0.58), and 85% for arm C (HR vs. A: 0.35, 95% CI 0.16 to 0.76).     In patients with unresectable metastatic melanoma, the treatment sequence of immune checkpoint inhibition followed by BRAF/MEK inhibitors was associated with longer periods of new brain metastases–free survival than the reverse sequence. A regimen in which immune checkpoint inhibition was sandwiched between BRAF/MEK inhibition also appeared to be protective against brain metastases.    Read the Original Article “Sequencing of Checkpoint or BRAF/MEK Inhibitors on Brain Metastases in Melanoma” by P.A. Ascierto et al.: https://eviden.cc/3XTlAKB    𝗙𝗨𝗥𝗧𝗛𝗘𝗥 𝗥𝗘𝗔𝗗𝗜𝗡𝗚  Editorial by Thomas A. Trikalinos, MD, PhD: Broader Options for Experimental Clinical Research in Melanoma — Time for Adaptive Platform Trials? https://eviden.cc/3Bs1wWU    #ClinicalTrials #MedicalResearch 

As an immunotherapy enthusiast, I have followed the immune checkpoint inhibitor (ICI) story, both successes and challenges, for the last decade. ICI and TIL (tumor-infiltrating T lymphocyte) approaches provide an antigen-agonistic approach to tumor elimination. While ICI is an "off-the-shelf" option, TIL therapy is patient specific and time/labor intensive. These approaches, and all immunotherapies, have both advantages and advantages. Newer technologies, including Bi-specific T cell Engagers (BiTEs) and antibody-drug conjugates (ADCs) have generated much excitement in both hematological and solid tumors. These approaches are similar to CAR-T (Chimeric Antigen Receptor T cells) in their requirement of a defined tumor-specific, or tumor-enriched, extracellular target. Long-term success of these therapies will undoubtedly require a multi-target approach as tumors evade the therapy. Loss of the target antigen has proven to be a major hurtle in CAR-T targeted therapies. https://lnkd.in/gRjVDdyX I am, however, encouraged by the recent FDA approval of Imdelltra (Amgen, tarlatamab-dlle) for extensive-stage small cell lung cancer (ES-SCLC), with a 40% ORR and 14.3-month median OS in heavily pretreated patients (DELLphi 301). This BiTE brings CD3+ T cells in close proximity to DLL+ (delta-like ligand 3) tumor cells. https://lnkd.in/gzeNUY8q https://lnkd.in/gmuxWzjm A phase III trial (DeLLphi-305) is underway to test the efficacy of Imdelltra in combination with durvalumab (AstraZeneca, IMFINZI; anti-PD-L1) versus durvalumab alone, following platinum and etoposide chemotherapy with durvalumab. This combination may be ideal for maximizing tumor death and antigen exposure (chemotherapy and BiTE), while potentiating the anti-tumor T cell response (durvalumab) of both tumor-specific and bystander T cells.

A combination of Trodelvy, Keytruda and carboplatin triggered 43.1% and 39% tumor response rates in treatment-naïve NSCLC patients with nonsquamous and squamous histologies, respectively, according to results from cohort C and D of the phase 2 EVOKE-02 trial presented at the 2024 World Conference on Lung Cancer. Nonsquamous patients who took the triplet lived a median 8.1 months without disease progression, compared with 11.1 months for squamous patients. in cohort B of the EVOKE-02 trial, Trodelvy and Keytruda—without chemo—showed a 44% response rate in front-line patients with PD-L1 tumor proportion scores (TPS) below 50% regardless of histology, according to results published last fall. In cohort A, the doublet pulled off a 67% response rate across histologies in PD-L1-high patients, according to an update in May. More than 80% of patients in cohort C and D had PD-L1 TPS scores below 50%. It’s worth noting that investigators had to lower Trodelvy’s dose from the original 10 mg/kg to 7.5 mg/kg in the triplet tests after a planned safety evaluation flagged an increased risk of neutropenia. About two-thirds of patients in the efficacy analysis received the lower dose. EVOKE-02 study arms (193 subjects enrrolled): - Sacituzumab Govitecan-hziy (SG) + Pembrolizumab (Cohort A) - SG + Pembrolizumab (Cohort B) - SG + Pembrolizumab + Carboplatin Safety Run-in - SG + Pembrolizumab + Cisplatin Safety Run-in (Optional) - SG + Pembrolizumab + Carboplatin or Cisplatin (Cohort C) - SG + Pembrolizumab + Carboplatin or Cisplatin (Cohort D) - SG + Pembrolizumab + Cisplatin (Cohort E) My comments: The tentative dose should be tested during phase 1, where only 10 mg/kg was tested (https://lnkd.in/g8aDpTHy), but it was included in phase 2, Safety Run-in with "de-escalating dose 10.0 mg/kg, 7.5 mg/kg, or 5.0 mg/kg. To me this is a clear flaw in protocol design, which impacted negatively to the company losing money, time, and almost killed the drug. To many investigational arm added too much complexity in the trial, which increase human errors (protocol deviations) during data collecting process too (monitoring, study coordinator, secondary investigators, etc.) The news: https://lnkd.in/gYmbn3Gn

Recurrent cancer after #resection: Can adjuvant #immunotherapy prevent it? Surgical resection is a curative-intent treatment for resectable solid-tumour patients; however, 40% of these patients develop recurrences within 5 years after resection¹. Adjuvant immunotherapy, anti-PD-1 or cancer vaccine or duo, have been administered to prevent recurrences. #Cancer #vaccine #mRNA-4157 plus anti-PD-1 and #Neovax (non-mRNA) cancer vaccine plus anti-PD-1 for resected melanoma patients, achieved 18-month recurrence-free survival (RFS)@79% (vs 62% for anti-PD-1 alone) and 48-month@75% respectively²⁻³. Thus, Neovax had better RFS. R0 resection surgery is not always achieved, there's an 8.85% average rate of positive margin⁴. Moreover, surgery-induced circulating tumour cells (CTC) in blood are prevalent (41-81% patients)⁵⁻⁶. Surgery-induced coagulation and thrombosis lead to the activation of platelets, coating CTCs, upregulating PD-L1, and producing a significant amount of TGFb⁷⁻⁸, which assists CTCs to foster immunosuppressive cells, TAM & Treg, to repopulate at metastatic sites¹, forming a postoperative tumour milieu, decreasing dendritic cell's (DC) functionality, and resulting in 'moderate' T-cell priming. Moreover, TGFb upregulates T-cell PD-1⁹ and drives T-cell exhaustion (see prior POST). mRNA-4157 and BNT122 used predicted short-peptide antigens to prime CD8⁺ T cells¹⁰, whereas Neovax used predicted long-peptide antigens to prime CD4⁺ T cells³. In postoperative tumour milieu, PD1ʰᶦCD8⁺ T cells are refractory to anti-PD-1 whereas PD1ʰᶦCD4⁺ T cells are responsive to anti-PD-1¹¹, albeit PD-1ᶦⁿᵗCD4⁺/CD8⁺ T cells being responsive. Thus, Neovax has more tumour-reactive central memory CD4⁺ T cells after anti-PD-1 treatment for protective memory immunity³ than mRNA-4157/BNT122's effector CD8⁺ T cells¹⁰. Lastly, although Neovax achieved 48-month RFS via central memory CD4⁺ T cells, recovered from exhaustion, its epigenetic profile is inherently distinct from non-exhausted memory T cells¹²⁻¹³. Thus, the protective memory immunity of these recovered central memory CD4⁺ T cells will not be long lasting (see prior POST). We deduced a 48-60-months RFS is most likely the upper limit for the recovered exhausted memory cells. Thus, for resectable solid tumours, we will recommend 1) resection surgery plus CD4T-based cancer vaccine plus anti-PD-1, or 2) resection surgery plus CD8T-based cancer vaccine plus bispecific PD-1xCD28 plus anti-PD-L1 (see prior POST), or 3) 'therapeutic' in vivo cancer vaccine with long-lasting immunity, like Imunani's (see prior POST), without resection. 1. J Predina, PNAS 2. J Weber, Lancet 3. Z Hu, Nat Med, 2021 4. R Orosco, Sci Rep 5. Weitz, Clin Cancer Res, 1998 6. M Tamminga, Clin Cancer Res 7. C Hinterleitner, Nat Commun 8. Meyer, Blood, 2012, Jan 9. Park, Cancer Discov, 2016 10. L Rojas, Nature 11. Balança, JCI Insight, 2021 12. K Pauken, Science 13. Sen, Science, 2016 #ImmunoOncology #Biotechnology

Intrinsic Subtype and Overall Survival of Patients with Advanced HR+/HER2− Breast Cancer Treated with Ribociclib and ET: Correlative Analysis of MONALEESA-2, -3, -7 Purpose: The MONALEESA-2, -3, -7 trials demonstrated statistically significant and clinically meaningful progression-free survival and overall survival (OS) benefits with ribociclib plus endocrine therapy (ET) versus ET alone in hormone receptor–positive, HER2-negative (HR+/HER2−) advanced breast cancer (ABC). Understanding the association of intrinsic subtypes with survival outcomes could potentially guide treatment decisions. Here, we evaluated the association of intrinsic subtypes with OS in MONALEESA-2, -3, -7. Experimental Design: Tumor samples from MONALEESA-2, -3, -7 underwent PAM50-based subtyping. The relationship between subtypes and OS was assessed using univariable and multivariable Cox proportional hazards models. Multivariable models were adjusted for clinical prognostic factors. Results: Overall, 990 tumors (among 2,066 patients) from ribociclib (n = 580) and placebo (n = 410) arms were profiled. Subtype distribution was luminal A, 54.5%; luminal B, 28.0%; HER2-enriched (HER2E) 14.6%; and basal-like, 2.8%; and was consistent across treatment arms. The luminal A subtype had the best OS outcomes in both arms, while basal-like had the worst. Patients with HER2E (HR, 0.60; P = 0.018), luminal B (HR, 0.69; P = 0.023), and luminal A (HR, 0.75; P = 0.021) subtypes derived OS benefit with ribociclib. Patients with basal-like subtype did not derive benefit from ribociclib (HR, 1.92; P = 0.137); however, patient numbers were small (n = 28). Conclusions: The prognostic value of intrinsic subtypes for OS was confirmed in this pooled analysis of the MONALEESA trials (largest dataset in HR+/HER2− ABC). While basal-like subtype did not benefit, a consistent OS benefit was observed with ribociclib added to ET across luminal and HER2E subtypes.

📃Scientific paper: Distal Versus Total D2-Gastrectomy for Gastric Cancer: a Secondary Analysis of Surgical and Oncological Outcomes Including Quality of Life in the Multicenter Randomized LOGICA-Trial Abstract: Background Distal gastrectomy (DG) for gastric cancer can cause less morbidity than total gastrectomy (TG), but may compromise radicality. No prospective studies administered neoadjuvant chemotherapy, and few assessed quality of life (QoL). Methods The multicenter LOGICA-trial randomized laparoscopic versus open D2-gastrectomy for resectable gastric adenocarcinoma (cT1–4aN0–3bM0) in 10 Dutch hospitals. This secondary LOGICA-analysis compared surgical and oncological outcomes after DG versus TG. DG was performed for non-proximal tumors if R0-resection was deemed achievable, TG for other tumors. Postoperative complications, mortality, hospitalization, radicality, nodal yield, 1-year survival, and EORTC-QoL-questionnaires were analyzed using Χ ^2-/Fisher’s exact tests and regression analyses. Results Between 2015 and 2018, 211 patients underwent DG ( n  = 122) or TG ( n  = 89), and 75% of patients underwent neoadjuvant chemotherapy. DG-patients were older, had more comorbidities, less diffuse type tumors, and lower cT-stage than TG-patients ( p  < 0.05). DG-patients experienced fewer overall complications (34% versus 57%; p  < 0.001), also after correcting for baseline differences, lower anastomotic leakage (3% versus 19%), pneumonia (4% versus 22%), atrial fibrillation (3% versus 14%), and Clavien-Dindo grading compared to TG-patients ( p  < 0.05), and demonstrated shorter median hospital stay (6 versus 8 days; p  < 0.001). QoL was better after DG (statistically sign... Continued on ES/IODE ➡️ https://etcse.fr/4QM ------- If you find this interesting, feel free to follow, comment and share. We need your help to enhance our visibility, so that our platform continues to serve you.

Is this practice changing? The NIAGARA trial was presented at ESMO 2024. This trial looked at whether adding perioperative durvalumab to neoadjuvant chemotherapy improved outcomes in cisplatin-eligible patients with bladder cancer. In the experimental arm, patients received four cycles of neoadjuvant durvalumab + gemcitabine/cisplatin, followed by 8 cycles of durvalumab 1500 mg after radical cystectomy. Patients only received neoadjuvant chemotherapy in the control arm. At median follow-up of 42.3 months, event-free survival (EFS) was significantly higher in the experimental arm, with a hazard ratio (HR) of 0.68 (0.56-0.82). Overall survival was also significantly higher, with a HR of 0.75 (0.59-0.93). The EFS benefit was unchanged across subgroups, so it didn't appear as if PD-L1 expression or creatinine clearance mattered. How does this apply to current practice? Based on the EFS and OS benefit, it appears as if we should be adding durvalumab to any patient getting neoadjuvant chemotherapy. Adding durvalumab did not appear to impact the amount of patients who went to surgery, may have improved pathological complete response rates, and there was no increase in adverse events leading to a delay in surgery. One unanswered question is, how much benefit does the neoadjuvant portion provide, and how much benefit does the adjuvant portion provide? Only 4 patients received adjuvant nivolumab, so there was almost no crossover in the placebo arm. In addition, the adjuvant nivolumab trial looked at a different patient population. As of right now, we can't make any conclusion on perioperative vs adjuvant approaches. In conclusion, perioperative durvalumab should be the new standard of care for bladder cancer patients receiving neoadjuvant cisplatin-based chemotherapy. I look forward to other trials reading out in this space, including a certain antibody-drug conjugate... #bladdercancer #imfinzi https://lnkd.in/eimEbHps

Advancing Treatment for Advanced Intrahepatic Cholangiocarcinoma 💡 Innovative Combination Therapy Shows Promise in Advanced ICC Treatment The study, "Hepatic arterial infusion chemotherapy combined with toripalimab and surufatinib for the treatment of advanced intrahepatic cholangiocarcinoma," by Songlin Song et al., introduces an encouraging therapeutic approach for this challenging malignancy. 🔑 Key Findings: Improved Outcomes: Objective response rate: 58% Disease control rate: 79% Median progression-free survival (mPFS): 9.5 months Overall survival (OS) rate: 83.3% Tolerable Safety Profile: Common adverse events included nausea/vomiting (100%) and abdominal pain (85.7%), with no treatment-related deaths reported. 🩺 Treatment Regimen: HAIC (mFOLFOX6): Targeted chemotherapy delivered via hepatic artery, improving drug concentration at the tumor site. Toripalimab: A PD-1 inhibitor enhancing the immune response against tumors. Surufatinib: A tyrosine kinase inhibitor targeting angiogenesis and immunomodulation pathways. 🌟 Why This Matters: Advanced ICC often resists standard systemic therapies, with dismal survival outcomes. This novel combination offers synergistic effects by integrating local chemotherapy with systemic immunotherapy and targeted agents, potentially redefining first-line treatment strategies. 📚 Future Perspectives: While these results are promising, larger-scale, randomized controlled trials are essential to confirm these findings and establish this combination as a standard treatment. 💬 Join the Discussion: How do you see the future of HAIC and immunotherapy in the treatment of advanced cholangiocarcinoma? #Oncology #Immunotherapy #Cholangiocarcinoma #HAIC #Toripalimab #Surufatinib #CancerResearch #ClinicalTrials

Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC A total of 216 patients who had undergone chemoradiotherapy were randomly assigned to receive osimertinib (143 patients) or placebo (73 patients). Osimertinib resulted in a significant progression-free survival benefit as compared with placebo: the median progression-free survival was 39.1 months with osimertinib versus 5.6 months with placebo, with a hazard ratio for disease progression or death of 0.16 (95% confidence interval [CI], 0.10 to 0.24; P<0.001). The percentage of patients who were alive and progression free at 12 months was 74% (95% CI, 65 to 80) with osimertinib and 22% (95% CI, 13 to 32) with placebo. Interim overall survival data (maturity, 20%) showed 36-month overall survival among 84% of patients with osimertinib (95% CI, 75 to 89) and 74% with placebo (95% CI, 57 to 85), with a hazard ratio for death of 0.81 (95% CI, 0.42 to 1.56; P=0.53). The incidence of adverse events of grade 3 or higher was 35% in the osimertinib group and 12% in the placebo group; radiation pneumonitis (majority grade, 1 to 2) was reported in 48% and 38%, respectively. A Global Study to Assess the Effects of Osimertinib Following Chemoradiation in Patients With Stage III Unresectable Non-small Cell Lung Cancer (LAURA) (LAURA) (https://lnkd.in/gZiq-st2) Primary endpoint: Progression-free survival (PFS) [Time Frame: Approximately 13 months] Key inclusion criterias: - Patients with histologically documented NSCLC of predominantly non-squamous Pathology who present with locally advanced, unresectable (Stage III) disease. - The tumor harbours one of the two common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations. - Patients must have received either concurrent chemoradiation or sequential chemoradiation including at least 2 cycles of platinum based chemotherapy and a total dose of radiation of 60 Gy ±10% The article: https://lnkd.in/gzyz37Nn

𝐁𝐚𝐬𝐚𝐥 𝑺𝒌𝒊𝒏 𝑪𝒂𝒏𝒄𝒆𝒓 𝑫𝒓𝒖𝒈𝒔 𝑪𝒍𝒂𝒔𝒔𝒊𝒇𝒊𝒄𝒂𝒕𝒊𝒐𝒏 𝒂𝒏𝒅 𝑮𝒆𝒏𝒆𝒓𝒂𝒍 𝑰𝒏𝒇𝒐𝒓𝒎𝒂𝒕𝒊𝒐𝒏 𝐈𝐧 𝐃𝐞𝐭𝐚𝐢𝐥𝐬 𝐃𝐨𝐰𝐧𝐥𝐨𝐚𝐝 𝐏𝐃𝐅 𝐂𝐨𝐩𝐲 https://lnkd.in/gKM-943E Basal cell skin cancer is the most common type of skin cancer globally, accounting for a significant portion of skin cancer diagnoses each year. As medical advancements continue to evolve, so too does the landscape of treatment options available to patients and healthcare providers. Market Overview and Growth The global basal cell skin cancer treatment market has been expanding steadily, driven by factors such as increasing awareness, early diagnosis, and advancements in treatment modalities. According to recent studies, the market is expected to continue its growth trajectory due to rising incidences of skin cancer worldwide, fueled by factors like prolonged sun exposure and changing environmental conditions. Treatment Modalities The treatment landscape for basal cell skin cancer is diverse, ranging from traditional surgical methods to more advanced therapies. Surgical excision remains a primary treatment option, offering high success rates, particularly for localized tumors. However, technological innovations have introduced alternatives such as Mohs surgery, which ensures precise removal of cancerous tissue while preserving healthy skin. Additionally, non-surgical approaches like radiation therapy and topical treatments have gained prominence, especially for patients who may not be suitable candidates for surgery due to health reasons or tumor location. Innovative Therapies and Emerging Trends Recent years have witnessed significant advancements in targeted therapies and immunotherapies for basal cell skin cancer. Hedgehog pathway inhibitors, such as vismodegib and sonidegib, have revolutionized treatment options for patients with advanced or metastatic basal cell carcinoma, offering improved outcomes and quality of life. Moreover, ongoing research into combination therapies and novel drug formulations aims to further enhance treatment efficacy and reduce adverse effects associated with current treatment modalities. Market Dynamics and Regional Insights Geographically, North America and Europe currently dominate the basal cell skin cancer treatment market, owing to well-established healthcare infrastructures and high awareness levels among the population. However, regions such as Asia-Pacific and Latin America are projected to witness robust growth in the coming years, driven by increasing healthcare expenditure and rising prevalence of skin cancer. 𝐊𝐞𝐲 𝐌𝐚𝐫𝐤𝐞𝐭 𝐏𝐥𝐚𝐲𝐞𝐫𝐬: Roche Sun Pharmaceuticals Bausch Health Companies Inc. Taro Pharmaceuticals Mylan #basalcellskincancertreatment