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Takeda’s Flagship Product Panitumumab (PAN)+mFOLFOX6 Versus bevacizumab (BEV) + mFOLFOX6

Panitumumab (PAN) + mFOLFOX6 Versus Bevacizumab

Patients in the Takeda-sponsored Phase III research comparing PAN + mFOLFOX6 to BEV + mFOLFOX6 as the first-line treatment for metastatic colorectal cancer (mCRC) (mCRC) (LBA1 abstract)

A completely human monoclonal antibody called panitumumab targets the epidermal growth factor receptor (EGFR). In 2019, the US FDA and the EMA approved panitumumab for the treatment of RAS wild-type metastatic colorectal cancer (mCRC) in combination with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (5-fluorouracil, leucovorin, and irinotecan) in the first-line setting, in combination with FOLFIRI in the second-line setting.

At a median follow-up of 61 months in the PARADIGM trial, panitumumab significantly improved OS in both the population with left-sided malignancies and the entire study population. With panitumumab, the median PFS for the entire population was 12.9 months as opposed to 12 months with bevacizumab. In the group with left-sided tumors, the stratified hazard ratio (HR) for mortality with panitumumab compared with bevacizumab was 0.82 (P =.031) and 0.84 (P =.030) in the complete analytic population. The group with left-sided tumors had median OS lengths of 37.9 months in the panitumumab arm and 34.3 months in the bevacizumab arm; however, the mPFS duration was not substantially different (13.7 vs. 13.2). The Response Rate, however, also supported panitumumab (80.2%).

KOL insights

According to Expert Opinion, "These data support the first-line use of panitumumab plus modified FOLFOX6 in patients with RAS wild-type and left-sided metastatic colorectal cancer."

Conclusion

Modified FOLFOX6 (mFOLFOX6) plus panitumumab significantly improved overall survival (OS) in patients with wild-type RAS metastatic colorectal cancer (mCRC) who had left-sided tumors when compared to mFOLFOX6 plus bevacizumab. No new safety signs were noticed, according to the study's researchers. The trial showed superiority with panitumumab over bevacizumab in combination with mFOLFOX6, they added. This was true for both left-sided tumors and the total mCRC populations.

Companies- Mirati Therapeutics, Merck Sharp & Dohme, Pfizer, Ono Pharmaceutical, G1 Therapeutics, Daiichi Sankyo, AstraZeneca, and others.

Also, read- ASCO Conference 2020 | ASCO 2020 Abstracts | ASCO 2021 Highlights

ASCO 2021 Abstracts

#metastatic colorectal cancer #colorectal cancer

ASCO Conference Highlights: Metastatic Colorectal Cancer, Bladder Cancer

ASCO conference emerged out to be a breakthrough platform for several oncology abstracts including Colorectal Cancer, Metastatic Colorectal Cancer, and Bladder Cancer. Here are a few abstracts covered from the field.

Olympia Trial - PARP inhibitors demonstrated activity in multiple cancers which are related to BRCA mutations. AstraZeneca’s Lynparza (olaparib), one such PARP inhibitor, is indicated for various advanced cancer types. Lynparza label was approved in 2017, for the treatment of patients with germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting, it is still not approved for use in high-risk HER2 negative early breast cancer with gBRCAm. The Olympia trial study evaluated Lynparza in patients with gBRCA1/2 mutated HER2 negative early breast cancer who have completed definitive local treatment and neoadjuvant or adjuvant chemotherapy. Olympia trial results were based on a randomized, double-blind, parallel-group, placebo-controlled multicenter Phase III trial, which, once complete, can provide Lynparza with the commercial opportunity in the adjuvant setting.

As per MSD the analysis of the Olympia trial breast cancer study, based upon the IDMC recommendation, could be able to represent a potential step forward for patients with early-stage, high-risk primary breast cancer with a germline BRCA mutation. Thus, the successful attainment of primary endpoints makes Olympiad Lynparza the first PARP inhibitor to demonstrate clinical benefit as an adjuvant treatment in early breast cancer.

BEACON encorafenib + cetuximab with or without binimetinib (Abstract No. 4001) - Assessment of the BEACON CRC study confirmed that encorafenib + cetuximab with or without binimetinib improved OS and ORR in previously treated patients with BRAF V600E mCRC compared with standard chemotherapy. Pfizer's intervention encorafenib plus cetuximab with or without binimetinib is a small molecule technology-based therapy for Metastatic Colorectal Cancer with BRAF V600E mutation. As per the published results at ASCO, encorafenib + cetuximab significantly improved OS, PF, and ORR relative to standard of care (control) in previously treated pts with BRAF V600E mCRC, a sub-population with historically dismal outcomes.

Merck’s anti-LAG-3 antibody, MK4280 (favezelimab) in combination with PD-1, Pembrolizumab (Abstract No. 3584): LAG-3 has been turned out to be a novel target in oncology which is expressed in some of the tumor types. Merck, one of them, has brought its anti-LAG-3 antibody MK4280- favezelimab to investigate it both as monotherapy and in combination with its own lead candidate Keytruda in previously treated, advanced microsatellite stable colorectal cancer. 20 patients participated in the study including the favezelimab arm (mono) and 80 patients in the favezelimab + pembrolizumab arm (combo). More than 85 percent of the patients have received ≥3 prior lines of therapy in the mono arm and 72.5% in the combo arm. 60 percent of the patients had PDL1 CPS ≥ 1 in the mono arm vs 45% in the combo arm. The cut-off data date of the study was October 2020. The early study results demonstrated a manageable safety profile in the mono and combo arm with promising anti-tumor activity in the combo arm, notably in patients with PDL1 CPS ≥1.

Check in-depth Information- Olympia Lynparza

#olympia lynparza #olympia trial #olympiad lynparza #olympia trial results

Making Way For Immunotherapy In The GI Cancers, Durvalumab To Become The New Standard of Care For Advanced Biliary Tract Cancers

TOPAZ-1 : Durvalumab Immunotherapy Highlights

Regional subgroup analysis of the Phase III TOPAZ-1 clinical trial of durvalumab (D) plus gemcitabine and cisplatin (GC) in advanced biliary tract cancer (BTC). (Abstract # 4075)

Durvalumab Mechanism of Action: Programmed cell death-1 ligand-1 inhibitors; T lymphocyte stimulants

In the pivotal Phase 3 TOPAZ-1 trial, a prespecified subgroup analysis was performed for efficacy outcomes, including OS for patients enrolled in Asia (China, Hong Kong, India, Japan, South Korea, Taiwan, Thailand) or the rest of the world (RoW; Europe [Bulgaria, France, Italy, Poland, Russia, Turkey, United Kingdom], North America [NA; USA], and South America [SA; Argentina, Chile]).

Patient numbers were balanced across regions (Asia, n=374 [54.6%]; RoW, n=311 [45.4%]). Baseline characteristics were balanced between regions except for modest differences in important pre-defined prognostic factors, including disease status: recurrent disease (Asia 23%; RoW 14.5%), ECOG performance status 1 (Asia 59.1%; RoW 41.2%), and metastatic disease (Asia 89.3%; RoW 82%) suggesting that the study was not adequately powered for the subgroup analyses

More pts in Asia received subsequent anti-cancer therapies in the Placebo arm than patients in RoW (53.6% vs 43.9%). The median duration of follow-up in censored patients was about 2 months longer in Asia versus RoW (14.8 vs 13.0 mo in D + GC; 13.8 vs 12.1 mo in PBO + GC). Regional level analysis showed outcomes were similar and approximated the overall population for Asia, Europe, and NA. Grade 3/4 adverse events were similar for Asia (D + GC 78.5%; PBO + GC 78.6%) and RoW (D + GC 72.7%; PBO + GC 76.7%).

Further results presented on the OS by viral hepatitis status also favored durvalumab + chemotherapy. The mOS for patients with or without hepatitis was 12.6 and 13.2 months, respectively. The placebo results for the same were 11.5 and 10.7, respectively, giving a 20-25% survival benefit to patients treated with durvalumab + chemotherapy arm.

KOL insights

We are hopeful that durvalumab plus gemcitabine and cisplatin will become a new standard of care for advanced BTC. Our first task at this time is boosting communication with patients and family members about the potential for this immunotherapy combination and what it may mean for their ongoing care” –Expert Opinion.

Conclusion

Despite some regional differences in prognostic characteristics, OS trends favored D + GC versus PBO + GC for patients enrolled in both Asia and RoW, supporting the use of D + GC as a potential new treatment option for all patients with advanced BTC.

Companies- AstraZeneca, Puma Biotechnology, Nordic Bioscience, Rafael Pharmaceuticals, Roche, Agios Pharmaceuticals, QED Therapeutics, Delcath Systems, Taiho Oncology, Merck Sharp & Dohme, Ipsen, BeiGene, Celgene, Eisai, Bristol-Myers Squibb, Bayer, Basilea Pharmaceutical.

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About ASCO 2022 Conference Updates

#asco 2022 conference #asco conference 2022

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ASCO Conference Abstracts - Major Data Readouts

Virtual ASCO conference schedule happened from May 29 to May 31 and was an exciting event for major Oncology Pharmaceutical companies and their key presentations. Merck Lynparza has been a key drug for a poster presentation. Lynparza emerged out to be the main therapy in Merck's prostate cancer research field.

Lynparza (Olaparib) is the first and best-in-class oral poly ADP-ribose polymerase (PARP) inhibitor and the first targeted treatment to block DDR in tumors harboring a deficiency in homologous recombination repair (HRR), such as mutations in BRCA1 and/or BRCA2. In addition to that Astrazeneca prostate cancer research is carried out in collaboration with Merck.

In January 2020, the US FDA accepted the supplemental New Drug Application for Lynparza (Olaparib) and granted Priority Review in the US for patients with metastatic castration-resistant prostate cancer (mCRPC) and deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene mutations, which have progressed following prior treatment with a new hormonal agent.

During the ASCO conference 2020, there were many abstracts presented related to oncology including Abstract No - 7507 where the tolerability and efficacy of the first-in-class anti-CD47 antibody magrolimab combined with azacitidine in MDS and AML patients was presented. The Phase Ib results of magrolimab MDS and magrolimab AML were indicative of efficacy with 91% and 64% ORR respectively.

Another abstract was presented by Bayer Healthcare and Orion Corporation on the studies of Nonmetastatic castration-resistant prostate cancer (nmCRPC). In June 2014, Orion and Bayer entered a global agreement for the development and commercialization of the compound ODM-201 (sold under the brand name Nubeqa) which is also known as darolutamide, an investigational novel oral androgen receptor inhibitor.

Under the terms of the agreement, Bayer AG paid USD 68 Million upfront for Orion Corporation's prostate cancer candidate ODM-201. Nubeqa is an oral androgen receptor inhibitor (ARi) with a distinct chemical structure that binds to the receptor with high affinity and exhibits strong antagonistic activity, thereby inhibiting the receptor function and the growth of prostate cancer cells. Bayer Nubeqa was granted fast-track designation by the US FDA for men with nmCRPC cancer in the year 2019.

Whereas In March 2020, the European Commission has granted marketing authorization in the European Union (EU) for Nubeqa for the treatment of men with non-metastatic castration-resistant prostate cancer (nmCRPC). Additionally, in January 2020, the Japanese Ministry of Health, Labor, and Welfare (MHLW) granted marketing authorization to Bayer Nubeqa for the treatment of men with non-metastatic castration-resistant prostate cancer (nmCRPC).

Also, Read- asco 2020 abstracts | Macrolimab | Merck Prostate Cancer | Lynparza Merck

#asco conference 2020 #asco 2020 abstracts #magrolimab mds #macrolimab #asco conference schedule #merck prostate cancer #lynparza merck #astrazeneca prostate cancer

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AbbVie’s Telisotuzumab Vedotin (Teliso-V) Demonstrated Encouraging Responses In C-MET NSCLC Patients Who Progressed On Previous Treatments

Phase II study of telisotuzumab vedotin in patients with c–MET+ NSCLC who have previously received not more than 2 lines prior systemic therapy (Abstract # 9016)

An anti-c-MET antibody-drug conjugate (ADC) called telisotuzumab vedotin is made up of a monoclonal antibody attached to monomethyl auristatin E. (MMAE). In the Phase I Study (MN14-237), Teliso-V and osimertinib are given to patients with previously treated NSCLC who have c-MET overexpression. Recently, the FDA granted the medication Breakthrough Therapy Designation (BTD) for use as monotherapy in patients with metastatic or advanced EGFR-wt non-squamous NSCLC whose cancer has progressed or grown after receiving platinum-based therapy.

Results of patients treated with Teliso-V and osimertinib in Phase I/Ib who had EGFR L858R, ex 19 deletions, and overexpression of c-MET. An ORR of 58 percent was seen when Teliso-V and osimertinib were combined. According to its recommended dosage, Teliso-V had an ORR of 3 (43%) out of 7 patients receiving 1.6 mg/kg and 8 (67%) out of 12 patients receiving 1.9 mg/kg.

A preliminary analysis from the Phase II LUMINOSITY trial, which involved 136 patients and of whom 122 could be evaluated for the main outcome, was given by AbbVie. The objective response rate (ORR) as determined by an impartial central review served as the primary endpoint. The Bayesian model predicts that stage 2 advancement is more likely if at least 70% of the genuine ORR is present. 131 (96%) of patients experienced treatment-emergent adverse events (TEAEs) of any grade, and 65 patients experienced Grade 3+ adverse events (48 percent of patients).

KOL insights

“Patients with NSCLC have a high unmet need, and telisotuzumab vedotin has the potential to provide them with an additional treatment option to manage their disease.”–Expert Opinion.

Conclusion

The effectiveness of both cytotoxic chemotherapy and targeted therapy is affected by the anti-cancer treatment class known as antibody-drug conjugates (ADCs), which can deliver cytotoxic medications directly to tumour cells. The use of ADCs is expanding quickly, and early research in lung cancer has produced encouraging results. ADCs that target HER2, HER3, TROP2, CEACAM5, and MET are now being tested in clinical studies for NSCLC.

Oncogene tyrosine kinase receptor (c-MET) is the term used to describe this substance. Numerous cellular processes can be regulated by c-MET, and when these processes are dysregulated, tumour cells are more likely to proliferate, survive, invade, and spread. Point mutations, amplification, fusion, and protein overexpression are c-MET changes found in NSCLC that are linked to a poor prognosis.

MET activation has previously been implicated as both a primary oncogenic driver mutation and a secondary driver of acquired resistance to targeted therapy in other genomic subpopulations, according to preclinical and clinical investigations. Agents that target c-MET are thus a possible therapeutic approach for NSCLC. There isn't currently a targeted medication that specifically targets NSCLC with c-MET overexpression. Therefore, obtaining a BTD can be essential in securing approval for the primary therapy in this patient group by providing this chemical.

Companies- Janssen, Cullinan Oncology, Immutep, Bristol Myers Squibb, Merck Sharp & Dohme, Surface Oncology, AbbVie, Daiichi Sankyo, Chugai Pharmaceutical, Regeneron, Sanofi, and others.

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Sermonix’s Lasofoxifene, a potent oral SERM, emerges as a critical player in ESR1 mutated advanced HR+ breast cancer

ASCO 2022: Sermonix’s Lasofoxifene

Phase II study of lasofoxifene (LAS) combined with abemaciclib (Abema) for treating pre-and postmenopausal women with locally advanced or metastatic ER+/HER2− breast cancer and an ESR1 mutation after progression on prior therapies.

The ELAINEII study evaluated lasofoxifene plus abemaciclib in ER+/HER2− metastatic breast cancer who had acquired ESR1 mutations on circulating tumor DNA (ctDNA) after progressing on 1 or 2 prior lines of therapy, 1 of which could have been chemotherapy. Lasofoxifene has been granted a Fast Track Designation by the FDA to treat women who have ER+ metastatic breast cancer with an ESR1 mutation.

The objective response rate (ORR) was 50% in a group of patients who had advanced on 1 or 2 prior lines of therapy, according to data given at the ASCO 2022 Annual Meeting, with a 24-week clinical benefit rate (CBR) of 69%. The median PFS after censoring was 55.7, or roughly 13 months.

Nine patients (50%) with detectable target lesions had partial responses (PRs). The median time to PR was 169 days, with a 164-day median response duration. Out of 4 patients who had previously progressed while receiving abemaciclib, 3 had significant clinical responses of PR in 1 and stable disease in 2. Clinical effect was seen in two out of three individuals who had previously been treated with fulvestrant + alpelisib (Piqray).

SafeSEQ next-generation sequencing technology was used to evaluate ESR1 mutant allele fractions by ctDNA at baseline and 4 weeks. At the start, 47 ESR1 mutant variants were discovered. After four weeks of treatment, 68% of these were undetectable, 23% were reduced, and just 9% increased.

“This clinically meaningful efficacy of [lasofoxifene plus abemaciclib] may offer a significant benefit than currently available therapies, with a differentiated profile from intra-muscular or oral SERDs [selective estrogen degraders], particularly in this patient population, and warrants further study. – Expert Opinion

CONCLUSION

Long-term endocrine therapy administration can lead to treatment resistance caused by acquired ESR1 mutations. In preclinical investigations, lasofoxifene showed an effect against ESR1 mutations alone or in conjunction with CDK4/6 inhibition vs. fulvestrant. Abemaciclib has also been demonstrated to be effective in patients with metastatic breast cancer who have progressed on previous CDK4/6 inhibitors. The results from the ELAINE 2 study have shown that the combination of lasofoxifene and abemaciclib (Verzenio) provided a meaningful progression-free survival (PFS) benefit and elicited encouraging responses with an acceptable toxicity profile in patients.

The company has also planned to start ELAINE 3 (lasofoxifene vs. Fulvestrant in monotherapy) and ELAINE 4 (lasofoxifene + CDK 4/6 Inhibitor in combination therapy) study in breast cancer that will be potentially registrational. In parallel, the company is assessing lasofoxifene as monotherapy compared to fulvestrant for the treatment of metastatic breast cancer with an ESR1 mutation post-CDK4/6i therapy in the ELAINE-1 study, which is fully enrolled, and the data will be presented in late Q3 of 2022.

Apart from lasofoxifene, the potential players that can mark a significant change in the ESR1 mutated breast cancer space are Radius Pharmaceuticals (Elacestrant), AstraZeneca (camizestrant [AZD9833]), Roche (giredestrant), H3 Biomedicine/Eisai (H3B-6545), and Eli Lilly (Imlunestrant) which are evaluating their lead candidates in different stages of clinical development, respectively.

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