FDA Approves Keytruda in Both Adjuvant and Neoadjuvant Setting in High-Risk Early-Stage TNBC

In July 2021, the US FDA approved pembrolizumab (Keytruda) for high-risk, early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment and then continued as a single agent as adjuvant treatment after surgery. This approval was based on Phase III KEYNOTE-522 trial (NCT03036488) and became the first immunotherapy regimen to be approved in high-risk early-stage TNBC, marking a milestone for breast cancer patients. Earlier in February 2021, the agency rejected Merck’s application to approve the drug for this population and requested more data from the pivotal trial. But with the promising results, the FDA changed its decision and approved Merck’s leading candidate in oncology. The FDA also granted regular approval to pembrolizumab combined with chemotherapy for patients with locally recurrent unresectable or metastatic triple-negative breast cancer whose tumors express PD-L1 (combined positive score [CPS] ≥ 10) to which it granted accelerated approval in November 2020. The Phase III trial (KEYNOTE-522) was the basis of the neoadjuvant and adjuvant approval and the confirmatory trial for the accelerated approval. The results showed that the pembrolizumab regimen resulted in a 37% reduction in the risk of disease progression and a 28% reduction in the risk of death. After a median follow-up of 39 months, the pembrolizumab regimen resulted in a 37% reduction in the risk of EFS events vs. the chemotherapy/placebo regimen. 

With this approval, the treatment paradigm is going to change with the inclusion of immunotherapy as part of the regimen for patients with high-risk early-stage TNBC as nearly 30–40% of the patients are at risk of relapse after standard neoadjuvant chemotherapy and surgery. The asset is the only competitor in the market till now for early TNBC; however, Roche’s Tecentriq (Atezolizumab) is also looking to hit the bull’s eye as the company presented the data from the Phase III IMpassion031 at ESMO 2020 virtual congress, which demonstrated that Tecentriq in combination with chemotherapy improved pathological complete response for patients with early triple-negative breast cancer (TNBC) when compared to placebo plus chemotherapy. Back then, the company stated that the IMpassion031 study was the second positive Phase III study from Roche demonstrating the benefit of Tecentriq in TNBC and the first Tecentriq study to demonstrate benefit in early TNBC. In addition, Roche is also evaluating Tecentriq in an adjuvant setting in Phase III IMpassion030 trial. Another Phase III investigator-sponsored trial (A-Brave) is also in progress by Istituto Oncologico Veneto IRCCS, which is investigating Pfizer and Merck KGaA’s Bavencio (Avelumab) in adjuvant TNBC. The data have not been released despite the primary completion date of June 2021. 

We await to see the excitement of the oncologists with these treatment options arrive in the adjuvant and neoadjuvant setting unfolding newer options for this patient population in the near future.

Following Inqovi and Reblozyl’s Approval, Abbvie’s Venetoclax is Expected To be the Next Big Move in the MDS Market

The FDA has granted breakthrough therapy designation (BTD) to the combination of venetoclax (Venclexta) and azacitidine (Vidaza) for the treatment of adult patients with previously untreated intermediate-, high- and very high-risk myelodysplastic syndromes (MDS) as per the revised International Prognostic Scoring System (IPSS-R) based on the Phase Ib M15-531 study (NCT02942290). The results from the study which supported the decision of the agency were presented during the American Hematology Association Annual Meeting and Exposition 2020, which demonstrated that the treatment with venetoclax plus azacitidine led to an objective response rate of 77%, which included complete responses in 42% and marrow CRs in 35%. The median OS was not reached in terms of survival and the median PFS was 17.5 months.

For high-risk patients with MDS who are not suitable for intensive treatment approaches, HMAs (AZA and DAC) represent the only approved therapeutics and current standard of care. As venetoclax is already approved in acute myeloid leukemia (AML), it would be the only BCL-2 inhibitor for the first-line MDS patients ineligible for intensive treatment if approved. As per Delveinsight’s analysis, the asset is expected to enter the market by 2022 and might generate a market size of approximately 900 million in the 7MM countries by 2030. We expect Venetoclax to compete with Gilead Sciences’ Magrolimab (anti-CD47 monoclonal antibody) and Takeda’s Pevonedistat (NEDD8-activating enzyme (NAE) inhibitor), both targeting the same patient population in the first-line setting. Both Pevonedistat and Magrolimab have received the Breakthrough designation; however, we expect Venetoclax to have the edge over both due to its oral route of the formulation.

Aprea Therapeutic’s Eprenetapopt Combined with Azacitidine Demonstrates Efficacy in TP53-positive MDS and AML

Recently, Aprea Therapeutics announced the Phase II results from the study evaluating eprenetapopt (APR-246) combined with azacitidine as post-transplant maintenance therapy for patients with TP53-mutant myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). It is an oral next-generation p53 reactivator that has secured the Breakthrough Therapy, Orphan Drug and Fast Track designations from the FDA, and Orphan Drug designation from the European Commission for MDS. The results from the study showed that, of 33 patients enrolled, the relapse-free survival (RFS) at 1-year post-transplant was 58%, and the median RFS was 12.1 months. The overall survival (OS) at 1-year post-transplant was 79%, with a median OS of 19.3 months. In terms of safety, eprenetapopt plus azacitidine was also a well-tolerated post-transplant regimen for patients with TP53-mutant MDS or AML.

The company recently, in its corporate presentation, stated about the failure of its Phase III trial, which evaluated eprenetapopt in combination with azacitidine versus azacitidine alone for the treatment of (tumor protein) TP53 mutant MDS. The company stated that the trial failed to meet its primary endpoint of complete remission (CR) rate due to dose modifications of eprenetapopt and azacitidine which led to undertreatment in the experimental arm that negatively impacted efficacy. The company plans to share the findings observed in the Phase II study with the FDA in the second half of 2021 and might present the data during an upcoming medical meeting.

The decision would depend on the FDA, which might or might not ask for the Phase III registration trial in a post-transplant maintenance setting. As per Delveinsight’s analysis, the drug might get approved in 2024 and is expected to target the <10% MDS patients undergoing for transplants.

FDA Issues a Complete Response Letter (CRL) to Incyte’s Retifanlimab for Locally Advanced or Metastatic Squamous Cell Carcinoma of the Anal Canal (SCAC) Subgroup

The FDA issued a complete response letter (CRL) to Incyte Corporation in response to the Biologics License Application (BLA) for the PD-L1 inhibitor, retifanlimab (formerly MGA012), for the treatment of adult patients with metastatic squamous cell carcinoma of the anal canal (SCAC) who have progressed on, or who are intolerant of, platinum-based chemotherapy.

Back in June 2021, the company announced that the Oncologic Drugs Advisory Committee (ODAC) of the US FDA reviewed the BLA for retifanlimab and voted 13-4 against the approval of retifanlimab for patients with SCAC. The BLA submission is based on data from the Phase II POD1UM-202 trial, and the results were presented at ESMO 2020, which showed an objective response rate (ORR) of 14% for retifanlimab monotherapy. The FDA determined that additional data are needed to demonstrate the clinical benefit of retifanlimab for treating patients with advanced or metastatic SCAC. The company is reviewing the letter and might discuss the next steps with the FDA.

As there are no approved options for the SCAC patients who have progressed after first-line chemotherapy, the approval of this drug might mark the entrance of new immunotherapy in historically neglected, yet important, tumor. The drug has been granted Orphan Drug Designation by the FDA to treat anal cancer, along with Priority Review in January 2021. 

Keytruda/Lenvima Combo Dazzles with Regular Approval in Endometrial Cancer 

Back in 2019, the US FDA granted accelerated approval to the combination of KEYTRUDA (Pembrolizumab; Merck), plus LENVIMA (Lenvatinib; Eisai) for the treatment of patients with advanced endometrial carcinoma that was not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), and who had disease progression following prior systemic therapy and were not candidates for curative surgery or radiation. This historic approval was based on a Phase II study (KEYNOTE-146/Study 111) which marked the first-ever approval of an anti-PD-1 antibody in combination with a kinase inhibitor for the indication. As 25–30% of the patients with endometrial cancer have high MSI, there are still 70–75% of the patients without this mutation. The companies targeted the above patient pool and observed the objective response rate (ORR) of 38.3%, with a complete response rate of 10.6% (n = 10) and a partial response rate of 27.7% with a tolerable safety profile. Back then, the US FDA announced that the continued approval for this indication would be contingent upon verification and description of clinical benefit in the confirmatory trial.

Therefore, the company initiated a Phase III confirmatory trial, KEYNOTE-775/Study-309 (NCT03517449), to evaluate the extended clinical benefit rate in the above patient population. In March 2021, the companies announced the positive results from the study, which indicated that the combination reduced the risk of death by 38% compared with placebo, with a median overall survival (OS) of 18.3 months vs. 11.4 months, respectively. On the secondary endpoint of progression-free survival, the combination reduced the risk of disease progression or death by 44% compared to placebo, with a median PFS in the two groups of 7.2 months and 3.8 months, respectively. The results come after Merck voluntarily withdrew another Keytruda approval as a second-line treatment for small cell lung cancer (SCLC) after a confirmatory trial failed to prove a survival benefit.

Based on the above topline data, the US FDA granted full approval for the combination in advanced dMMR/MSI-H endometrial cancer in July 2021, following the priority review by the US FDA in May 2021. It seems as if Merck already had known that the deal with Eisai would work out well when they both signed an agreement for the worldwide co-development and co-commercialization of Lenvima in early 2018. Also, assuming the achievement of all development and commercial goals for all indications (six indications), the total amount of upfront, option, and regulatory and sales milestone payments can reach up to USD 5.76 billion, which would be shared equally by both the companies.

Merck and Eisai also compare the first-line use of Keytruda/Lenvima against chemotherapy in endometrial cancer in the LEAP-001 trial that will read out in 2023. If approved, the combination could stand out in the first-line patient pool and rule the second-line pool with the non-dMMAR/MSI-H patient pool.

However, the combination is expected to face tough competition in renal cell carcinoma where the companies are trying out the combination in Phase III CLEAR trial (NCT02811861). Recently, the duo achieved the priority review from the US FDA to treat patients with advanced RCC receiving therapy in the frontline setting. The results were recently presented at ASCO 2021, which showed the clinical benefit of RCC patients and might pave its way to successful approval later this year. The other options in kidney cancer including Keytruda’s pairing with Pfizer’s Inlyta, Bristol Myers Squibb’s combo of Opdivo and Yervoy, and an Opdivo pairing with Exelixis’ Cabometyx.

The above recent results of the combination prove that both the companies might generate a good market size in the upcoming years and might prove to be superior combinations with the highest prescription rates by the oncologists.