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## Noted This Week - 2022

Archive of cancer-related news briefs, by week, for 2022

### May 2022

#### May 13–19

• Federal agencies, Congress, and others need to improve representation of minority groups and underrepresented populations in clinical trials and research, according to a report from the National Academies of Sciences, Engineering, and Medicine (NASEM 2022 May 17 [Epub ahead of print]). Lack of representation may limit access to medical interventions and new therapies for some patients and increase health disparities, which could cost the United States hundreds of billions of dollars over the next 30 years. Among the report’s recommendations: require study sponsors to ensure that trial cohorts reflect the demographics of the condition under study, establish a task force to investigate new incentives for drug and device trials for which enrollment reflects the general population, and press the NIH to consider participant representation when assessing the impact of a grant proposal.
• The FDA has placed a partial clinical hold on a phase I study of FHD-286 (Foghorn Therapeutics) for patients with relapsed/refractory acute myelogenous leukemia and myelodysplastic syndrome following the death of a patient with potential differentiation syndrome. Patients currently enrolled in the study and benefiting from the BRG1 and BRM inhibitor may continue to receive it, but no new patients can be enrolled until the hold is lifted; the hold does not apply to patients with metastatic uveal melanoma in a separate phase I trial.
• According to the American Cancer Society, Medicaid expansion under the Affordable Care Act is associated with a 2-year increase in overall survival (OS) in patients newly diagnosed with cancer, especially among non-Hispanic Black people and people living in rural areas (J Natl Cancer Inst 2022 May 18 [Epub ahead of print]). Researchers analyzed data of over 2.5 million patients ages 18–62 in cancer registries from 42 states diagnosed with cancer before and after Medicaid expansion. OS increased from 80.58% to 82.23% in states that expanded Medicaid coverage and from 78.71% to 80.04% in those that didn’t—an increase of 0.44% in expansion states after adjusting for sociodemographic factors.
• Researchers found that children with certain liver tumors have better outcomes when they underwent transplantation rather than having chemotherapy and surgery alone (J Hepatol 2022 May 13 [Epub ahead of print]). Researchers observed that some aggressive tumors have histologic features unlike hepatoblastomas or hepatocellular carcinomas, as well as molecular profiles that don’t fit into a single disease category, but both. The team found that these tumors tended to be more resistant to standard chemotherapy and have poor outcomes when not treated with more aggressive surgical approaches, including transplantation, indicating the need for molecular testing to guide treatment.

### Earlier This Year:

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### Noted This Week Archive:

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• In a case–control study in England and Wales, researchers found that male infertility is associated with a statistically significant increase in men’s risk of invasive breast cancer (Breast Cancer Res 2022;24:29). Researchers interviewed 1,998 men diagnosed with the disease between 2005 and 2017 and 1,597 male controls, including questions about infertility and the number of children fathered. They calculated that the infertile men had a significantly higher risk of breast cancer, as did men who had not fathered children, with odds ratios of 2.03 and 1.50, respectively, although the researchers said these results require further investigation.

#### April 29–May 5

• The FDA granted regular approval to fam-trastuzumab deruxtecan-nxki (Enhertu; Daiichi Sankyo) for patients with inoperable or metastatic HER2-positive breast cancer who have previously received anti-HER2–based regimens. The decision was based on DESTINY-Breast03, the confirmatory trial for this antibody–drug conjugate’s accelerated approval in 2019. Among 524 patients who received either fam-trastuzumab deruxtecan-nxki or ado-trastuzumab emtansine (Kadcyla; Genentech), the median progression-free survival was not reached in the fam-trastuzumab deruxtecan-nxki arm versus 6.8 months in the control group. Overall response rates were 82% and 36.1%, respectively.
• Compared with fulvestrant (Faslodex; AstraZeneca) alone, adding ribociclib (Kisqali; Novartis) increased overall survival (OS) by 16 months in patients with breast cancer. According to an updated analysis of the phase III MONALEESA-3 study, which provided more than 2.5 years of additional follow-up, patients given first-line ribociclib plus fulvestrant upfront were able to delay subsequent chemotherapy by another 1.5 years. To date, ribociclib is the only CDK4/5 inhibitor to show an OS benefit when combined with fulvestrant as first-line therapy for postmenopausal women with advanced or metastatic HR+/HER2- disease.
• State affirmative action bans significantly reduced the number of minority students enrolled in U.S. public medical schools (Ann Intern Med 2022 May 3 [Epub ahead of print]). The study of 21 affected institutions concluded that underrepresented racial groups—Black, Hispanic, American Indian or Alaska Native, and Native Hawaiian or Pacific Islander—accounted for only 14.8% of medical students 1 year prior to ban implementation; afterward, this percentage dropped by 5.5 points, translating to a relative reduction of 37%. This finding indicates that state-level admissions policies remain an important factor in influencing enrollment diversity.
• St. Jude Children’s Research Hospital will improve diagnostics for pediatric blood cancers globally, providing Oxford Nanopore Technologies’ MinION DNA and RNA portable sequencing tool to low- and middle-income countries. A proof-of-concept study has shown that this device could help doctors better distinguish acute myeloid leukemia, B-cell acute lymphoblastic leukemia, and T-cell acute lymphoblastic leukemia (JCO Precis Oncol 2022 Apr 20 [Epub ahead of print]). St. Jude will also make its cloud computing services available to participating hospitals to shorten the turnaround time for these powerful analyses.
• Gilead paid 300 million to Dragonfly Therapeutics to collaborate on advancing the latter’s natural killer (NK) cell engager–based immunotherapies. Gilead now has exclusive worldwide licensing for DF7001, which targets 5T4, a protein associated with poor prognosis in several tumor types, including non–small cell lung cancer, pancreatic cancer, and head and neck squamous cell carcinoma. Gilead also has the option to develop and commercialize additional immune engagers using Dragonfly’s Tri-specific NK Engager (TriNKET) platform. • The Department of Defense (DOD) will expand its Applied Proteogenomics Organizational Learning and Outcomes (APOLLO) Network. First created in 2016 as part of the original White House Cancer Moonshot initiative, APOLLO successfully created a network of 13 DOD and Veterans Affairs hospitals that launched eight cancer-specific programs, including for lung, breast, prostate, and brain cancers. Now that the Cancer Moonshot program has been revived, APOLLO aims to extend its network to all Defense Health Agency hospitals and widen research efforts to include all cancer types. ### April 2022 #### April 22–28 • The FDA proposed a ban on menthol flavoring in cigarettes and cigars. This could dramatically lower disease and death resulting from tobacco use, thus playing a crucial role in the Cancer Moonshot program’s goal to reduce cancer-related deaths by 50% in the next 25 years. If successful, the ban could diminish the appeal of cigarettes to young people, reduce the likelihood of tobacco experimentation among nonsmokers, and improve smoking cessation rates. • Compared with physician’s choice of endocrine monotherapy, Roche’s oral selective estrogen receptor degrader (SERD) giredestrant failed to improve progression-free survival as a second- or third-line treatment in patients with ER-positive, HER2-negative advanced breast cancer. Overall survival data from this phase II trial, acelERA, are still immature, and investigators noted "encouraging" efficacy, particularly among patients with highly estrogen-dependent disease. Giredestrant is also being evaluated in two phase III trials, lidERA and persevERA, respectively testing the SERD as adjuvant therapy for early disease and combined with the CDK 4/6 inhibitor palbociclib (Ibrance; Pfizer) as initial treatment for metastatic breast cancer. • Nkarta reported that two of its lead chimeric antigen receptor (CAR) natural killer (NK) cell therapies, NKX101 and NKX019, showed promising efficacy in acute myeloid leukemia (AML) and non-Hodgkin lymphoma (NHL). NKX101, which targets NKG2D, induced a complete response (CR) rate of 60% with full hematologic recovery among five patients with relapsed/refractory AML. With NKX019, which targets CD19, the CR rate was 50% and the objective response rate was 83% among six patients with NHL. The company said both agents caused fewer adverse side effects compared with CAR T-cell treatments and had no dose-limiting toxicities. • Nektar cut 70% of its staff as part of a company reorganization. It will now focus on the development of NKTR-255, an IL15 agonist, to treat both solid and blood cancers, and NKTR-358, in development with Eli Lilly, for the treatment of autoimmune inflammatory diseases. The company will also pursue new research programs, including a collaboration with Biolojic Design utilizing Biolojic’s artificial intelligence platform to develop a computationally designed antibody targeting TNFR2. • The National Comprehensive Cancer Network (NCCN) updated its COVID-19 vaccination recommendations for patients with cancer (available at https://www.nccn.org/COVID-19). The organization now encourages those who are immunocompromised to receive three primary mRNA COVID-19 vaccines plus two booster shots. The NCCN also provided updated dosing recommendations for pre-exposure prevention with tixagevimab plus cilgavimab (Evusheld; AstraZeneca), information on receiving booster shots following the Johnson & Johnson COVID-19 vaccine, and data on whether receiving vaccines from different companies might affect efficacy. #### April 15–21 • Through the analysis of 851 human cancer cell lines, researchers at the Broad Institute of MIT and Harvard’s Cancer Dependency Map project determined that dysregulation of the XPR1-KIDINS220 protein complex leads to toxic buildup of phosphate in ovarian and uterine cancers (Nat Cancer 2022 April 18 [Epub ahead of print]). These cancers frequently overexpress the phosphate importer SLC34A2. By disabling XPR1-KIDINS220, toxic buildup of phosphate leads to cancer cell death, suggesting a novel treatment for these malignancies. • An FDA advisory panel voted unanimously that randomized data should be required for approvals of PI3K inhibitors for blood cancers due to concerns about toxicity, overall survival, dose optimization, and limitations of single-arm studies. The Oncologic Drugs Advisory Committee’s recommendation aligns with the thinking of federal regulators, which was published last week, that randomized data is imperative for accurate risk–benefit evaluations (Lancet Oncol 2022 Apr 14 [Epub ahead of print]). • According to data presented at the American Society of Clinical Oncology’s monthly Plenary Series, patients with recurrent/metastatic nasopharyngeal cancer who receive tislelizumab (BeiGene) experience longer progression-free survival (PFS) than those who receive a placebo. In the phase III RATIONALE-309 study, 263 patients received either tislelizumab plus chemotherapy or placebo plus chemotherapy; median PFS was 9.6 months versus 7.4 months, respectively, with a 50% reduction in the risk of disease progression with tislelizumab. Median PFS in the tislelizumab group after a subsequent treatment regimen was not reached, and overall survival (OS) was 23 months; median PFS and OS in the placebo group were 13.9 months and 23 months, respectively. • Emory University’s Winship Cancer Institute in Atlanta, GA, opened the Rollins Immediate Cancer Center, the state’s first center dedicated solely to caring for patients experiencing acute cancer-related symptoms, such as severe pain, high fevers, or vomiting. At the center, oncologists and oncology nurses can appropriately triage patients and diagnose and treat patients with pressing cancer-related needs; patients with life-threatening or complicated medical issues will still visit the emergency room. The center was funded with a7 million gift from The Ma-Ran Foundation.
• The Vera Bradley Foundation for Breast Cancer donated $12.5 million to Indiana University (IU) School of Medicine in Indianapolis to fund immunotherapy research on triple-negative breast cancer. Previous support from the foundation has helped the school hire physicians and scientists, upgrade technology, and boost resources to advance targeted breast cancer therapies. To date, the foundation has contributed$37.5 million to the IU School of Medicine for breast cancer research.
• Noting that 14% of global lung cancer cases are caused by air pollution, The International Association for the Study of Lung Cancer issued a list of steps that should be taken to reduce the risk of the disease. For example, the organization called for, among other things, the restriction of air emission targets "to the lowest levels as recommended by the World Health Organization," disinvestment in fossil fuel companies, and research into the pathophysiological and carcinogenetic effects of a specific type of particulate matter called PM2.5.

#### April 8–14

This week: Special coverage of the American Association for Cancer Research (AACR) Annual Meeting 2022, as well as other news.

• Reflecting on changes to clinical trial conduct during the COVID-19 pandemic, Lola Fashoyin-Aje, MD, MPH, of the FDA, said that some traditional requirements, such as having patients return to the study site for in-person consent or to receive medications that could be shipped to their homes, could be waived for cancer clinical trials to optimize trial diversity and participation. There’s a general sentiment, she said, that "we cannot and should not reflexively revert to traditional site-centered approaches to our clinical trials. Instead, we should leverage all that we learned during the pandemic to determine best practices," focusing on "patient safety, patient convenience, and trial quality to answer important clinical questions."
• Lisa Coussens, PhD, formally began her 1-year term as president of the AACR at its annual meeting. A researcher at the Oregon Health and Science University in Portland, she succeeds David Tuveson, MD, PhD, of Cold Spring Harbor Laboratory in New York. (For more information about Coussens, see Cancer Discov 2022 Mar 30 [Epub ahead of print]).
• In the phase III CheckMate 816 trial, neoadjuvant nivolumab (Opdivo; Bristol Myers Squibb) plus chemotherapy led to significantly longer event-free survival and higher likelihood of a pathologic complete response (pCR) than chemotherapy alone in patients with operable non–small cell lung cancer (NSCLC), researchers reported at the AACR meeting and in The New England Journal of Medicine (N Engl J Med 2022 Apr 11 [Epub ahead of print]). Median event-free survival was 31.6 months in the nivolumab arm compared with 20.8 months in the chemotherapy-alone arm; pCR rates were 24% and 2.2%, respectively. No increase in the incidence of adverse events or impediments to surgery was observed in the nivolumab arm.
• At the AACR meeting, Grace Dy, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, NY, reported that 2-year overall survival was 32.5% in patients with KRASG12C-mutated NSCLC who received sotorasib (Lumakras; Amgen) in the phase II CodeBreaK 100 study. In addition, the overall response rate was 41%, the disease control rate was 84%, and the median duration of response was 12.3 months—with no new safety concerns. These findings mimic those of previously reported efficacy data for the KRASG12C inhibitor (N Engl J Med 2021;384:2371–81).
• Dual treatment with KSQ-4279 and a PARP inhibitor showed synergistic activity across different lineages, reported Andrew Wylie, PhD, of KSQ Therapeutics. A potent and selective USP1 inhibitor, KSQ-4279 also showed dose-dependent efficacy and durable tumor regression in ovarian cancer patient-derived xenograft models when combined with olaparib (Lynparza; AstraZeneca). The drug is now being tested in phase I trials in tumors with homologous recombination deficiency.
• In a phase Ib trial presented at the AACR meeting, the oral ataxia telangiectasia and Rad3-related (ATR) inhibitor elimusertib yielded durable objective responses in patients with a variety of cancers harboring ATM alterations. Some patients experienced grade 3 adverse advents—namely anemia and other hematologic effects that were manageable and reversible. Additional studies assessing elimusertib in combination with PARP inhibitors or PD-1 inhibitors are underway.
• "One of the key problems in the rare cancer space is lack of appropriate models in which to prosecute hypotheses," said Andrew Futreal, PhD, of The University of Texas MD Anderson Cancer Center in Houston, during his AACR meeting presentation on genomic profiling of patients with rare cancers. As part of the Rare Tumor Initiative, MD Anderson has partnered with the Broad Institute of Harvard and MIT and The Rare Cancer Research Foundation to help develop 2D and 3D models of these diseases to aid in extending research efforts.
• Speaking at the AACR meeting about prostate ductal adenocarcinoma (PDAC), Christine Iacobuzio-Donahue, MD, PhD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, NY, said, "There are evolutionary features of locally advanced PDAC that are clinically relevant." She suggested that future research on this lethal disease should focus on rethinking stromal targeting and investigate the mechanistic underpinnings of phenotypic differences within the disease.
• Charles Swanton, MD, PhD, of The Francis Crick Institute and University College London in the UK, presented some early results from the TRACERx 421 Patient Cohort comprised of 421 prospectively recruited patients with stage I-IIIA NSCLC. He announced that primary tumor subclone expansion matters and can contribute to worse outcomes and disease recurrence.
• Broadening the search into autoimmunity gene variants could provide further information regarding antitumor immunity, explained Thomas Gajewski, MD, PhD, of the University of Chicago in Illinois, during his AACR presentation. Inspired by findings that PTPN22 variants predispose individuals to autoimmune diseases, he demonstrated that myeloid cell PTPN22 regulated CD8+ T cell–mediated tumor control.
• Luis Diaz Jr., MD, of MSKCC spoke about the dichotomy of hypermutagenesis at the AACR meeting. His work revealed that foreignness of a mutation is a driving factor of self-peptidome immune recognition, where those with a greater degree of sequence divergence from the self-peptidome are more responsive to immune checkpoint blockade, ultimately suggesting a strategy for conversion of tumors from immune-cold to more immunogenic.

In other news:

• GlaxoSmithKline (GSK) will acquire Sierra Oncology, based in San Mateo, CA, for $1.9 billion. GSK will enhance its hematology portfolio—which includes the BCMA-targeted agent belantamab mafodotin (Blenrep) for the treatment of multiple myeloma—with the addition of momelotinib, which is under investigation for the treatment of myelofibrosis. Momelotinib inhibits multiple signaling pathways: ACVR1/ALK2; JAK1, and JAK2; in the phase III MOMENTUM trial, demonstrated statistically significant and clinically meaningful benefits in symptom management, splenic response, and anemia. • Four pharmaceutical companies launched the Precision Cancer Consortium (PCC) to boost access to genomic testing for patients with cancer around the world. The PCC aims to increase the use of precision diagnostics such as next-generation sequencing, improve access to routine care and clinical trials, and communicate the value of genomic testing to health care providers. The founding companies are Bayer, GSK, Novartis, and Roche. • Toronto, Canada–based Nurosene Health subsidiary NetraMark announced it will collaborate with the Ontario Institute for Cancer Research to identify genetic biomarkers of pancreatic cancer using artificial intelligence (AI). This initiative could increase understanding of how to treat the disease and point to the most effective medication for each patient. Nurosene Health specializes in "delivering innovative AI-based technology solutions that support mental performance and wellness." #### April 1–7 • The FDA approved axicabtagene ciloleucel (axi-cel; Yescarta; Kite/Gilead) as the first CAR T-cell therapy to treat adults with large B-cell lymphoma (LBCL) that is refractory to or relapses within 12 months of receiving first-line chemoimmunotherapy. The decision was based on the landmark ZUMA-7, in which 40.5% of patients who received axi-cel were alive after 2 years compared with 16.3% of those who received standard care. In addition, event-free survival was longer with axi-cel than standard care—8.3 months versus 2 months, respectively. • In a study published in the Journal of Clinical Oncology, researchers reported that women with breast cancer have a higher risk of cardiovascular disease than women without the disease (J Clin Oncol 2022 Apr 6 [Epub ahead of print]). In the Pathways Heart Study, researchers compared 13,642 women with breast cancer diagnosed between 2005 and 2013 who were treated with chemotherapy, radiation therapy, or endocrine therapy with 68,202 women without the disease. Although degree of risk varied by treatment, the researchers found that women undergoing breast cancer treatment were more likely to experience stroke, arrhythmia, cardiac arrest, venous thromboembolic disease, cardiovascular disease–related death, and death from any cause compared with women without a history of breast cancer. • The UK's National Institute for Health and Care Excellence (NICE) decided to recommend avelumab (Bavencio; Merck/Pfizer) as a first-line maintenance therapy for bladder cancer. NICE initially nixed the PD-L1 inhibitor, saying the benefit didn’t justify the cost. However, thanks to a drop in price and additional evidence of a benefit from the company, avelumab will be recommended for use in patients with locally advanced or metastatic urothelial carcinoma whose disease has not progressed after platinum-based chemotherapy. • In what the company deems a first of its kind for the pharmaceutical industry, Sanofi launched its Diversity, Equity & Inclusion (DE&I) Board, which includes experts from outside the company. The company said that its strategy is "built around three key pillars: building representative leadership, creating a work environment where employees can bring their whole selves, and engaging with the company’s diverse communities." The new DE&I Board will offer advice on how to speed advancements in diversity, equity, and inclusion at the company and monitor progress. • American Association for Cancer Research (AACR) members chose Philip Greenberg, MD, as the organization’s president-elect for 2022–2023; he will assume the position next week at the AACR 2021 Annual Meeting in New Orleans, LA, when Lisa Coussens, PhD, becomes the AACR president. An internationally recognized pioneer in cancer immunology whose work fueled the advancement of adoptive T-cell therapy, Greenberg heads the immunology program at Fred Hutchinson Cancer Research Center in Seattle, WA. He has served on the AACR’s board of directors and the Annual Meeting program committee, among others, and is co–editor-in-chief of the AACR journal Cancer Immunology Research. ### March 2022 #### March 25–31 • Under President Joe Biden’s proposed budget for fiscal year (FY) 2023, the NCI would face a budget cut of$199 million compared with FY2022. If approved by Congress, the NCI would receive $6.714 billion, even though the agency requested$7.766 billion. However, the proposed budget would provide a $41 million increase for cancer programs at the Centers for Disease Control and Prevention and a one-time increase of$20 million for the FDA Oncology Center of Excellence. In addition, the new Advanced Research Projects Agency for Health (ARPA-H) would receive 5 billion. • Debate over where ARPA-H will be "housed" has come to an end: It will be part of the NIH, although a few measures have been taken to provide some autonomy to the agency. For example, the director of ARPA-H will report to the secretary of Health and Human Services instead of the NIH director, and it will not be located at the NIH’s headquarters in Bethesda, MD. • The Telomere to Telomere (T2T) consortium has generated the first gapless sequence of a human genome (Science 2022;376:6588). Analysis of the sequence will offer insight into genomic variations within 622 medically relevant genes and allow researchers to better understand how chromosomes segregate and divide. The work could also lead to more discoveries about how genetic factors contribute to disease. Several related papers were published in the same issue of Science and other journals. • Roche/Genentech reported that in the phase III SKYSCRAPER-02 study, the combination of tiragolumab and atezolizumab (Tecentriq) plus chemotherapy failed to improve progression-free survival and overall survival (OS) in patients with extensive-stage small-cell lung cancer. The regimen of the anti-TIGIT and anti–PD-L1 drugs, respectively, continues to be assessed in PD-L1–high patients with non–small cell lung cancer in the phase III SKYSCRAPER-01 trial. Data will be presented at an upcoming medical meeting. • Researchers determined that a living-donor liver transplant (LDLT) is a viable treatment alternative to chemotherapy for patients with inoperable colorectal liver metastasis (JAMA Surg 2022 Mar 30 [Epub ahead of print]). Of 10 patients who received an LDLT, the estimated recurrence-free survival after a median of 18 months was 62%; estimated OS was 100%. Recent studies have suggested that patients receiving an LDLT from a living donor live longer than patients with liver cancer who receive a liver from a deceased donor. #### March 18–24 • The FDA approved lutetium Lu 177 vipivotide tetraxetan (Pluvicto; Novartis)—formerly 177Lu-PSMA-617—the first radioligand therapy to treat patients with PSMA-positive metastatic castration-resistant prostate cancer who have already received other therapies. The decision was based on the phase III VISION study, in which patients who received the agent and standard-of-care treatment had a 38% reduction in the risk of death and a 60% reduction in the size of tumors compared with standard care alone. • The FDA declined to approve sintilimab (Lilly/Innovent), a PD-1 inhibitor, for the treatment of nonsquamous non–small cell lung cancer. Clinical trials of the drug took place only in China, and regulators expressed concern about the lack of diversity in the trials. In February, a panel of FDA advisers said that the companies should be required to conduct a trial of sintilimab and demonstrate its benefit in a diverse population; the companies are exploring next steps for the drug in the United States. • Merck announced that the FDA approved pembrolizumab to treat advanced endometrial carcinoma that is mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H) in patients with progressive disease who aren’t candidates for surgery or radiation. Among 90 patients enrolled in two cohorts of the KEYNOTE-158 trial, 12% had a complete response and 33% had a partial response. In addition, the agency approved the companion diagnostic VENTANA MMR RxDx Panel (Ventana Medical Systems/Roche Tissue Diagnostics) to select patients with dMMR eligible for treatment; a test from Foundation Medicine to detect MSI-H tumors was already approved. • Patients diagnosed with early cervical cancer have a higher likelihood of disease-free survival (DFS) after having a hysterectomy with open surgery compared with minimally invasive surgery (MIS). The DFS for open surgery was 96%, while the MIS DFS was 85%. This final analysis, which was presented at the Society of Gynecologic Oncology Annual Meeting, supports the initial 2018 findings from the Laparoscopic Approach to Cervical Cancer trial, and national guidelines now consider open surgery the standard for early-stage cervical cancer. • St. Jude Children’s Research Hospital researchers discovered two gene variations associated with accelerated biological aging in survivors of childhood cancer compared with chronologic aging (Genome Med 2022;14:32). Through genome-wide association studies, they tested more than 8 million genetic variants and found two distinct single-nucleotide polymorphisms in the DNA of survivors—one mapped to the SELP gene and the other to the HLA locus—compared with controls. Using this information, they may be able to identify patients at high risk of accelerated aging and find potential drug targets. • The annual Monitoring the Future survey, conducted by the University of Michigan, polled teens and found the rate of failed attempts to quit nicotine among adolescents rose to 5.74% in 2020, a level not seen since 2004 (JAMA 2022;327:1179–81). This can largely be attributed to electronic cigarette use. While the survey indicated an overall decline in the use of the devices in 2021, researchers are concerned that electronic cigarette use will increase now that teens have returned to school, which could further increase the percentage of those unable to kick the habit. #### March 11–17 • Merck announced that the FDA approved another indication for olaparib (Lynparza)—this time for the adjuvant treatment of patients with germline BRCA-mutant, HER2-negative high-risk early breast cancer who have already received chemotherapy. The approval was based on findings from the OlympiA trial, in which olaparib reduced the risk of invasive breast cancer recurrences, second cancers, or death by 42% versus placebo. At this week’s European Society for Medical Oncology Virtual Plenary, researchers presented updated results showing that the PARP inhibitor reduced the risk of death by 32%, a statistically significant improvement in overall survival (OS). • However, Merck said the combination of olaparib and the PD-1 inhibitor pembrolizumab (Keytruda) did not demonstrate an improvement in OS in patients with metastatic castration-resistant prostate cancer compared with the control arm, in which patients received either abiraterone or enzalutamide. As a result, the phase III KEYLYNK-010 trial assessing the combination will be discontinued. • Racho Jordanov and Rose Lin, founders of JHL Biotech, were sentenced to a year plus 1 day in prison for stealing trade secrets from Genentech, followed by 3 years of supervised release—including 9 months of home confinement for Jordanov. The two hired former or current Genentech employees to obtain confidential information between 2011 and 2019 to "cheat, cut corners, solve problems, provide examples, avoid further experimentation, eliminate costs, lend scientific assurance, and otherwise help" the start-up, according to the U.S. District Attorney for the Northern District of California. The Taiwanese company used the confidential purloined documents to hasten the development of biosimilars of several drugs, including the anti-CD20 mAb Rituxan (rituximab), the anti-HER2 mAb Herceptin (trastuzumab), and the angiogenesis inhibitor Avastin (bevacizumab). • Sanofi's revealed that amcenestrant did not meet its primary endpoint of improving progression-free survival in patients with estrogen receptor (ER)–positive, HER2-negative advanced or metastatic breast cancer whose disease progressed while on or after taking hormone therapies. In the phase II AMEERA-3 trial, the oral selective ER degrader as a monotherapy proved no better than a single-agent endocrine therapy of the physician’s choice. Trials evaluating the drug in combination with palbociclib (Ibrance; Pfizer), for example, will continue. • In a phase III trial, Exelixis's tyrosine kinase inhibitor (TKI) cabozantinib (Cabometyx) "showed neither improvement nor detriment in OS" when combined with the PD-L1 inhibitor atezolizumab (Tecentriq; Genentech) to treat newly diagnosed advanced hepatocellular carcinoma (HCC) compared with the TKI sorafenib (Nexavar; Bayer), the company announced. As a result, Exelixis will not seek FDA approval for the indication. The drug is already approved to treat multiple malignancies, including advanced renal cell carcinoma and HCC already treated with sorafenib. #### March 4–10 • The U.S. Congress passed a1.5 trillion spending bill to fund the government for fiscal year (FY) 2022, which had been operating under a series of continuing resolutions since October 1. The NIH received nearly $45 billion, an increase of 4.7% over FY21; the NCI,$6.9 billion, up by 5.3%; the FDA, $3.3 billion, up by 3%; and the Centers for Disease Control and Prevention,$8.5 billion, up by 6.8%—although its cancer programs received an increase of just $4 million. The bill also included$1 billion directed to the U.S. Department of Health and Human Services to launch the Advanced Research Projects Agency for Health to drive transformative biomedical breakthroughs—money that can be used through September 30, 2024.
• The U.S. Congress also gave the FDA’s Center for Tobacco Products the authority to regulate synthetic nicotine. The FDA has had the authority to regulate nicotine derived from tobacco but whether the agency could regulate nicotine from other sources has been unclear. Thus, some companies have continued to sell flavored electronic cigarettes, which appeal to children and teenagers, that contain synthetic nicotine. The agency can now regulate nicotine no matter its source; companies need to submit new product applications for any items containing synthetic nicotine—unless they had already been pulled from the market—within 90 days.
• Regulatory Focus reported that a newly introduced bill would codify the FDA’s authority requiring drug companies to complete postmarking studies on agents granted accelerated approval. Introduced by Rep. Frank Pallone (D-NJ), the Accelerated Approval Integrity Act would limit the amount of time drugs could stay on the market without confirming their clinical benefit to 5 years. Under the current system, Pallone said, drugs have been allowed to stay on the market "for far too long without clinical trials" demonstrating their value.
• Postmenopausal patients with HR-positive, HER2-negative metastatic breast cancer had a significant overall survival (OS) benefit with ribociclib (Kisqali; Novartis) plus endocrine therapy, researchers reported (N Engl J Med 2022;386:942–50). With the CDK4/6 inhibitor and the aromatase inhibitor letrozole, patients experienced a median overall survival OS of 63.9 months compared with 51.4 months with hormone therapy alone. This is the first study to show a survival advantage with a CDK4/6 inhibitor plus an aromatase inhibitor as a first-line treatment in these patients, prompting researchers to say that it should become standard of care for most.
• Adding bortezomib to chemotherapy significantly improves overall survival in children and young adults just diagnosed with T-cell lymphoblastic lymphoma (T-LL) or acute lymphocytic leukemia (ALL), researchers reported (J Clin Oncol 2022 Mar 10 [Epub ahead of print]). The 4-year event-free survival for patients with T-LL who received chemotherapy alone was 76.5% compared with 86.4% for those who received the proteasome inhibitor as well; the 4-year OS was 78.3% and 89.5%, respectively. There was no significant improvement with bortezomib in patients with ALL.

• During his State of the Union address, President Joe Biden emphasized his goal to cut cancer death rates by at least 50% over the next 25 years by reigniting the Cancer Moonshot program launched in 2016 under President Barack Obama. The Moonshot will largely focus on screening, prevention, and early detection initiatives. He then called upon Congress to fund the Advanced Research Projects Agency for Health (ARPA-H) to drive breakthroughs in cancer and other conditions; a bill passed last year by the U.S. House of Representatives would provide 3 billion to establish ARPA-H. • After years of legal wrangling, the U.S. Patent and Trademark Office ruled that the genome editing technology CRISPR belongs to the Broad Institute of Harvard and Massachusetts Institute of Technology (MIT). In 2012, Jennifer Doudna, PhD, of the University of California, Berkeley, and Emmanuelle Charpentier, PhD, of the Max Planck Institute for Infection Biology in Berlin, Germany, showed how CRISPR could be used to edit DNA in test tubes; less than 6 months later, Feng Zhang, PhD, of Cambridge, MA’s MIT, and colleagues demonstrated that CRISPR could be used to edit DNA in eukaryotic cells (Science 2012;337:816–21; Science 2013;339:819–23). The patent ruling hinged on Zhang’s group being the first to apply the technology to mouse and human cells. • Legend Biotech and Janssen announced that the FDA approved ciltacabtagene autoleucel (cilta-cel; Carvykti) to treat adults with relapsed or refractory multiple myeloma who have already received at least four therapies. A chimeric antigen receptor T-cell therapy, cilta-cel was approved based on the pivotal CARTITUDE-1 study, which demonstrated an overall response rate of 98% and a stringent complete response rate of 78%. Cilta-cel is the second CAR T-cell therapy approved for multiple myeloma, following idecabtagene vicleucel (Abecma; Bristol Meyers Squibb/2seventy bio). • Writing on Medium, six leaders in the life sciences industry called for businesses to pledge to "cease all business involvement in Russia" in response to that nation’s unprovoked attack on Ukraine. Leaders of dozens of companies involved in funding and conducting cancer research—including Mirati, Seagen, Astellas Biopharma, Ikena Oncology, and Arch Oncology—subsequently signed the pledge. As of March 3, more than 700 people had cosigned the letter. • CTI Biopharma announced that the FDA granted accelerated approval to pacritinib (Vonjo) for the treatment of myelofibrosis. Pacritinib is a novel oral kinase inhibitor with specificity for JAK2 and IRAK1, without inhibiting JAK1. Approval was based on the phase III PERSIST-2 study, in which 29% of patients with baseline platelet counts below 50 x 109/L treated with 200 mg of pacritinib had a reduction in spleen volume of at least 35%, compared with 3% of patients receiving best available therapy. • Cambridge, MA–based Epizyme said it will cut 12% of its staff and end two clinical trials involving its EZH2 inhibitor tazemetostat (Tazverik): the phase II SYMPHONY-2 trial testing a combination of tazemetostat and rituximab in patients with follicular lymphoma (FL), and the phase I EZH-1301 basket trial assessing tazemetostat in combination with a variety of other drugs to treat solid tumors. Tazemetostat is FDA-approved to treat FL and epithelioid sarcoma. ### February 2022 #### February 18–24 • Researchers reported that, for patients with previously untreated chronic lymphocytic leukemia (CLL), taking ibrutinib (Imbruvica; AbbVie/Janssen) plus venetoclax (Venclexta; AbbVie/Genentech) for a fixed duration could result in deep, durable responses and provide meaningful clinical benefit, even in those with high-risk disease (Blood 2022 Feb 23 [Epub ahead of print]). In the phase II CAPTIVATE study, 159 patients received three cycles of ibrutinib followed by 12 cycles of the combination, with both drugs taken orally. For the 136 patients without del(17p), the complete response (CR) rate was 56%; for the entire group, the CR rate was 55%, and the 24-month progression-free survival (PFS) and overall survival (OS) rates were 95% and 98%, respectively. • Atara Biotherapeutics reported that enrollment in a clinical study of ATA2271 has been voluntarily paused due to the death of a patient with advanced, recurrent malignant pleural mesothelioma who had a history of multiple cancers and other comorbidities. Researchers are gathering information to determine the precise relationship between the death and the treatment. ATA2271 is a next-generation autologous chimeric antigen receptor T-cell therapy that targets mesothelin. • Merck/EMD Sorono’s tepotinib (Tepmetko) was approved by the European Commission to treat adults who have advanced non–small cell lung cancer (NSCLC) with MET exon 14 skipping alterations and require systemic therapy following treatment with immunotherapy and/or platinum-based chemotherapy. The approval was based on results of the pivotal phase II VISION study (N Engl J Med 2020;383:931–43). Researchers are now assessing the combination of tepotinib and osimertinib (Tagrisso; AstraZeneca) in patients with MET-amplified advanced or metastatic NSCLC and activating EGFR mutations that progressed after first-line treatment with osimertinib. • Seagen and Genmab announced that tisotumab vedotin (Tivdak) demonstrated a manageable safety profile and promising preliminary antitumor activity in patients with squamous cell carcinoma of the head and neck, with an objective response rate of 16% (five of 31 patients). In the phase II innovaTV 207 trial, the median follow-up was 10 months, the disease control rate was 58.1%, median PFS was 4.2 months, and median OS was 9.4 months. An antibody–drug conjugate, tisotumab vedotin received accelerated approval from the FDA in September 2021 for previously treated recurrent or metastatic cervical cancer. • The FDA authorized marketing of the first condoms specifically indicated for use during anal sex to reduce the spread of sexually transmitted infections (STI), such as human immunodeficiency virus and human papillomavirus (HPV). The condoms, marketed as One Male Condom (Global Protection Corp.), can also be used during vaginal intercourse to reduce the risk of pregnancy and transmission of STIs. HPV is the most common STI and is a common cause of cervical, anal, penile, and oropharyngeal cancers. #### February 11–17 • Robert Califf, MD, was confirmed as FDA Commissioner by the U.S. Senate by a vote of 50–46. He replaces Janet Woodcock, MD, who held the role on an interim basis since Stephen Hahn, MD, who was appointed by President Donald Trump, left the FDA on January 20, 2021. • President Joe Biden tapped two scientists to handle the responsibilities of Eric Lander, PhD, who resigned earlier this month as director of the White House Office of Science and Technology Policy (OSTP) and as Science Advisor to the President, on an interim basis. Alondra Nelson, PhD, currently OSTP's deputy director for Science and Society, will perform the duties of the OSTP director; Francis Collins, MD, PhD, who recently stepped down as NIH director, will serve as science advisor and as co-chair of the President's Council of Advisors on Science and Technology "until permanent leadership is nominated and confirmed," the White House said. • A study conducted at Moores Cancer Center at University of California San Diego Health found that significant increases in the severity of breast cancer diagnoses exist due to the COVID-19 pandemic. In 2019, 63.9% of breast cancers diagnosed there were classified as stage I compared with 51.3% in 2020; stage IV disease was diagnosed in 1.9% and 6.2%, respectively (JAMA Netw Open 2022;5:e2148581). Data from January through March 2021 showed a continuing trend, with 41.9% of patients diagnosed with stage I disease compared with 8% for stage IV disease. • At the American Society of Clinical Oncology (ASCO) Genitourinary (GU) Cancers Symposium in San Francisco, CA, researchers reported that Bayer's darolutamide (Nubeqa) plus androgen deprivation therapy (ADT) and docetaxel significantly increased overall survival in patients with metastatic hormone-sensitive prostate cancer compared with ADT plus docetaxel (N Engl J Med 2022 Feb 17 [Epub ahead of print]). In the phase III ARASENS trial, the drug trio reduced the risk of death by 32.5% compared with ADT plus docetaxel. After 4 years, survival was higher with darolutamide than with placebo—62.7% versus 50.4%—with no major differences in adverse events. Darolutamide is approved for the treatment of patients with nonmetastatic castration-resistant disease. • Also at the ASCO GU Symposium, researchers announced that AstraZeneca's PARP inhibitor olaparib (Lynparza) plus abiraterone yielded statistically significant and clinically meaningful improvement in radiographic progression-free survival (rPFS) as a first-line treatment for metastatic castration-resistant prostate cancer compared with standard-of-care abiraterone regardless of homologous recombination repair gene mutations. In an interim analysis, the addition of olaparib reduced the risk of disease progression or death by 34%. Median rPFS was 24.8 months for olaparib plus abiraterone versus 16.6 months for abiraterone alone. #### February 4–10 • Presidential Science Advisor and Director of the Office of Science and Technology Policy (OSTP) Eric Lander, PhD, resigned from his Cabinet-level position on February 7, after a Politico article reported that he created a toxic workplace and bullied and mistreated staff. His departure raises questions about the future of the Advanced Research Projects Agency for Health—intended to accelerate biomedical research for widespread diseases—and the reboot of the Cancer Moonshot announced by President Joe Biden last week. The White House has not yet announced an acting director for the OSTP. • In a nearly unanimous vote of 14–1, the FDA's Oncologic Drugs Advisory Committee recommended against approving the PD-1 inhibitor sintilimab (Eli Lily/Innovent) to treat non–small cell lung cancer based on the findings of the ORIENT-11 study. FDA officials who attended the meeting criticized the companies for submitting an application for approval based solely on data from China, which doesn't reflect the heterogenous population in the United States. In addition, the FDA representatives criticized the companies for failing to alert patients that the standard of care had changed to the PD-1 inhibitor pembrolizumab (Keytruda; Merck) and to offer patients the opportunity to take that drug instead. • Researchers reported that patients with cervical cancer who received the PD-1 inhibitor cemiplimab survived significantly longer than those who received investigator's choice of single agent chemotherapy for recurrent disease following initial treatment with platinum-based chemotherapy (N Engl J Med 2022;386:544–55). For the 304 women who received the Regeneron/Sanofi drug in the phase III trial, the median overall survival was 12 months compared with 8.5 months in the 304 women who received chemotherapy. Notably, objective responses occurred in patients with PD-L1 expression greater than 1% and less than 1%—18% and 11% respectively. • In patients with early triple-negative breast cancer, neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab after surgery, resulted in significantly longer event-free survival than neoadjuvant chemotherapy alone (N Engl J Med 2022;386:556-67). After a median follow-up of 39.1 months, the estimated event-free survival at 36 months was 84.5% compared with 76.8%, respectively. Researchers reported that adverse events occurred mainly during neoadjuvant treatment and were consistent with what has been previously reported. • The FDA issued its first Notice of Noncompliance to Acceleron Pharma for failure to submit required summary results of a trial to ClinicalTrials.gov; the agency had previously sent Acceleron a Pre-Notice of Noncompliance to the company to encourage the company to post findings. The clinical trial in question evaluated the safety and effectiveness of Acceleron's ALK1 inhibitor dalantercept in combination with the tyrosine kinase inhibitor axitinib (Inlyta; Pfizer) to treat patients with advanced renal cell carcinoma. The company has 30 days to submit the required information or face civil monetary penalties. • The prospective phase II GALAHAD trial found that about one third of patients with previously treated BRCA-mutant metastatic castration-resistant prostate cancer responded to niraparib (Nerlynx; Puma Biotechnology), a PARP inhibitor (Lancet 2022 Feb 4 [Epub ahead of print]). After a median follow-up of 10 months, the objective response rate in the cohort of 76 patients with measurable disease was 34.2%. The most common treatment-emergent adverse events of any grade were nausea, anemia, and vomiting (58%, 54%, and 38%, respectively); the most common grade 3 or higher side effects were anemia, thrombocytopenia, and neutropenia (33%, 16%, and 10%, respectively). #### January 28–February 3 • The FDA is investigating a possible increased risk of death with umbralisib (Ukoniq; TG Therapeutics), which is approved to treat adults with certain marginal zone and follicular lymphomas, while it continues to evaluate findings of the phase IIb/III UNITY trial testing the drug. The agency has also suspended enrollment of new patients in other clinical trials of umbralisib, the only oral inhibitor of PI3Kδ and CK1ε. Last month, TG Therapeutics announced a partial clinical hold on trials testing the combination of umbralisib and ublituximab, an investigational glycoengineered mAb targeting CD20-expressing B cells. • Regeneron Pharmaceuticals and Sanofi announced the withdrawal of their application for cemiplimab (Libtayo) as a second-line treatment for advanced cervical cancer after the companies and the FDA couldn't agree on some postmarketing studies; discussions with regulators outside the United States are continuing. A PD-1 inhibitor, cemiplimab is approved in certain patients with advanced basal cell carcinoma, cutaneous squamous cell carcinoma, and non–small cell lung cancer (NSCLC). • In a phase II/III study, the MEK inhibitor trametinib (Mekinist; Novartis) reduced the risk of disease progression or death in patients with low-grade serous ovarian carcinoma by 52% compared with standard-of-care therapies, with an objective response rate of 26%, researchers reported (Lancet 2022;399:541–53). Median progression-free survival with trametinib was 13 months compared with 7.2 months for standard treatment, and the median overall survival (OS) was 37.6 months compared with 29.2 months, respectively. The drug is approved by the FDA for use with dabrafenib (Tafinlar; Novartis) for certain patients with BRAFV600-positive malignancies, including melanoma, NSCLC, and anaplastic thyroid cancer. • According to long-term results of the PREOPANC trial, neoadjuvant chemoradiotherapy significantly improved OS in patients with pancreatic cancer compared with standard adjuvant gemcitabine-based chemoradiotherapy, researchers reported. Earlier trial results failed to demonstrate improved OS after a median of 27 months (J Clin Oncol 2020;38:1763–73). Now, after a median of 59 months, neoadjuvant therapy with gemcitabine-based treatment has proven superior: Despite a small difference in median OS between the groups—15.7 months versus 14.3 months, respectively—the estimated 3-year OS was 27.7% compared with 16.5%, respectively, and the 5-year OS was 20.5% compared with 6.5%. • The International Atomic Energy Agency (IAEA) announced the launch of an initiative to fight cancer by helping to provide care in low- and middle-income countries in Africa and other parts of the world. The agency will work closely with donors and countries receiving funding to establish facilities for radiotherapy, medical imaging, and nuclear medicine to detect and treat cancers. The IAEA noted that of the African Union's 55 members, more than 20 nations do not have a single radiotherapy machine. ### January 2022 #### January 21–27 • The FDA greenlighted Immunocore's tebentafusp-tebn (Kimmtrak) for the treatment of HLA-A*02:01–positive adults with inoperable or metastatic uveal melanoma. The decision was based on the results of the phase III IMCgp100-202 clinical trial, in which overall survival was 73% in the tebentafusp group compared with 59% in the control group after 1 year (N Engl J Med 2021;385:1196–206). Tebentafusp-tebn is the first bispecific T-cell engager approved by the agency to treat a solid tumor and the only FDA-approved therapy for this indication. • The FDA placed a partial clinical hold on Gilead's studies testing magrolimab plus azacitidine due to what the company called "an apparent imbalance in investigator-reported suspected unexpected serious adverse reactions between study arms." Magrolimab is a potential first-in-class investigational mAb against CD47 and a macrophage checkpoint inhibitor designed to interfere with recognition of CD47 by the SIRPα receptor on macrophages, blocking the "don't eat me" signal used by cancer cells to avoid ingestion by macrophages. It is under evaluation for the treatment of hematologic malignances, such as myelodysplastic syndrome, and solid tumors. • Speaking at the B. Riley Securities' 2022 Virtual Oncology Investor Conference, TG Therapeutics' CEO announced that the FDA placed a partial hold on studies of its "U2" combination—umbralisib (Ukoniq) and ublituximab—for chromic lymphocytic leukemia and non-Hodgkin lymphoma. The hold wasn't prompted by new data, but over "earlier concerns" expected to be addressed at a spring meeting of the FDA's Oncologic Drugs Advisory Committee. Umbralisib, approved to treat adults with relapsed/refractory marginal zone lymphoma (MZL) or relapased/refractory follicular lymphoma (FL), is the only oral inhibitor of PI3Kδ and CK1ε; ublituximab is an investigational glycoengineered mAb targeting CD20-expressing B cells. • Incyte announced that it will no longer seek FDA approval for its PI3Kδ inhibitor, parsaclisib, for the treatment of relapsed/refractory FL, MZL, and mantle cell lymphoma, saying that confirmatory studies in support of the drug's accelerated approval could not be "completed within a time period that would support the investment." The decision relates only to those indications in the United States. The company will also opt out of continuing the development of MCLA-145, a bispecific antibody under study for the treatment of solid tumors, with Merus. • According to findings from a just-published study, deaths from ovarian cancer are predicted to drop by 17% in the UK and by 7% in European Union (EU) nations in 2022 compared with 2017, although the effect of COVID-19 remains unclear (Ann Oncol 2022 Jan 25 [Epub ahead of print]).The researchers attributed the anticipated declines largely to long-term use of oral contraceptives. The report also estimates that overall cancer mortality rates in the EU will drop by 6% in men and 4% in women between 2017 and 2022. • In a prospective study of 32 patients with HIV and cancer, Merck's PD-1 inhibitor pembrolizumab (Keytruda) reversed human immunodeficiency virus (HIV) latency in CD4+ T cells, which express PD-1 and are preferentially infected with HIV (Sci Transl Med 2022;14:eabl3836). Latency reversal is a method of inducing HIV antigen expression, which could prompt the proliferation of HIV-targeting CD8+ T cells. "Together with enhanced immune clearance, this approach could potentially eliminate cells that contain replication-competent HIV," the researchers wrote. #### January 14–20 • IBM announced the sale of its Watson Health division to Francisco Partners, a global firm that invests in technology companies, including those focused on health care. Launched in 2015, Watson Health spent billions of dollars to collect health information and patient data to create artificial intelligence tools to aid in drug discovery, offer advice on cancer care, and drive other efforts. However, Watson Health failed to live up to expectations and lost substantial sums, prompting the sale of its assets; financial details weren't disclosed. • Gilead announced that it will withdraw two indications for idelalisib (Zydelig): relapsed follicular B-cell non-Hodgkin lymphoma and relapsed small lymphocytic leukemia. In 2014, the FDA granted accelerated approval to idelalisib to treat these conditions, contingent upon receiving additional evidence of clinical benefit. However, the company said that patient enrollment in a confirmatory study proved challenging, prompting the withdrawal of these indications in the United States. • According to data presented at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, patients with advanced biliary tract cancer who received the PD-L1 inhibitor durvalumab (Imfinzi; AstraZeneca) and chemotherapy as their first treatment lived longer than those who received chemotherapy alone. In the phase III TOPAZ-1 trial, patients who received the combination experienced a 25% reduction in the risk of disease progression or death compared with standard-of-care chemotherapy. Median progression-free survival was 7.2 months and 5.7 months, respectively, potentially making durvalumab plus chemotherapy a new standard of care. • Results from the phase III HIMALAYA trial, also presented at the ASCO Gastrointestinal Cancers Symposium, demonstrated that durvalumab plus the CTLA4 inhibitor tremelimumab (AstraZeneca) significantly improved overall survival in patients with advanced, inoperable hepatocellular carcinoma compared with patients who received durvalumab alone or monotherapy with the multikinase inhibitor sorafenib (Nexavar; Bayer). After 3 years, 30.7% of those who received the combination were still alive compared with 24.7% who received durvalumab and 20.2% who received sorafenib. The overall response rates were 20.1%, 17%, and 5.1%, respectively. • Scotland approved AstraZeneca's osimertinib (Tagrisso) as a first-line therapy for adults with locally advanced or metastatic non–small cell lung cancer with activating EGFR mutations. The approval was based on the phase III FLAURA trial, which randomly assigned 556 patients to receive osimertinib or one of two other EGFR tyrosine kinase inhibitors. Patients who received osimertinib lived a median of 38.6 months compared with 31.8 months for patients in the comparison group; those who received osimertinib also reported fewer adverse events. #### January 7–13 • In a deal worth up to5.2 billion, Sanofi announced it will collaborate with Exscientia to develop up to 15 novel small-molecule candidates to treat cancer and immune-mediated diseases, taking advantage of Exscientia's artificial intelligence (AI) expertise. By applying AI and machine learning to tissue samples, researchers will shorten drug discovery and development times—and design higher-quality and more-effective targeted therapies, the companies said. Exscientia will initially receive \$100 million, with additional payments for meeting specific milestones.
• Daiichi Sankyo announced that it will shutter Plexxikon at the end of March. The Japanese company said that it wanted to maximize its investments in three antibody–drug conjugates for cancer, including, in partnership with AstraZeneca, trastuzumab deruxtecan (Enhertu); trastuzumab deruxtecan is approved to treat HER2-positive breast cancer and gastric cancers. Plexxikon's portfolio includes the BRAF inhibitor vemurafenib (Zelboraf) and the CSF1R inhibitor pexidartinib (Turalio).
• Takeda announced it will acquire Adaptate Biotherapeutics to obtain Adaptate's antibody-based γδ T-cell engager platform, including preclinical and discovery pipeline programs. The γδ T-cell engagers are designed to modulate γδ T-cell–mediated immune responses at tumor sites while sparing healthy cells. Financial terms were not disclosed.
• Three European organizations launched an initiative to "transform how clinical trials are initiated, designed, and run," dubbed Accelerating Clinical Trials in the EU (European Union; available at https://www.ema.europa.eu/en). The aim, according to the European Commission (EC), the Heads of Medicines Agencies, and the European Medicines Agency, is to "further develop the EU as a focal point for clinical research, further promote the development of high-quality, safe, and effective medicines, and to better integrate clinical research in the European health system." Among the measures: greater use of innovative clinical trial designs; an increased number of large, international trials, especially at academic medical centers; and harmonized regulatory requirements among EU nations.
• The FDA gave Allogene the OK to resume testing its allogeneic chimeric antigen receptor (CAR) T-cell therapies. The agency had placed a clinical hold on five of the company's trials of "off-the-shelf" CAR therapies in October after a chromosomal abnormality was detected in a patient with blood cancer who received ALLO-501a. An investigation determined that the anomaly wasn't related to the company's gene editing and manufacturing processes and had no clinical significance.
• The EC approved Amgen's sotorasib (Lumakras) for patients with KRASG12C-mutated advanced non–small cell lung cancer (NSCLC). The decision was based positive results from the phase II CodeBreaK 100 clinical trial in which 126 patients with NSCLC and the mutation demonstrated an objective response rate of 37.1% and a median duration of response of 11.1 months. Sotorasib is now approved in nearly three dozen countries.

#### December 30–January 6

• New recommendations for COVID-19 vaccination for people with cancer were issued by the National Comprehensive Cancer Network (available at https://www.nccn.org/COVID-19). Among the recommendations: Patients with cancer should get fully immunized—including third doses and/or any approved boosters, preferably with mRNA vaccines—and patients receiving hematopoietic cell transplantation or chimeric antigen receptor T cells should wait 3 months after treatment to receive a vaccine to maximize its efficacy. The guidance also offers information on the preventive use of tixagevimab–cilgavimab (Evusheld; AstraZeneca), a long-acting combination of monoclonal antibodies directed against the SARS-CoV-2 spike protein.
• Researchers showed that 48% of 90 women with advanced endometrial cancer experienced a complete or partial response (PR) to the PD-1 inhibitor pembrolizumab (Keytruda; Merck); all had microsatellite instability–high or mismatch repair–deficient tumors and had previously been treated for the disease (J Clin Oncol 2022 Jan 6 [Epub ahead of print]). Median duration of response and median overall survival were not reached; median time from first dose to data cutoff was 42.6 months. About three quarters of the patients had at least one treatment-related adverse event (TRAE), with 12% experiencing grade 3 or 4 TRAEs.
• In Massachusetts, a statewide ban on menthol-flavored tobacco products led to a significant drop in cigarette sales, researchers reported (JAMA Intern Med 2022 Jan 4 [Epub ahead of print]). After the ban was implemented in June 2020, the unadjusted 4-week sales of packs of cigarettes per 1,000 people dropped for menthol (404.93 to 32.24), nonflavored (916.37 to 856.79), and all (1,321.32 to 887.69) cigarettes. Compared with states without local or statewide bans, the adjusted 4-week sales of all cigarettes decreased by 282.65 packs per 1,000 people in Massachusetts.
• Eleven of 33 evaluable women with advanced ovarian cancer had a PR to STRO-002, a folate receptor alpha (Fol-Rα)–targeting antibody–drug conjugate, Sutro Biopharma announced. Also in the ongoing phase I trial, eight of 17 patients who started at the higher of two drug doses experienced a PR. Higher Fol-Rα expression levels correlated with higher response rates.
• Curis announced updated clinical data from its phase I/II open-label study of CA-4948, a small-molecule IRAK4 inhibitor, in patients with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) and a U2AF1 or SF3B1 spliceosome mutation. Among five evaluable patients with AML, the rate of complete remission and complete remission with partial hematologic recovery was 40%; among seven patients with MDS, the objective response rate was 57%. IRAK4 plays an essential role in the Toll-like receptor and IL1 receptor signaling pathways.
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