Combining Biomarkers for Immunotherapy

Published OnlineFirst October 30, 2018; DOI: 10.1158/2159-8290.CD-NB2018-143

NEWS IN BRIEF also showed that it could be applicable Dacomitinib Approved, to CD22-targeted CAR T-cell therapy. “What’s really interesting is that but Might Not Be Used they uncovered a gene transfer–related The FDA approved the EGFR inhibi- mechanism of relapse, which I don’t tor dacomitinib (Vizimpro; Pfizer) as a think has been seen before,” says first-line therapy for patients with meta- Marcela Maus, MD, PhD, of Massachu- static, EGFR-mutant non–small cell setts General Hospital Cancer Center lung cancer (NSCLC). Clinicians, how- Structural formula for dacomitinib. in Boston. Inadvertent CAR19 trans- ever, doubt that the drug will be used duction aside, she notes, this single much in clinical practice, as it joins a treating brain metastases (J Clin Oncol B cell likely possessed additional char- crowded field of EGFR inhibitors that 2018 Aug 28 [Epub ahead of print]). acteristics that enabled it to survive includes osimertinib (Tagrisso; Astra- “I still think that osimertinib remains the therapy manufacturing process, Zeneca), the current standard of care. the standard for first-line [therapy] because engineered T cells are typically Instead, they are focused on the next based on toxicity, and based on its quick to eliminate any leukemic cells wave of therapeutic options. ability to elicit meaningful responses in in the patient-derived product. Dacomitinib was approved based on patients with brain metastasis,” he says. Ruella agrees that “some combina- the results of the phase III ARCHER Joshua Bauml, MD, of the Perelman tion of factors, possibly unique to this 1050 trial, in which patients treated with School of Medicine at the University patient, triggered an exceptionally rare the drug had a median progression- of Pennsylvania in Philadelphia, is form of resistance.” In a retrospective free survival (PFS) of 14.7 months and interested in new therapeutic strate- analysis of data from 368 patients a median overall survival of 34.1 months, gies to extend survival of patients who treated with tisagenlecleucel, the compared with 9.2 months and 26.8 receive first-line osimertinib to address team found no other relapses driven months, respectively, in patients who tumor heterogeneity and resistance. by CD19 epitope masking. That said, received the EGFR inhibitor gefitinib “We have all these drugs, they’re highly “we thought it was worth alerting the (Iressa; AstraZeneca) (Lancet Oncol active, but they are not cures. Patients will scientific community to the fact that 2017;18:1454–66; J Clin Oncol 2018;36: develop resistance, and they will unfor- this could happen,” he says. 2244–50). Serious side effects, most tunately die from that,” he says. “What “It’s something to be on the lookout commonly diarrhea, rash, and a skin we need to really do is to delve into the for with autologous CAR T-cell ther- condition called paronychia, affected science and see how we can advance the apy,” Maus says, “and probably more 27% of patients. care for these patients.” specific to leukemia, among hemato- In addition to gefitinib and osimer- Sequist and her colleagues recently logic malignancies. With lymphoma tinib, the EGFR inhibitors erlotinib established that acquired RET fusions or multiple myeloma, tumor cells (Tarceva; Genentech and Astellas) drive resistance in some patients, and usually aren’t found in large numbers and afatinib (Gilotrif; Boehringer these patients may benefit from receiving in peripheral blood.” Ingelheim Pharmaceuticals) are also osimertinib in combination with the RET Might the addition of a “kill switch” to approved as first-line therapies. inhibitor BLU-667 (Blueprint Medicines; the CAR19 construct have proven useful? Lecia Sequist, MD, MPH, of Massa Cancer Discov 2018 Sep 26 [Epub ahead “In hindsight, it does seem like we could chusetts General Hospital in Boston, of print]). Similarly, MET amplification have turned off that wave of CARB cells MA, says that comparing dacomitinib can cause osimertinib resistance, but if a suicide gene had been incorporated,” to gefitinib made sense when the trial some research has shown that that can Ruella observes. “But the data aren’t was designed. In the interim, however, be countered with osimertinib plus the black-and-white on how completely such osimertinib was approved and quickly MET inhibitor savolitinib (AstraZeneca switches eliminate their target.” became the new standard of care and Chi-Med). In addition, researchers No FDA-approved CAR T-cell because it extended PFS and caused are exploring the use of EGFR inhibitors therapies include kill switches; clini- fewer side effects than gefitinib or with chemotherapy. Levy notes that there cians are figuring out other ways to erlotinib. is also interest in testing combinations manage potential toxicities, chiefly “More knowledge and more options are of immunotherapies, chemotherapy, and cytokine release syndrome. As such, “any always important, but I’m not sure there’s angiogenesis inhibitors. proposed [CAR] construct modification going to be much uptake of dacomitinib “If you’re going to give osimertinib would need careful evaluation, to not in the front-line setting,” she says. front line, the question really is, what do affect the remarkable clinical outcomes Benjamin Levy, MD, of Johns Hop- you do next and what are the most active seen so far”—including with this patient, kins University in Baltimore, MD, and therapies?” Levy says. –Catherine Caruso n whose survival was ultimately extended Washington, DC, agrees, adding that a with tisagenlecleucel, Ruella notes. major benefit of osimertinib over dac- With CAR T-cell therapy being a omitinib is its toxicity profile: Osimer- Combining Biomarkers young, evolving field, “we have a lot to tinib is generally well tolerated, whereas for Immunotherapy learn, and this case suggests the need dacomitinib frequently causes diarrhea, for further optimization of manufactur- acne, and rashes. Moreover, data from To validate two of the most widely ing protocols,” he adds. “There’s always the phase III FLAURA trial suggests used candidate biomarkers for immuno room for improvement.” –Alissa Poh n that osimertinib may be effective at therapy—tumor mutation burden

1500 | CANCER DISCOVERY DECEMBER 2018 www.aacrjournals.org

NEWS IN BRIEF

(TMB) and gene expression profiles defined patient groups exhibit lower and prostate cancers who were treated (GEP) indicative of a “hot” T cell– response rates to pembrolizumab. with SABR had longer overall survival inflamed microenvironment—Merck However, the biomarkers reflect a (OS) and progression-free survival (PFS) has released an analysis involving degree of molecular dysregulation than patients who received lower-dose tumor samples from 315 patients with specific to each tumor type as well, standard-of-care palliative radiation 22 types of cancer who received its anti– indicating that the clinical utility of therapy. Results of the trial were pre- PD-1 drug pembrolizumab (Keytruda) TMB and GEP will likely vary from sented at the 2018 American Society for as part of four separate clinical proto- one indication to the next. Radiation Oncology Annual Meeting in cols (Science 2018;362:eaar3593). Erin Schenk, MD, PhD, of the Uni- San Antonio, TX, October 21–24. By mining this large pan-tumor data- versity of Colorado Anschutz Medical “In the past, patients with metastatic set, the authors show that TMB and Center in Aurora, says she could envi- cancers have generally been considered GEP independently predict response sion using the joint biomarker analy- to be incurable, and treatment would to checkpoint blockade, yet exhibit sis, if prospectively validated, to rule be aimed at prolonging life or slowing low correlation. Considering both out pembrolizumab as a monotherapy down the cancer, but not trying to cure biomarkers, they concluded, offered the in certain patients with lung cancer. the disease completely,” said David greatest predictive utility and helped Just as she currently uses PD-L1 levels Palma, MD, of the London Health reveal patterns of underlying, targetable to determine whether to administer Sciences Centre in Ontario, Canada, molecular and genetic activity. chemotherapy alongside the anti–PD-1 who presented the findings. How- The findings suggest that each drug, low scores on both the TMB and ever, some data from single-arm and biomarker captures a distinct aspect GEP tests could indicate whether a nonrandomized studies have suggested of cancer immunobiology—tumor patient needs a second drug alongside that patients with only a few small antigenicity and T-cell activation state, pembrolizumab to render the tumor metastases might benefit from aggres- respectively. “Both are important,” says susceptible to checkpoint blockade. sive, localized treatment with SABR. James Gulley, MD, PhD, head of the “This is most helpful in identifying To investigate further, Palma and Immunotherapy Group at the NCI those patients who will not likely his colleagues launched the SABR- Center for Cancer Research, who was respond,” Schenk says. For everyone COMET trial, enrolling 99 patients not involved in the study. Although else, the biomarkers are still not sensi- with up to five metastases—mainly in smaller, single-tumor-type studies tive enough to offer actionable guides the bones, liver, or lungs—from a vari- made similar inferences in the past, “we for precision cancer care, she says, but ety of malignancies, most commonly haven’t had as big a dataset before.” they could prove valuable as selection breast, colorectal, lung, and prostate To parse the data, Razvan Cristescu, criteria in clinical protocols to enrich cancers. Patients were assigned 2:1 to PhD, senior principal scientist at the for participants most likely to benefit. receive either SABR targeted at the Merck Research Laboratories in Bos- Merck, in a 192-person trial metastases or standard-of-care pallia- ton, MA, and his colleagues stratified launched in October, is now seeking tive radiation therapy. the 315 trial participants into four to prospectively validate the utility of Patients treated with SABR had biomarker-defined groups based on the joint biomarker in patients with their tumors’ TMB and GEP scores. a median OS of 41 months and a non–small cell lung cancer treated Cristescu’s team showed that patients median PFS of 12 months, com- with pembrolizumab plus either the with high levels of both biomarkers pared with 28 months and 6 months, anti-LAG3 antibody MK-4280 or the had the greatest response rates to respectively, in patients who received anti-VEGFR drug lenvatinib (Lenvima; pembrolizumab—37% to 57%, depend- palliative therapy. Quality of life did Eisai). The goal is to confirm that ing on the cutoff values used to deline- not differ between the treatment arms, patients with high GEP and high TMB ate high and low TMB. Response rates although 28.8% of patients treated have the highest response rate, patients were under 10% for patients with low with SABR had treatment-related side with low GEP and low TMB have the levels of both biomarkers, and between effects, compared with 9.1% of patients 11% and 42%, depending on the cut- lowest response rate, and patients with receiving palliative care. Additionally, offs, among those with high TMB and mixed GEP and TMB levels fall some- three patients in the SABR arm died low GEP, or vice versa. where in between. –Elie Dolgin n from side effects related to treatment, Cristescu’s team also cross-validated whereas there were no such deaths in the biomarkers against transcriptomic SABR Combats the palliative care arm. and genomic profiles from thousands Palma acknowledged that the initial of tumor samples in The Cancer Gen- Metastatic Disease OS results, although promising, will ome Atlas, which confirmed that TMB Stereotactic ablative radiotherapy require more time to mature—he and and GEP offer tumor type–agnostic (SABR), or stereotactic body radiation his team plan to follow patients for an signatures of biological processes therapy, a focused, high-dose, and high- additional 10 years. He added, how- related to cell proliferation, vascular precision form of radiation therapy ever, that many drugs are approved invasion, myeloid infiltration, and delivered in one or a few sessions, may based on PFS or other surrogate end- stromal signaling. Cristescu says this improve survival of patients with meta- points, “so we don’t always need an provides a biological explanation for static cancer. In a phase II trial, patients OS benefit to treat.” The researchers why certain pan-tumor, biomarker- with metastatic breast, colorectal, lung, will soon launch two phase III trials of

DECEMBER 2018 CANCER DISCOVERY | 1501

Combining Biomarkers for Immunotherapy

Cancer Discov 2018;8:1500-1501. Published OnlineFirst October 30, 2018.

Updated version Access the most recent version of this article at: doi:10.1158/2159-8290.CD-NB2018-143

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