Andrew D. Smith

Nearly 15 years have passed since pathologists at Memorial Sloan Kettering Cancer Center (MSK) conducted gene expression analyses on breast cancer primary tumors and described a potential role for a novel target, which quickly became a major research focus for their colleague Tiffany A. Traina, MD.

Investigators found that a significant number of the hormone receptor–negative samples they examined demonstrated androgen receptor (AR) pathway activity.

 The discovery suggested that androgen-targeting strategies developed to treat prostate cancer might also benefit a subset of women with breast cancer, and Traina was eager to investigate. After years of work in this area, she is poised to co-lead the first randomized trial comparing the AR inhibitor enzalutamide (Xtandi) versus chemotherapy in patients with triple-negative breast cancer (TNBC) through the Translational Breast Cancer Research Consortium.

Androgen deprivation strategies are just 1 area of research interest for Traina, a medical oncologist at MSK in New York, New York, who specializes in the exploration of novel targeted therapies for TNBC. Clinical investigations are, in turn, just part of a career that includes a full practice, leadership roles at MSK and the American Society of Clinical Oncology, and a commitment to sharing her knowledge with other physicians, both at MSK and at professional conferences around the world.

 conference, which is hosted by Physicians’ Education Resource

). The 3-day event will take place November 4 through November 6 and feature live, interactive virtual presentations on the practice-changing innovations in cancer diagnosis, treatment, and supportive care that occurred over the past year. 

Traina is organizing the sessions with her cochairs, Benjamin P. Levy, MD, and William K. Oh, MD. Levy is clinical director of medical oncology at Johns Hopkins Sidney Kimmel Cancer Center in the DC Region, and Oh is chief of hematology and medical oncology and deputy director at The Tisch Cancer Institute at Icahn School of Medicine at Mount Sinai in New York, New York.

The conference provides clinically useful insights into best practices and emerging approaches for a broad range of cancer types, including hematologic malignancies, genitourinary cancers, and lung cancers. The agenda also will feature a section on the impact of the coronavirus 2019 disease (COVID-19) in oncology.

 will be particularly provocative for breast cancer. “There were a few areas within breast cancer that saw really exciting advances over the past year or so, and they will naturally be major areas of focus for the symposium,” Traina said in an interview with 

“First, in the space of women with HER2- positive advanced breast cancer, we’ve seen 2 new agents approved by the FDA since December 2019. These have both produced impressive efficacy results and offer valuable new options for our patients with HER2-positive disease,” she said, referring to fam-trastuzumab deruxtecan-nxki (Enhertu) and tucatinib (Tukysa). 

“The other area with significant advances for review is triple-negative breast cancer,” Traina said. “The FDA has approved use of a novel antibody-drug conjugate [ADC] for patients with metastatic TNBC being treated in the third line or later [sacituzumab govitecan-hziy; Trodelvy]. This is an area of tremendous unmet need, with often short duration of response and poorer outcome with conventional chemotherapies.  Additionally, we’re seeing an expanded role for immunotherapy in triple-negative breast cancer, both in the early-stage setting and in first-line metastatic disease.”

Traina’s expertise in translating such research developments into clinical practice also will be integrated into the breast cancer discussions, where she will serve as a moderator. “Tiffany is a respected colleague and a thought leader in triple-negative breast cancer,” said Shanu Modi, MD, a medical oncologist at MSK who has worked with Traina on several studies. “She has led the pioneering studies of androgen receptor-expressing triple negative breast cancer, and she manages a diverse portfolio of novel agents focused on this subtype of aggressive cancer.”

The recent spate of breast cancer advancements began in December 2019, when the FDA accelerated approval of trastuzumab deruxtecan for patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior H ER2-targeting therapies.

Approval for trastuzumab deruxtecan, an ADC that combines an anti-HER2 antibody with a cytotoxic topoisomerase I inhibitor, hinged upon findings from the DESTINYBreast01 trial (NCT03248492), which reported objective responses in 60.9% (95% CI, 53.4%-68.0%) of 184 heavily pretreated participants. The median response duration was 14.8 months (95% CI, 13.8-16.9), and the median duration of progression-free survival (PFS) was 16.4 months (95% CI, 12.7–not reached).

Interestingly, trastuzumab deruxtecan also showed a high response rate among patients whose tumors had low expression of HER2 in data from a phase 1 trial (NCT02564900). In all, 20 (37%) of the 54 women who had low expression of HER2, defined as an immunohistochemistry score of 1+ or 2+ with negative in situ hybridization, responded to treatment.

In April 2020, the FDA approved the oral tyrosine kinase inhibitor tucatinib for patients with advanced or metastatic HER2-positive breast cancer who have received at least 1 prior HER2-targeting regimen, based on results from the HER2CLIMB trial (NCT02614794), in which 612 patients were randomized to receive trastuzumab and capecitabine plus tucatinib or placebo.

Median PFS in patients receiving tucatinib was 7.8 months (95% CI, 7.5-9.6) compared with 5.6 months (95% CI, 4.2-7.1) for patients enrolled in the control arm (HR, 0.54; 95% CI, 0.42- 0.71; 

 < .001). Median overall survival (OS) in patients who received tucatinib was 21.9 months (95% CI, 18.3-31.0) compared with 17.4 months (95% CI, 13.6-19.9) for patients in the control arm (HR, 0.66; 95% CI, 0.50-0.88; 

Screen Shot 2020-09-14 at 11.32.06 AM.png

Tucatanib also has demonstrated efficacy in patients with brain metastases. Median PFS for patients with baseline brain metastases was 7.6 months with tucatinib (95% CI, 6.2-9.5) and 5.4 months with placebo (95% CI, 4.1-5.7), which translated into a 52% lower risk of disease progression or death (HR, 0.48; 95% CI, 0.34-0.69; 

“We have these 2 powerful new agents to help improve outcomes for women with advanced HER2-positive breast cancer,” Traina said, adding that highly effective therapies for patients with brain metastases have been elusive. “CNS disease has posed a real clinical challenge.”

The FDA also expanded the indication of neratinib (Nerlynx), an orally available tyrosine kinase receptor inhibitor of EGFR, HER2, and HER4. The drug was previously approved in 2017 as monotherapy for extended adjuvant treatment of adults with early-stage HER2-positive breast cancer following trastuzumab (Herceptin)–based therapy.

In February 2020, neratinib gained approval in combination with capecitabine for adults with advanced or metastatic HER2-positive breast cancer who have received 2 or more previous anti-HER2– based regimens in the metastatic setting.

The new indication is based on data from the NALA trial (NCT01808573), which demonstrated a statistically significant improvement in PFS with the neratinib combination compared with lapatinib (Tykerb) plus capecitabine (HR, 0.76; 95% CI, 0.63- 0.93; 

 = .0059). The PFS rate at 18 months was 16.3% (95% CI, 11.3%-22.1%) for the neratinib arm compared with 7.4% (95% CI, 4.1%-12.0%) with the lapatinib regimen. The overall incidence of intervention for CNS disease also was lower with neratinib at 22.8% (95% CI, 15.5%- 30.9%) versus 29.2% (95% CI, 22.5%-36.1%) for lapatinib (Gray’s test for equality, 

The treatment options for patients with TNBC also grew with the introduction of sacituzumab govitecan, an ADC that targets TROP-2. The FDA granted the agent an accelerated approval in April 2020 for patients with metastatic TNBC who have received 2 or more prior lines of therapy in the metastatic setting.

The approval was based on findings from the phase 1/2 IMMU-132-01 trial (NCT01631552), in which sacituzumab govitecan demonstrated a response rate of 33.3% (95% CI, 24.6-43.1) and a median duration of response of 7.7 months (95% CI, 4.9-10.8) in a heavily pretreated population. Median PFS was 5.5 months (95% CI, 4.1-6.3), and median OS was 13.0 months (95% CI, 11.2-13.7).

The randomized phase 3 ASCENT study (NCT02574455) testing sacituzumab govitecan versus physician's choice chemotherapy (ie, eribulin, capecitabine, gemcitabine, or vinorelbine) in relapsed/refractory TNBC has been completed and results are expected at the Virtual 2020 European Society for Medical Oncology (ESMO) Congress.

Clinical trials of immunotherapy in TNBC have produced a mix of findings. Atezolizumab (Tecentriq), a PD-L1 immune checkpoint inhibitor (ICI), became the first immunotherapy approved for breast cancer in March 2019. The FDA granted an accelerated approval for atezolizumab in combination with nab-paclitaxel (Abraxane) for patients with unresectable locally advanced or metastatic PD-L1–positive TNBC based on PFS findings from the IMpassion130 trial (NCT02425891). PD-L1 positivity was defined as staining on tumor-infiltrating cells of any intensity covering at least 1% of the tumor area.

Screen Shot 2020-09-14 at 11.31.43 AM.png

The median PFS with atezolizumab plus nab-paclitaxel was 7.4 months (95% CI, 6.6-9.2) compared with 4.8 months (95% CI, 3.8-5.5) for those receiving placebo with nab-paclitaxel (stratified HR, 0.60; 95% CI, 0.48-0.77; 

 < .0001). The objective response rates were 53% versus 33% for the atezolizumab and the placebo-containing arms, respectively.

However, data from the phase 3 IMpassion131 study (NCT03125902) evaluating atezolizumab in combination with paclitaxel failed to confirm a statistically significant PFS benefit compared with placebo plus paclitaxel in treatment-naïve patients with inoperable locally advanced or metastatic TNBC, according to Roche, the company developing the drug.

There also was a negative trend for OS, although the study was not powered for this end point and the data were immature at the time of the analysis, Roche said. Full findings from trial are being discussed with global health authorities and are planned for presentation at the Virtual 2020 ESMO Congress.

On September 8, the FDA issued an alert advising providers not to substitute paclitaxel for nab-paclitaxel in clinical practice and noted that the combination of atezolizumab plus paclitaxel is not an approved use for patients with breast cancer. The agency also said continued approval of atezolizumab plus nab-paclitaxel may be contigent upon findings from additional clinical trials.

Traina said she would have to examine the findings before forming an opinion about the results of IMpassion131. “We haven’t seen the data yet and haven’t had an opportunity to really dive into the details for a greater understanding of how trial design and population differences may account for the unexpected outcome,” she said. “We are certainly trying to understand why the earlier IMpassion study partnered with nab-paclitaxel was a positive trial and this one missed its primary end point.”

Nevertheless, ICIs are displaying positive signals in earlier disease settings. Results from the phase 3 IMpassion031 trial (NCT03197935) showed a statistically significant and clinically meaningful improvement in pathological complete response (pCR) for atezolizumab as neoadjuvant therapy combined with nab-paclitaxel, followed by doxorubicin and cyclophosphamide, compared with chemotherapy plus placebo in patients with early-stage TNBC.

The benefit was observed regardless of PD-L1 expression, according to Genentech, a member of the Roche Group. Findings are planned for presentation at the Virtual 2020 ESMO Congress and will be discussed with the FDA and other regulatory authorities, the company said.

In the KEYNOTE-355 trial (NCT02819518), patients with previously untreated, locally recurrent, inoperable or metastatic TNBC were randomized to receive pembrolizumab (Keytruda), a PD-1 inhibitor, plus chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin) or placebo plus chemotherapy. Results were stratified by combined positive score (CPS) of the number of PD-L1–positive tumor cells, lymphocytes, and macrophages divided by the total number of tumor cells multiplied by 100.

For participants with a CPS of 10 or more, the median PFS for the pembrolizumab regimen was 9.7 months compared with 5.6 months for chemotherapy alone (HR, 0.65; 95% CI, 0.49-0.86; 

 = .0012). For those with a CPS of less than 10, median PFS was 5.8 months with the pembrolizumab combination versus 5.7 months with chemotherapy alone (HR, 0.94; 95% CI, 0.76-1.16).

Investigators said the findings show the potential for adding pembrolizumab to first-line TNBC therapy. The FDA has granted a breakthrough therapy designation for pembrolizumab plus chemotherapy as neoadjuvant treatment for patients with high-risk, early-stage TNBC.

Additionally, pembrolizumab plus as neoadjuvant therapy in the I-SPY 2 trial (NCT01042379) in patients with early-stage, high-risk hormone receptor–positive/HER2- negative breast cancer or TNBC.

Final estimated pCR rates were 44% versus 17%, 30% versus 13%, and 60% versus 22% for pembrolizumab plus neoadjuvant chemotherapy compared with standard neoadjuvant chemotherapy in the HER2-negative, hormone receptor–positive/HER2-negative, and TNBC cohorts, respectively.

Traina believes that recent study findings are charting an effective course for ICI therapy in the treatment paradigm. “I think we’ve come to see that for select patients with metastatic TNBC, introducing these agents early in the first-line setting has greater promise than using them in a later line,” she said. “We are also now seeing from early-stage trials that moving these checkpoint inhibitors up into the neoadjuvant setting, even potentially the adjuvant setting, may have meaningful benefit.”

Screen Shot 2020-09-14 at 11.31.35 AM.png

In her research, Traina focuses on investigating novel therapeutic strategies and targeted therapies to treat TNBC. Early in her career, she was among MSK investigators who established that a dose-dense adjuvant chemotherapy regimen, delivered at shorter intervals than the conventional time frame, is tolerable and feasible.

Under the mentorship of Clifford A. Hudis, MD, and Larry Norton, MD, a 2016 Giants of Cancer Care

 award winner, Traina helped develop a 7 days on, 7 days off dosing schedule for capecitabine that allows for higher doses with decreased gastrointestinal toxicities than conventional 14-day continuous dosing.

Her current projects include testing patritumab deruxtecan (U3-1402), a HER3- directed ADC, in patients with HER3-positive metastatic TNBC; evaluating durvalumab (Imfinzi) plus olaparib (Lynparza) in TNBC; and studying postoperative atezolizumab therapy plus chemotherapy in patients with stage II or III TNBC.

Traina is particularly enthusiastic about the prospect of conducting further studies into the potential for AR-directed strategies in TNBC. In 2018, Traina and colleagues reported that patients with locally advanced or metastatic AR-positive TNBC, defined as AR greater than 0% on immunohistochemistry staining, derived clinical benefit from enzalutamide therapy in the phase 2 MDV3100-11 study (NCT01889238).

Results demonstrated that the clinical benefit rate, defined as confirmed complete or partial responses or stable disease, with enzalutamide monotherapy was 33% (95% CI, 23%-45%) at 16 weeks and 28% (95% CI, 19%-39%) at 24 weeks among evaluable patients (n = 78) and 25% (95% CI, 17%-33%) and 20% (95% CI, 14%-29%), respectively, for the intention-to-treat population (N = 118).

In another study (NCT02750358), Traina and coinvestigators examined the feasibility of 1 year of adjuvant enzalutamide therapy for patients with early-stage AR-positive (≥ 1%) TNBC. Overall, 33 of 47 evaluable patients were able to complete 52 weeks of therapy, according to findings presented at the 2019 American Society of Clinical Oncology Annual Meeting. The 1-year disease-free survival rate was 93.5% (95% CI, 86.6%-100%).

The early signals have been strong enough to secure funding from the Breast Cancer Research Foundation and support from the Translational Breast Cancer Research Consortium to launch a randomized trial that will test enzalutamide against therapies chosen by individual physicians at multiple locations in the United States, Traina said.

“It’s been exciting to move from that initial observation, that the androgen receptors existed, to multiple phase 1 trials to establish that these prostate cancer drugs are safe in women with breast cancer, to early phase 2 trials and now to a randomized trial,” Traina said.

“If your cancer is very driven by hormones, then actually targeting that pathway instead of using chemotherapy may offer a really well-tolerated approach. The idea is that you could start with an endocrine approach in these androgen-driven triple-negative cancers and, at some point, introduce chemotherapy if necessary, not unlike the way we manage an estrogen-driven cancer with [estrogen receptor]– targeted therapies,” she said.

For Traina, specializing in medicine in general and oncology in particular was a natural choice. “I unfortunately had the experience of losing my mother to cancer while I was quite young, and I believe that is what first inspired me to enter into this field,” she said. “I couldn’t imagine doing anything else, to be honest. This is such meaningful work, and it is a privilege to partner with my patients and their families during this experience.

“It is empowering to be able to offer guidance and hope for my patients through their individual journeys,” she added. “Also, this is a tremendously exciting time in the science of oncology. It’s humbling to be a part of the research that is [affecting] survival for women with breast cancer.”

Traina has spent more than 20 years in the medical field, having obtained her medical degree from Weill Cornell Medicine in 1999. She joined the staff at MSK after participating in a fellowship in medical oncology and hematology at the center. She completed a residency in internal medicine at NewYork-Presbyterian Weill Cornell and served as chief resident and chief fellow at MSK.

As Traina and colleagues continue their search for better therapies, they now face an entirely novel challenge—delivering care safely and effectively amid the COVID-19 pandemic. This year’s CFS

 agenda features presentations on the association of inflammation, cancer, and COVID-19 and a panel discussion on experiences with COVID-19 in the oncology arena. Norman E. “Ned” Sharpless, MD, director of the National Cancer Institute, is scheduled to provide the agency’s perspective on COVID-19.

“It’s impossible to ignore the global pandemic and how it’s [affecting] our delivery of care, so it’s one of the major issues that will be addressed at the symposium,” Traina said. “We are all finding innovative ways to continue to deliver high-quality care in a safe environment, one that incorporates social distancing, appropriate PPE [personal protective equipment], psychosocial support, and family safety. Speakers and panelists and, presumably, many participants will be talking about their personal experiences.

“There’s a portion of the agenda that is dedicated to telemedicine and how there’s a digital transformation going on in health care delivery, one that may remain, at least in part, after the pandemic is over,” she added. 

The medical field’s understanding of the risk that COVID-19 poses to patients with cancer, including those undergoing active treatment, continues to evolve. Findings from a study of 423 patients with COVID-19 treated at MSK indicate that age older than 65 years and treatment with ICIs were associated with higher rates of hospitalization and severe disease, but chemotherapy and major surgery were not.

 Meanwhile, concern is growing about the future burden of cancer among patients who delay screenings or medical visits that could lead to a diagnosis.

“When the pandemic began, patients were fearful of leaving their homes to receive important cancer care. People also have delayed age-appropriate screening studies, where the risk-benefit balance might have favored avoiding coronavirus and putting off screening and surveillance studies,” Traina said.

“There is a body of literature that suggests we’ll see a wave of cancer diagnoses ahead, perhaps at a later stage, because of the delays in diagnosis that have happened as a result of the pandemic,” she noted.

In addition to necessitating changes in the delivery of cancer care, the pandemic has altered the realm of continuing medical education conferences. PER

 quickly adapted its offerings to a live, interactive, virtual format, and Traina anticipates a smooth experience for CFS

“Now that we are several months into the COVID-19 pandemic, we have become quite familiar with using virtual platforms to effectively convey meeting content,” she said. “Our presenters will be able to deliver the content as effectively via the internet as they could do in person.”

Indeed, Traina believes that the virtual symposium could improve upon standard conferences in several ways. For example, live chat features will allow all participants to engage in the meeting in a way that might not have been possible in person.

The real challenge involves translating a conference’s social element to the virtual realm. “We are working to create that sense of community and reinvent the social aspect of the meeting,” Traina said. “We are looking for ways to facilitate interactions between participants and leaders in the field. I’m optimistic that we’ll meet that goal.”

Doane AS, Danso M, Lal P, et al. An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen. 

. 2006;25(28):3994-4008. doi:10.1038/sj.onc.1209415

Hematology/oncology (cancer) approvals & safety notifications. FDA. Updated September 1, 2020. Accessed September 1, 2020. https://bit.ly/2EA9iRS

Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. 

. 2020;382(7):610-621. doi:10.1056/NEJMoa1914510

Modi S, Park H, Murthy RK, et al. antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low–expressing advanced breast cancer: results from a phase Ib study. 

 2020;38(17):1887-1896. doi:10.1200/JCO.19.02318

Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. 

. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609. Published correction appears in 

Saura C, Oliveira M, Feng YH, et al; NALA Investigators. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: phase III NALA trial. 

. Published online July 27, 2020. doi:10.1200/JCO.20.00147

Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. 

. 2019;380(8):741-751. doi:10.1056/NEJMoa1814213

FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast cancer. FDA. Updated March 18, 2019. Accessed September 1, 2020. https://bit.ly/3gMHeYg

Roche provides update on phase III study of Tecentriq in combination with paclitaxel for people with metastatic triple-negative breast cancer. News release. Roche. August 6, 2020. Accessed August 7, 2020. 

FDA alerts health care professionals and oncology clinical investigators about efficacy and potential safety concerns with atezolizumab in combination with paclitaxel for treatment of breast cancer. News release. FDA. September 8, 2020. Accessed September 9, 2020. https://bit.ly/328EFvy

Genentech’s Tecentriq in combination with chemotherapy (including Abraxane) meets primary endpoint of improved pathological complete response, regardless of PD-L1 status, as initial treatment for people with early triple-negative breast cancer. News release. Genentech. June 18, 2020. Accessed August 25, 2020. https://bwnews.pr/3ehYynM

Cortes J, Cescon DW, Rugo HS, et al. KEYNOTE-355: randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. 

. 2020;38(suppl 15):1000. doi:10.1200/JCO.2020.38.15_suppl.1000

Nanda R, Liu MC, Yau C, et al. Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: an analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial. 

. 2020;6(5):676-684. doi:10.1001/jamaoncol.2019.6650

Drullinsky P, Sugarman SM, Fornier MN, et al. Dose dense cyclophosphamide, methotrexate, fluorouracil is feasible at 14-day intervals: a pilot study of every-14-day dosing as adjuvant therapy for breast cancer. 

. 2010;10(6):440-444. doi:10.3816/CBC.2010.n.057

Traina TA, Dugan U, Higgins B, et al. Optimizing chemotherapy dose and schedule by Norton-Simon mathematical modeling. 

. 2010;31(1):7-18. doi:10.3233/BD-2009-0290

Cadoo KA, Gajria D, Suh E, et al. Decreased gastrointestinal toxicity associated with a novel capecitabine schedule (7 days on and 7 days off): a systematic review. 

 2016;2:16006. doi:10.1038/npjbcancer.2016.6

Traina TA, Miller K, Yardley DA, et al. Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast cancer. 

. 2018;36(9):884-890. doi:10.1200/JCO.2016.71.3495

Traina TA, Boyle LA, Arumov A, et al. Adjuvant enzalutamide for the treatment of early-stage androgen receptor-positive (AR+) TNBC. 

2019;37(suppl 15):546. doi:10.1200/JCO.2019.37.15_suppl.546

Robilotti EV, Babady NE, Mead PA, et al. Determinants of COVID-19 disease severity in patients with cancer. 

 2020;26(8):1218-1223. doi:10.1038/s41591-020-0979-0

Articles

Nearly 15 years have passed since pathologists at Memorial Sloan Kettering Cancer Center conducted gene expression analyses on breast cancer primary tumors and described a potential role for a novel target, which quickly became a major research focus for their colleague Tiffany A. Traina, MD.

Traina Helps Navigate Surge of New Breast Cancer Therapies

When Kenneth C. Anderson, MD, first arrived at Dana-Farber Cancer Institute in Boston, Massachusetts, 40 years ago, he immediately joined ongoing efforts to develop and test what would become the first generation of monoclonal antibodies, agents subsequently used for the diagnosis and treatment of B-cell malignancies. He was on the leading edge of a treatment revolution in multiple myeloma.

The treatment of myeloma has benefited from many advancements over the ensuing years, and Anderson remains at the forefront of discovery in this disease type. A 2014 winner of the Giants of Cancer Care

award in myeloma, Anderson is program director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber.

: Hematologic Malignancies, to be held Saturday, July 11, 2020, at the InterContinental New York Times Square in New York. The 1-day conference gives oncologists and hematologists a practical overview of important developments in the myeloma treatment landscape.

At Dana-Farber, Anderson is leading clinical trials that may bring both new immunotherapies and new targeted medications, alone or in combination, to patients with myeloma. His lab is undertaking foundational investigation needed to produce and design the next generation of medications and trials.

But research is not Anderson’s only professional interest. He maintains a full clinical practice and is passionate about sharing his wisdom with other physicians.

“Ken has made many seminal contributions to the field of myeloma over the past 3 decades,” said Shaji Kumar, MD, another leading myeloma investigator who has collaborated with Anderson many times over the years.

“His laboratory has played a key role in understanding the disease biology of myeloma, which has translated into development of several new therapies for the disease and led to improved survival,” said Kumar, a professor of medicine and a consultant in the Division of Hematology, Department of Internal Medicine, at Mayo Clinic in Rochester, Minnesota. “He is an outstanding investigator, a beloved clinician, and, importantly, an admired teacher who has drawn a generation of researchers into the field of plasma cell disorders.”

“Ken is a giant in the field of multiple myeloma,” added Noopur Raje, MD, a professor at Harvard Medical School and director of the Multiple Myeloma Program at Massachusetts General Hospital in Boston. “His leadership has led to our better understanding of this disease, and he has been the force behind the approval of several drugs for myeloma, including bortezomib [Velcade], lenalidomide [Revlimid], and pomalidomide [Pomalyst]. Getting a perspective from Ken himself is a real treat, and I always continue to learn whenever he presents,” said Raje, who also collaborates frequently on investigations with Anderson.

Also the Kraft Family Professor of Medicine at Harvard Medical School in Boston, Anderson has mentored dozens of young myeloma investigators during his tenure at Dana-Farber. He has also participated in many conferences designed to provide continuing education for clinical practitioners.

 conference on hematologic malignancies, experts will discuss trial results that are changing or have potential to change standards of care. Conference faculty include cochairs Elias Jabbour, MD, a professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, and Anas Younes, MD, a professor and chief of the Lymphoma Service in the Division of Hematologic Oncology at Memorial Sloan Kettering Cancer Center in New York, New York.

Anderson recently sat down for an in-depth interview with 

 to preview the conference and share his thoughts about the major trends in myeloma care. “There has been very rapid progress, both in targeted therapy and immune therapy. The targeted therapy venetoclax [Venclexta], to use an example, is very effective in 11;14 translocation or BCL-2—expressing myeloma. On the immune side, there are B-cell maturation antigen [BCMA]–directed immunotoxins, bispecific T-cell engagers [BiTEs], and chimeric antigen receptor [CAR] T cells, all of which are looking very promising in clinical trials,” Anderson said.

And the progress extends beyond the creation of new monotherapies.

“We have been developing new classes of drugs and then combining them with existing agents based on preclinical rationale, suggesting that they’re either additive or synergistic. For example, in patients with newly diagnosed myeloma, the combination of lenalidomide, bortezomib, and dexamethasone [RVd] is used broadly and achieves a very high rate and extent of response,” Anderson said.

“The monoclonal antibody daratumumab [Darzalex] has now been added to RVd, and at December’s American Society of Hematology [2019 ASH] meeting, RVd/daratumumab was shown to achieve an even higher rate and an even deeper extent of response than RVd alone, including a high frequency of minimal residual disease [MRD]—negative responses,” Anderson noted.

Venetoclax, which blocks the BCL-2 family of proteins, made headlines in 2019 when investigators in the phase III BELLINI trial (NCT02755597) reported that in patients with myeloma, usage was associated with an increased risk of death, and the FDA temporarily suspended new enrollment in trials testing venetoclax in myeloma.

 Subsequent analysis suggested, however, that in the treatment of hematologic malignancy, venetoclax provided significant benefits to nearly half of all patients whose myeloma was t(11;14) positive or high in BCL-2 expression.

On March 2, the FDA approved isatuximab-irfc (Sarclisa) in combination with pomalidomide and dexamethasone for the treatment of adults with multiple myeloma who have received at least 2 prior regimens, including lenalidomide and a proteasome inhibitor.

Investigators tested the monoclonal antibody, which binds to the CD38 receptor and produces antitumor activity via multiple mechanisms of action, in a similar population of 307 patients with relapsed/refractory (R/R) disease in the ICARIA-MM trial (NCT02990338). Patients were randomized equally to isatuximab, pomalidomide, and dexamethasone or pomalidomide and dexamethasone alone. At a median follow-up of 11.6 months, the median PFS was 11.5 months (95% CI, 8.9-13.9) in the isatuximab group versus 6.5 months (95% CI, 4.5-8.3) in the control group (HR for progression, 0.596; 95% CI, 0.44-0.81; 

The approval makes isatuximab the second anti-CD38 therapy available to patients with myeloma. The first, daratumumab, was initially approved for the treatment of refractory myeloma in late 2015, but recently released trial data may be enough to make the agent part of the standard of care for most patients with newly diagnosed disease.

In the phase II GRIFFIN study (NCT02874742), investigators randomized patients with transplant-eligible multiple myeloma evenly to RVd with daratumumab (D-RVd) or without. The trial enrolled 207 patients, who received 4 induction cycles, stem cell mobilization, high-dose therapy, autologous stem cell transplant (ASCT), 2 consolidation cycles, and maintenance lenalidomide for 24 months.

According to data presented at 2019 ASH in December, the stringent complete response (sCR) rate after a median follow-up of 22.1 months was 62.6% with D-RVd and 45.4% with RVd (OR, 1.98; 95% CI, 1.12-3.49; 

 = .0177). The overall CR rate (sCR + partial CR) was also improved with D-RVd (79.8% vs 60.8%; 

 = .0045), and the proportion of patients achieving MRD negativity was twice as high with D-RVd. At 24 months, both regimens had led to PFS rates exceeding 85% and OS rates exceeding 90%.

The addition of daratumumab to a similar regimen of bortezomib, thalidomide, and dexamethasone (D-VTd or VTd) had previously demonstrated improved response rates and PFS as induction and consolidation therapy for transplant-eligible patients with newly diagnosed myeloma in the phase III CASSIOPEIA trial (NCT02541383). Investigators randomized 1085 patients evenly to receive 4 pretransplant induction cycles and 2 posttransplant consolidation cycles of VTd or D-VTd. At day 100 after transplant, 157 of 543 patients (29%) in the D-VTd group and 110 of 542 patients (20%) in the VTd group had achieved sCR (OR, 1.60; 95% CI, 1.21-2.12; 

Investigators observed MRD negativity in 64% of patients receiving D-VTd and 44% of those on VTd. Neither group reached median PFS, but those who received D-VTd were less likely to progress by the time of analysis (HR, 0.47; 95% CI, 0.33-0.67; 

 <.0001). Investigators reported 46 deaths (14 vs 32, respectively; HR, 0.43; 95% CI, 0.23-0.80).

Another monoclonal antibody approved in the refractory myeloma setting, the immunostimulatory agent elotuzumab (Empliciti), which binds to the SLAMF7 protein on natural killer cells, also has shown promise as a frontline agent in a phase II study conducted in Japan.

However, the addition of elotuzumab to lenalidomide and dexamethasone did not demonstrate a statistically significant improvement in PFS compared with lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma, previously untreated, transplant-ineligible myeloma in the ELOQUENT-1 trial (NCT01335399), according to a statement from Bristol Myers Squibb, a codeveloper of the drug. Full results are expected to be presented at an upcoming medical meeting.

Another trial that Anderson believes is a potential practice changer is the phase III IFM/DFCI2009 trial (NCT01191060), which set out to randomize 700 patients ≤65 years with newly diagnosed myeloma to RVd and maintenance lenalidomide until progression, with or without ASCT and high-dose melphalan. The goal is to see whether modern medications work well enough to dispense with ASCT, which has been the cornerstone of myeloma care for decades. The trial has been under way since 2009, with continuous maintenance lenalidomide, and is still not mature.

Investigators published results in 2017 on patients treated identically, with the exception of 1 year of maintenance lenalidomide. Among these patients, median PFS was significantly longer in the group who underwent transplant than in the group who received RVd alone (50 vs 36 months; adjusted HR for disease progression or death, 0.65; 

 <.001). However, OS at 4 years did not differ significantly between the transplant group and the RVd-alone group (81% and 82%, respectively), and the rate of grade 3/4 adverse events (AEs) was significantly higher in the transplant group: neutropenia, 92% versus 47%, respectively; gastrointestinal disorders, 28% versus 7%; infections, 20% versus 9%.

“These single agents and combination therapies that are currently undergoing trials have been informed by preclinical science, both in the laboratory and in animal models, which suggests cytotoxicity directed at myeloma cells. Preclinical research also suggests which combinations can act synergistically or at least additively. But this work in the lab is also refined by observations at the bedside, which are then brought back to the laboratory and result in further experimentation. That experimentation produces insights that go back to the clinic for testing, so there’s basically an iterative cycle of discovery and testing that has been producing improvements,” said Anderson. “It’s bench to bedside to bench to bedside.”

Several already approved myeloma treatments extend lives by stimulating immune response. Lenalidomide, pomalidomide, and thalidomide are all FDA-approved immunomodulatory drugs, and newer immunotherapies have produced such positive outcomes in early-stage trials that regulatory approvals could come soon.

“The excitement in the immune trials is in 3 main areas,” Anderson said. “First, there is the BCMA immunotoxin, where clinical trials are showing significant prolongation of progression-free survival in relapsed multiple myeloma that should provide the benefit for its FDA approval. Second, there are now [BiTEs]. The early data presented at ASH showed that once the correct dose is defined, these agents produce high rates of MRD-negative responses. Third, the clinical trials of CAR T cells are numerous and very promising. The responses in far-advanced myeloma are very common and extremely deep. Often, MRD-negative complete responses are achieved in spite of multiple lines of prior therapy.”

The BCMA immunotoxin belantamab mafodotin (GSK2857916) does not work solely by binding to BCMA. It is an antibody- drug conjugate that binds to BCMA and then releases the microtubule-disrupting agent monomethyl auristatin F. Investigators have shared results only from 1 early-stage study of belantamab mafodotin, but they were impressive. In the DREAMM-2 trial (NCT03525678), 196 heavily pretreated patients with R/R multiple myeloma were randomized to receive either 2.5 mg/kg or 3.4 mg/kg of the experimental drug once every 3 weeks. The ORR was 31% (97.5% CI, 20.8%-42.6%) among those who received the lower dose (n = 97) and 34% (97.5% CI, 23.9%- 46.0%) in those who took the higher dose (n = 99). Investigators considered the safety profile manageable; there were 2 deaths potentially related to treatment (1 case each of sepsis and hemophagocytic lymphohistiocytosis) and the most common grade 3/4 AEs included keratopathy, thrombocytopenia, and anemia.

Other trials are already under way, including DREAMM-6 (NCT03544281), which is testing belantamab mafodotin in combination with dexamethasone and either lenalidomide or bortezomib in patients with R/R multiple myeloma.

BiTEs are antibodies with 2 components. The first binds to a particular protein commonly expressed in the target. The second activates immune cells and leads them to attack. The first such compound to win FDA approval was blinatumomab (Blincyto), which has been available for the treatment of acute lymphoblastic leukemia since 2014. A pair of BiTEs designed to target multiple myeloma, AMG 420 and AMG 701, have demonstrated the ability in vitro to kill myeloma cells and potentially induce autologous tumor cell lysis. Both agents are undergoing early-stage clinical trials,

 but only 1 of those trials has reported any results to date.

In that trial (NCT02514239), 42 heavily pretreated patients with R/R myeloma and high tumor burden were treated with AMG 420 for a mean of 2.5 treatment cycles. The compound produced some response in 13 patients (31%) patients. The data showed sCR in 6 patients (14.2%), very good partial response (VGPR) in 2 patients (5%), and partial response (PR) in 2 patients (5%). Among those who responded, 11 responded in the first treatment cycle, and the median duration of response was 1 month. Serious AEs were reported in 19 patients (45%). Four deaths were reported, 2 from AEs, neither of which was treatment related.

Trials of CAR T-cell treatments in myeloma are both more numerous and further advanced. CAR T cells targeting BCMA have been investigated in numerous studies and have demonstrated significant diseaseremitting activity.

In 2019, investigators published results for 33 patients with R/R multiple myeloma enrolled in a phase I CAR T-cell study of anti-BCMA CAR T-cell therapy idecabtagene vicleucel (ide-cel; bb2121). The objective response rate was 85% (95% CI, 68.1-94.9), and 15 patients (45%) experienced CRs. Median PFS was 11.8 months (95% CI, 6.2-17.8). Sixteen evaluable responders were MRD negative (≤10

 nucleated cells), and CAR T cells persisted up to 1 year after the infusion. However, grade ≥3 AEs occurred in 97% of patients. The most common included neutropenia (85%), leukopenia (58%), anemia (45%), and thrombocytopenia (45%). Investigators observed cytokine release syndrome (CRS) in 25 (76%) patients, but it was grade 1 or 2 in 23 of those patients and grade 3 in the other 2.

 The FDA granted ide-cel breakthrough status in 2017.

Kenneth C. Anderson, MD, discusses key trials in multiple myeloma that have reported promising findings or are poised to shed light on novel treatments.

A Myeloma Pioneer Sees More Innovation

Early in this decade, Jeffrey S. Weber, MD, PhD, saw how well nivolumab (Opdivo) performed against advanced melanoma and recognized a good thing. He had a hunch the PD-1 inhibitor would reduce relapse rates by stimulating immune response against any cancer cells that escaped the surgeon’s knife.

Weber urged the drug’s developer, BristolMyers Squibb (BMS), to launch a trial of nivolumab in the adjuvant setting for patients with newly resected stage III or IV melanoma, but BMS officials were skeptical. They thought the drug was unlikely to work in the absence of a tumor microenvironment and were unwilling to fund trials.

In most cases, such a refusal would have prevented investigation, but Weber, a 2016 Giants of Cancer Care

 award winner, thought the chance to significantly lower relapse rates justified an independent pilot study. He secured the funding, the pilot took place, and the results led BMS to launch the CheckMate 238 trial (NCT02388906) of adjuvant immunotherapy with nivolumab versus ipilimumab (Yervoy) in patients with resected advanced melanoma.

 The trial was positive and earned nivolumab an FDA approval in this setting in 2017. Adjuvant treatment with nivolumab or the PD-1 inhibitor pembrolizumab (Keytruda) is now a standard of care (SOC) in patients with newly resected stage III or IV melanoma.

“It took a huge amount of effort to make that pilot happen. I really didn’t buy their reasoning for why adjuvant treatment wouldn’t work, so I just stuck with it,” said Weber, the deputy director of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Health in New York, New York. “The historic rate of relapse for resected stage III melanoma was over 60%. Adjuvant treatment [with a PD-1 inhibitor] cuts that down to about 40%. That’s a big diminution, and it applies to a big patient population. There have to be 20,000 patients with stage III melanoma in the United States each year.”

The effort that helped usher in the adjuvant use of PD-1 inhibitors may be Weber’s greatest achievement as a researcher so far, but he has been investigating melanoma treatment for decades, which is why he was selected to cochair the 

 International Symposium on Melanoma and Other Cutaneous Malignancies

 February 8, 2020, at the InterContinental New York Times Square in New York City.

“Dr Weber is an outstanding physicianscientist who has pioneered the development of immunotherapies for patients with melanoma and other cancers for the last several decades,” said Steven A. Rosenberg, MD, PhD, chief of the National Cancer Institute’s Surgery Branch in Bethesda, Maryland.

The conference, hosted by Physicians Education Resource

), will provide a concise and complete update on new investigations and updated standards for physicians who treat skin cancers. Key topics include best practices for using immune checkpoint inhibitors (ICIs) and other immunotherapeutic agents alone or in combination; emerging investigation into other therapeutic targets, such as activity related to 

; and strategies for mitigating adverse events (AEs) arising from ICIs and targeted treatments. Speakers include many eminent researchers, such as Weber and Omid Hamid, MD, director of the Melanoma Center and Phase I Immuno-Oncology at The Angeles Clinic and Research Institute in Los Angeles, California. Hamid also serves as a cochair of the symposium.

Immunotherapy Combinations are Introduced

The combination of nivolumab and the CTLA-4 inhibitor ipilimumab is the only treatment for metastatic melanoma for which median overall survival (OS) has not been reached at 5 years, according to CheckMate 067—trial investigators.

Most recently, the CheckMate 067 trial established the existence of an impressive 60-month plateau for patient groups that received regimens containing nivolumab. Long-term survival figures compared ipilimumab monotherapy with both nivolumab monotherapy and ipilimumab plus nivolumab. At a minimum follow-up of 5 years, median overall survival (OS) was 19.9 months (26%) in the ipilimumab monotherapy group, 36.9 months (44%) in the nivolumab-alone group, and not yet reached (52%) in the ipilimumab-plus-nivolumab group (

 This represented a huge bump up from historically dismal 5-year survival rates among patients with metastatic melanoma.

“Those survival data should make ipilimumab plus nivolumab [ipi-nivo] the presumptive treatment for pretty much any patient without some contraindication, and even for patients with targetable mutations,” Weber said. “If you look at the median survival, for patients who start out with targeted therapy, it’s between 25 and 33 months. If you look at the median survival of frontline ipi-nivo, it’s more than 5 years. You tell me what you want: median survival of 25 to 33 months [with targeted therapy] or median survival of more than 5 years? Some patients choose otherwise, but I’d accept the increased toxicity and go for the longer survival.”

Figure. Survival and TRAEs for Nivolumab + Ipilimumab at 5-Year Mark

Weber has witnessed many patients with no treatment options die within months; to him, a treatment that keeps half of all patients alive more than 5 years seems nearly miraculous. However, serious toxicity drawbacks with the combination of ipilimumab and nivolumab spurred a number of phase III trials designed to investigate alternatives. The high cost of treatment may be a problem that trials cannot solve. The price tag for a year of nivolumab and ipilimumab is astronomical—over $250,000

—and novel therapies that demonstrate improved survival could cost more.

Some Novel Regimens Falter in Phase III Trials

However, many experts hope that experimental combinations will produce fewer AEs and work at least as well as ipilimumab and nivolumab, especially in patients who never respond or stop responding to this combination.

“There are certainly a lot of people looking for new drugs to combine with PD-1 blockade that wouldn’t significantly increase the toxicity. You might not have to use ipi-nivo, which, frankly, can be a pretty toxic combination,” Weber said. “We’ve had some pretty interesting early-stage results from several combinations, but the few late-stage trials so far have been total failures.”

The first of those trials was reported at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting. A total of 706 patients in the phase III ECHO-301/KEYNOTE-252 study were randomized evenly to pembrolizumab with either placebo or the IDO1 enzyme inhibitor epacadostat. After a median follow-up of 12.4 months, median progression-free survival (PFS) was 4.7 months with the combination and 4.9 months with pembrolizumab alone. These findings were consistent across PD-L1 and 

The phase III trial was launched in part because the combination of pembrolizumab and epacadostat produced an objective response rate (ORR) of 55% in a phase I/II trial.

 However, in the larger trial, ORRs in the combination group and the pembrolizumab and placebo group were 34.2% versus 31.5%, respectively.

Grade 3/4 treatment-related AEs (TRAEs) occurred in 21.8% of patients who received the combination and 17.0% of those who received pembrolizumab monotherapy. In CheckMate 067, by contrast, 59% of all patients who received ipilimumab and nivolumab experienced grade 3/4 TRAEs.

Another combination, the PD-L1 inhibitor atezolizumab (Tecentriq) and the MEK inhibitor cobimetinib (Cotellic), failed to meet the primary end point of the phase III IMspire170 trial (NCT03273153) to show improved PFS over pembrolizumab monotherapy in patients with previously untreated 

 V600 wild-type melanoma. Genentech, which manufactures atezolizumab and is sponsoring the trial, announced that it will present the findings at an upcoming medical meeting.

“It is depressing that both of the most recent phase III trials have apparently produced negative results. We don’t know how the atezolizumab combination fared because they haven’t published details— maybe there’s something to salvage&mdash;but the pembro [and epacadostat] trial was the most negative trial I’ve seen in a long time,” Weber said. “Having a couple major failures in a row gets me thinking back to the part in the book of Genesis about the 7 years of feasts followed by the 7 years of famine. We definitely had 7 years of feasts between 2010 and 2017. I hope we haven’t started 7 years of famine.”

Weber worries that more negative results are a very real possibility because he believes several ongoing phase III trials of anti—PD-1/ PD-L1 antibodies plus novel treatments have been launched with modest supporting evidence from earlier trials.

The MASTERKEY-265/KEYNOTE-034 trial (NCT02263508),

 which is assessing pembrolizumab and talimogene laherparepvec (Imlygic; T-VEC) in advanced, unresectable melanoma, expanded straight from a stage phase Ib trial to a phase III trial. The phase I portion of the trial included 21 patients who were treated with the combination. The ORR was 62%, with a complete response (CR) rate of 33%.

Those results triggered the phase III portion, which will randomize roughly 700 patients with advanced melanoma to pembrolizumab and placebo or T-VEC, a type 1 herpes simplex virus genetically modified to break down cancer cells without harming normal cells. The FDA approved T-VEC in 2015 as monotherapy for the local treatment of unresectable, subcutaneous, and nodal lesions in patients with melanoma that recurs after initial surgery.

The phase III ILLUMINATE 301 trial (NCT03445533) is a relatively large study that sits on a foundation of results from a small patient population.

 ILLUMINATE-301 is comparing ipilimumab with and without tilsotolimod (IMO-2125) in patients with anti—PD-1 refractory advanced melanoma. Ipilimumab monotherapy is a common treatment for this population, but the response rate is roughly 13%.

Tilsotolimod is a toll-like receptor 9 (TLR9) agonist that could improve response to ipilimumab by activating innate and adaptive immune responses. A preliminary analysis from a phase II study of the combination reported an ORR of 47% (n = 15), and 3 patients exhibited stable disease.10 The phase III trial will randomize 454 patients between ipilimumab monotherapy and ipilimumab plus tilsotolimod.

ILLUMINATE 301 is not the only phase III trial testing a TLR inhibitor with an ICI in patients with melanoma, and a number of early-stage trials have produced promising results. For example, in patients with PD-1 inhibitor—refractory advanced melanoma, a combination of pembrolizumab and the TLR9 inhibitor CMP-001 produced an ORR of 22.5% among 40 patients dosed weekly and 7.7% among 13 patients treated every 3 weeks.

Also, in patients naïve to anti—PD-1/PD-L1 treatment with unresectable melanoma, the combination of pembrolizumab and another TLR9 agonist, SD-101, produced an ORR of 76% (including 8 CRs and 26 PRs) among 45 participants treated with 2-mg intratumoral SD-101 and 49% (including 4 CRs and 16 PRs) among 41 patients treated with an 8-mg dose.

Another phase III trial (NCT03635983) of nivolumab with or without bempegaldesleukin (NKTR-214)

 is under way in 764 patients with previously untreated unresectable or metastatic melanoma. Bempegaldesleukin is an investigational CD122-preferential interleukin-2 pathway agonist that increases the activity of some immune T cells and some natural killer cells. The phase III trial isn’t scheduled to be completed until 2025, but the combination might not have to wait that long for FDA approval.

The agency gave the combination a breakthrough therapy designation based on results from the phase I/II Pivot-02 trial, which were presented orally at the 2019 ASCO Annual Meeting. Some 53% of patients with metastatic melanoma and 48% with metastatic urothelial carcinoma who received the bempegaldesleukin and nivolumab combination responded to the treatment, including those whose tumor surroundings were deemed least favorable, patients with low levels of PD-L1 expression and T cells.

 The phase III trial of nivolumab and bempegaldesleukin is also assessing the efficacy of a triplet that includes ipilimumab.

Another ongoing phase III study combines the MEK inhibitor cobimetinib and the BRAF inhibitor vemurafenib (Zelboraf) with either placebo or atezolizumab in 513 patients with previously untreated 

Jeffrey S. Weber, MD, PhD, looks to earlier use of immunotherapy and novel combinations in melanoma.

Author | Andrew D. Smith

Articles

Traina Helps Navigate Surge of New Breast Cancer Therapies

A Myeloma Pioneer Sees More Innovation

The New Horizon in Melanoma

Shaping the Future in Lung Cancer