Growing up in Long Island, New York, Dan Haller, MD, didn’t always know that he wanted to become a doctor. He spent most summers doing what he calls “odd jobs” and claims that he never really had any true role models when it came to a career path. But then, in the hot summer of 1965, one of those odd jobs serendipitously led him to the medical industry.

“I went to the Nassau County unemployment office,” he recalled. “It turned out that they had a job as an orderly at the county hospital, Meadowbrook Hospital, now Nassau University Medical Center.”

Haller spent the summer making beds, feeding patients, and being on the ward—all for $1 an hour. “I had to walk a mile to take 2 buses to get to the hospital by 7 o’clock in the morning,” he said. “But once I was on the ward, I knew that’s where I wanted to be, period.”

Soon after his first introduction to medicine, Haller went on to Syracuse University as the second in his family to attend college (his brother was the first) with a full scholarship. Surprisingly, he arrived on campus with an undeclared major.

Taking a variety of advanced placement classes, he found himself not having enough to do and not doing well in his classes. “I just examined myself, and I realized when I don’t have much to do, I don’t get things done. And when I’m really pressured and have a lot to do, I get more done,” he said. “So what did I do? I looked in the campus newspaper, and a job as an orderly [was] posted at a hospital adjacent to the campus.”

It was a full-time job, 3 pm to 11 pm, in the emergency department at Crouse-Irving Hospital. “It turned out it made me really focus on my studies because I had to get [them] done,” he explained. “It changed everything. His grades improved, he added premed courses, and he also became more socially active—even finding time to sing in the Hendricks Chapel Choir at Syracuse University.

He graduated magna cum laude from Syracuse University in 1969 with a BA in political science, a minor in journalism, and a full scholarship to medical school at the University of Pittsburgh.

After finishing medical school, Haller applied to be an intern at the Hospital of the University of Pennsylvania, but that didn’t work out. “I was disappointed, but it ended up that I went to Georgetown [University Hospital in Washington, DC],” he said, noting that he eventually became a resident and then fellow. “And the benefit of that is I met my wife there.”

At the time, his wife, Eileen, was a nephrology nurse at Georgetown. During his second year in the program, oncologists Philip S. Schein, MD, DSc (Hon); John S. Macdonald, MD; and Paul Woolley, MD, PhD, left the National Institutes of Health (NIH) to establish an oncology practice at Georgetown. Haller joined a class of 4 fellows, working 7 days a week every 4 weeks for 2 years.

“I learned very early on that I had a very personal relationship with my patients,” he said. “I remember so many of them by name. Forty-four years later, I still get a Christmas card from a patient I entered on my first clinical trial.”

Haller was surprised when he didn’t end up getting a full-time job at Georgetown after his fellowship, but as he describes it now, that also turned out to be serendipitous. Soon after, Schein recommended him to the late Franco M. Muggia, MD, a chemotherapy pioneer who headed one of the extramural programs at NIH. Muggia helped Haller get a job with the Cancer Therapy Evaluation Program at the institution.

“Then finally, after about 2 years, I [got] a call from John Glick at Penn Medicine,” Haller said. The University of Pennsylvania needed more faculty in the clinical oncology department and offered him a job as an attending physician and assistant professor. He accepted and has been at the institution for more than 40 years.

John H. Glick, MD, served as director of Penn’s Abramson Cancer Center from 1985 to 2006. Today, he is the Madlyn and Leonard Abramson Professor of Clinical Oncology, a professor of medicine, and president of the Abramson Family Cancer Research Institute.

Although gastrointestinal (GI) oncology had been his main focus at Georgetown, Haller dove into breast cancer and other solid tumors to broaden his knowledge. “In the mid-1970s, no one wanted to do GI oncology,” he explained. “It was all breast and leukemia.” Once the faculty grew, he was able to return to GI.

From 1980 to 1994, he climbed the ladder at Penn Medicine, rising from attending physician to medical director of hematology-oncology. In 1992, he also became a coleader for the clinical oncology research program at Penn and an associate medical director for Penn Home Infusion Therapy. He later added another responsibility—associate chief for clinical affairs in the Division of Hematology-Oncology.

Even his minor in journalism came in handy. Throughout his career, Haller has held a number of editorial positions with high-profile medical journals including Journal of Clinical Oncologyand Annals of Oncology. Four years after officially retiring, he continues working as an editor to keep his skills sharp and his knowledge current.

“I always want to keep up-to-date, which is why I enjoy editing things—even in areas I don’t know. I like keeping my brain going,” he explained. “[I] semi joke that if I have to go to a meeting to learn something, [then] I’m already out of date, right? I should know this already, or I should have anticipated it.”

Haller has received several awards, recognitions and accolades throughout his career, such as being named a fellow of the Royal College of Physicians in 2013. Upon arriving to London for the induction, Haller was invited to one of the Queen of England’s garden parties.

“We were introduced, and she congratulated me. I simply said, ‘Thank you, ma’am,’” he recalled.

Haller also has an endowed chair named after him at Penn Medicine: the Deenie Greitzer and Daniel G. Haller Associate Professorship in Gastrointestinal Medical Oncology.

“When I got the endowed chair, a number of fellows who I taught in the past were there,” Haller recalled. “I said to them, ‘Tell me, honestly, do you remember anything I taught you?’ And one said, ‘The factual things really didn’t matter because we have ways of finding [those] out. You taught us how to treat people, and not just medically, but how to treat people as colleagues, how to treat your patients, [and] how to talk to people. That made more of an impact.’”

Haller estimates that he’s spent about one-third of his life in clinical trials. He has participated in at least 70 clinical trials throughout his career, starting back when he was a fellow at Georgetown.

After his fellowship, he became the project officer of the GI Tumor Study Group and was involved in many clinical trials around adjuvant therapy. Later, at Penn Medicine, he became the principal investigator for the Eastern Cooperative Oncology Group (ECOG).

During this time, he was lead author for Intergroup 0089, which is still the largest colon cancer adjuvant treatment trial for patients with high-risk disease. The trial accrued more than 3700 patients and looked at a treatment regimen of fluorouracil, leucovorin, and levamisole in high-risk, stage II and III colon cancers. “What we were able to do [was] drop levamisole out of the accepted regimen and cut 6 months off treatment based on that and other trials,” he said.

“We instituted the first large-scale anal cancer study,” Haller said of another trial, which was based on the Wayne State University experience examining the efficacy of infusional fluorouracil and mitomycin C with radiation. “Before that, people were having surgery, and then it was found out at certain institutions like Princess Margaret [Cancer Centre] and Wayne State that a combination of 2 drugs plus radiation therapy cured most people with early-stage disease.

But it had only been done in single institutions, which is sometimes misleading. We had to show that everybody could do it.”

Forty years later, infusional fluorouracil and mitomycin C with radiation are still the standard of care for anal cancer.

He also participated in ECOG’s EST-1282 study, another major trial that showed how chemo-radiotherapy was better than radiation alone for early-stage squamous cell carcinoma of the esophagus. Today, this regimen is the standard of care.

In 2013, Haller became the cochair emeritus of the National Cancer Institute Gastrointestinal Intergroup, empowering him to approve or reject cooperative group trial proposals. “Of all the jobs I’ve had, that was the one I missed the least when I finished because it had the possibility of being contentious,” he said. “I generally tend to be a collaborative person, not a contentious person.”

Haller has always enjoyed traveling because he loves learning new things and meeting new people. Although many trips were for work, he was able to sneak in some vacations with his wife.

One year, the pair spent 3 weeks in Australia, mixing work with a celebration of his 50th birthday. Together, they explored the Great Barrier Reef and the city of Cairns in Queensland and the Blue Mountains in New South Wales. Next, they headed to Melbourne and then to Sydney, where they stayed at the Park Hyatt Sydney hotel overlooking the Sydney Opera House.

Haller says it was the longest vacation he had ever taken. “I spent 2 hours lecturing and 3 weeks minus 2 hours vacationing,” he said, adding that, “Australia [will] always [be] one of my favorite countries. I’ve been to Perth, Adelaide, Melbourne, and Tasmania. Will I get back? I’m not ruling it out.”

A few years ago, he also spent 2 weeks in Scotland with his church. “I did spend a semester of medical school at the University of Edinburgh my senior year,” he recalled. “It [was] great to go back to Edinburgh more than 40 years later, almost 50, actually, to see how things had changed.” He notes the Royal Infirmary of Edinburgh as the biggest change, which had been built in 1879. No longer a functional hospital, it has been converted into offices and condos.

He’s also visited most of the countries in South America and Europe and been to Jordan twice and London at least 20 times. He hopes to one day visit Egypt and Israel. The only continent he has yet to step foot on is Antarctica.

Haller noted that he and wife Eileen have “been married 43 years this year.” During that time, they’ve welcomed 4 golden retrievers into their family, the most recent being 6-year-old Buddy.

Haller has also picked up a variety of interests and hobbies, but the one he is most passionate about is singing, which stems from his mother enlisting him in the church choir at age 7. “I’ve sung all 4 parts over my life,” he said. “I went from a boy soprano, through an alto, to bass, and now I’m a second bass.”

Today, he is part of the 85-member choir at Bryn Mawr Presbyterian Church. “It has a fabulous music tradition and one of the best organs in Philadelphia. The church seats about 1000 people, and we almost fill it on Sundays,” he said.

In the past, Haller has also enjoyed needlepoint, claiming that he’s made enough Christmas stockings and pillows to last a lifetime.

During the pandemic, he became interested in diving deeper into his family history and was able to trace his father’s family back 13 generations to the early 1500s in Germany. “My great-great grandfather actually died in the Battle of Chattanooga in the Civil War,” he said.

He notes one similarity throughout his family tree. “Not one of them had a college degree or even high school diploma,” he said. “They were all blue-collar workers and worked with their hands.” Haller broke that pattern, making his parents proud.

“My life has been one of cheerful serendipity,” he concluded. “I’ll just rely on that.”

Articles

Daniel G. Haller, MD, says he has relied on “cheerful serendipity” throughout his life and career. 

From the Ground Up: Daniel G. Haller, MD, Gets Giants of Cancer Care Award in GI Cancer

Clinical limit of detection (cLOD) may be a reasonable metric for evaluating cell-free DNA (cfDNA) for multi-cancer early detection, according to recent data from the Circulating Cell-Free Genome Atlas (CCGA) study (NCT02889978).

In particular, a whole-genome methylation assay performed better than whole-genome sequencing or targeted sequencing without the need for additional white blood cell sequencing for clonal hematopoiesis.

Data from the study, which evaluated cell-free DNA multi-omics in prototype cfDNA-based multi-cancer early detection tests, were presented at the 2021 ESMO Congress.

In the study, researchers collected plasma and matched white blood cells before sequencing them from CCGA study participants (n = 2,800). Tumor biopsies were also sequenced when available.

Furthermore, 6 cfDNA-omics were used to detect circulating tumor fraction, including whole-genome methylation data from whole-genome bisulfite sequencing (30x); small somatic variant data from error-corrected targeted sequencing ( 60,000x); somatic copy-number aberration; fragment length; fragment endpoint; and allelic imbalance data from whole-genome sequencing (30x).

Samples were then split into independent training and validation sets, while 10 classifiers were trained to identify solid cancer (carcinomas, sarcomas, lymphomas) using 1 per-omic, 2 corrected for clonal hematopoiesis using germline DNA from paired white blood cell sequencing, 1 pan-omics and 1 clinical data only. These metrics were assessed for cancer detection and cLOD, which was estimated as the probability of detecting cancer as a function of circulating tumor fraction using matched tumor biopsies. Researchers also trained three additional classifiers to predict cancer signal origin.

Of the 2,800 participants, 2,261 had analyzable results, of whom 1,414 were in the training set and 847 were in the validation set. Because training and validation results were similar, results from the validation set are featured in the abstract.

Researchers found that circulating tumor fraction accounted for greater than 72% of the variance in cancer detection scores, while the cLOD was at least 1.5-fold lower for whole-genome methylation than any whole-genome sequencing or targeted sequencing classifier. Cancer signal origin prediction was at least 1.8-fold more accurate using whole-genome methylation than targeted sequencing or somatic copy-number aberration.

“These data informed the design of a significantly improved targeted methylation MCED test for further CCGA substudies to support clinical use,” the researchers wrote in the abstract.

Liu MC, Jamshidi A, Klein EA, et al. Evaluation of cell-free DNA approaches for multi-cancer early detection. Presented at 2021 ESMO Congress; September 16-21, 2021; Virtual. 1123O

Clinical limit of detection may be a reasonable metric for evaluating cell-free DNA for multi-cancer early detection. 

cLOD May Provide More Accurate Evaluation of Cell-Free DNA in Multi-Cancer Early Detection

Patients with renal cell carcinoma (RCC) and their families may have a lack of understanding about the disease, clinical trials, and psychosocial impact.

Results from the global survey were presented as a poster during ESMO Congress 2021.

“(This) indicates opportunities to improve communication about diagnosis, psychosocial impacts, and clinical trials, as well as biopsies, physical exercise, and patient engagement,” wrote Dr. Rachel H. Giles, chair of the International Kidney Cancer Coalition, and colleagues wrote in the poster.

Of note, kidney cancer is the seventhmost common cancer, although little is known about variations in patient experience and best practices in different countries.

The survey consisted of 35 questions focused on the diagnosis, management, and burden of RCC. It was distributed in 13 different languages to patients with kidney cancer and their caregivers between October 29, 2020, and January 5, 2021. The survey reached 2,012 (1,586 patients, 417 caregivers, 9 undisclosed) participants from 41 countries.

“The survey identified several actionable deficits,” according to the poster.

According to the survey, 42% of participants reported that the likelihood of surviving their cancer beyond 5 years was not explained, whereas 51% reported that they were involved as much as they wanted to be in developing their treatment plan. Fifty percent of younger-onset patients (< 46 years) did not know their tumor subtype and 56% experienced barriers to their treatment. Of the surveyed population, 74% took fewer than 3 months to obtain a correct diagnosis.

Regarding clinical trials and perspectives on biopsies, 41% of respondents indicated that no one discussed cancer clinical trials with them, 46% had a biopsy and 3% said they were not willing to undergo an additional biopsy if asked.

For physical activity, survey results that 45% of respondents were insufficiently active and 55% said that they very often or always experienced a fear of recurrence.

Several questions in the survey also focused on psychosocial effects of the disease. Nearly a quarter (26%) of respondents reported that they either very often or always experienced stress related to financial issues and 50% experienced disease-related anxiety very often or always. More than half of participants (52%) reported talking to their doctors or health care teams about their psychological well-being.

Giles RH, Maskens D, Martinez R, et al. Patient-Reported Experience of Diagnosis, Management, and Burden of Renal Cell Carcinomas: Results from a Global Patient Survey in 41 Countries. Presented at 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract 671P

Patients with renal cell carcinoma and their families may have a lack of understanding about the disease, clinical trials, and psychosocial impact.

Improved Communication Needed for Patients With RCC Subtype

 fusion–positive non-small cell lung cancer (NSCLC), pralsetinib (Gavreto) demonstrated promising results regardless of previous therapies, according to data from the Chinese cohort of the global ARROW study (BLU-667-1101; NCT03037385).

“So far, both in America and in China, this drug has been approved for RET fusion positive non-small cell lung cancer patients based on the global trial ARROW study,” said lead study author Qing Zhou, MD, of the Guangdong Lung Cancer Institute in Guangdong, China, during his presentation at the 2021 World Conference on Lung Cancer.

There were 63 patients enrolled in the Chinese cohort of the study: 33 had prior platinum-based chemotherapy treatment while 30 had no prior systemic treatment. 

Of those who had chemotherapy prior there was an overall response rate (ORR) of 66.7% (n=22; 95% Cl: 48.2-82.0) at a median follow-up of 17.0 months (range: 16.3-18.1) . Three percent (n=1) had a complete response (CR) and 63.6% (n=21) had a partial response (PR). Researchers reported that the median time to first response among this pretreated patient cohort was 1.87 months (range, 1.7-3.8). Six-month and 9-month duration of response (DOR) rates were 77.3% (95% Cl: 59.8-94.8) and 50.0% (95% Cl: 29.1-70.9), respectively. Treatment duration had a median of 14.65 months (range: 0.9-20.0).

In the group of patients who did not receive prior therapy, the ORR was 80% (n=24; 95% Cl, 61.4-92.3), of which 6.7% (n=2) experienced a CR and 73.3% (n=22) experienced a PR. Median follow-up for these patients was 8.2 months (range: 7.1-8.6), while the median treatment duration was 7.13 months (range: 0.5-14.0) . Median time to first response among the group was 1.87 months (range, 1.7-3.8) . DOR rates were 76.7% (95% Cl: 55.6-97.8) and 38.3% (95% Cl: 0.0-92.5), at the 6- and 9-month marks, respectively.

Of note, 68.18% (n=15) of responders who were on platinum-based chemotherapy prior and 79.17% (n=19) of those without prior treatment remain on the treatment.

“I think the pralsetinib should be a new standard of care for both Chinese patients and other global patients with RET fusion-positive advanced non-small cell lung cancers,” Zhou said.

Data from the study reported that pralsetinib was well-tolerated in the Chinese patient cohort with a manageable safety profile. Treatment-emergent adverse events (TRAEs) were experienced in all 68 patients, 7 of which discontinued treatment due to a TRAE.

“I think compared to other targeted treatment, we should pay more attention to the hematological toxicities,” Zhou explained, highlighting neutropenia, anemia and platelet count decrease as some of the hematological adverse events to look out for.

Any-grade TRAEs included aspartate aminotransferase increase (80.9%), white blood cell count decrease (60.3%), alanine aminotransferase increase (57.4%), blood creatine phosphokinase increase (45.6%), hypertension (35.3%), blood creatine increase (29.4%), bilirubin conjugated increase (27.9%), constipation (27.9%), gamma-glutamyltransferase increase (27.9%), blood alkaline phosphatase increase (26.5%), malaise (25.0%), blood bilirubin increase (23.5%) and hypocalcemia (20.6%).

Grade 3 or 4 TRAEs that occurred in 5% or more were decreased lymphocyte counts (5.9%), leukopenia (5.9%), and hypophosphataemia (11.8%).

“I think to conclude, pralsetinib is a promising type of treatment with rapid and durable clinical activity in Chinese are patients with RET fusion-positive non-small cell lung cancer regardless of the previous treatment. And the safety profile is manageable and the tolerable,” Zhou said.

Zhou Q, Wu Y-L, et al. Efficacy and Safety of Pralsetinib in Chinese Patients with Advanced RET Fusion+ Non-Small Cell Lung Cancer. Presented at: 2021 World Conference on Lung Cancer; September 8-14, 2021. Virtual. Abstract M02.02.

In patients with advanced RET fusion–positive non-small cell lung cancer, pralsetinib demonstrated promising results regardless of previous therapies. 

Pralsetinib Elicits Promising Activity in Advanced RET Fusion+ NSCLC 

Although cardiovascular health of patients with myeloproliferative neoplasms (MPN) was relatively good, an estimated 11% to 22% of patients were not prescribed appropriate medications for management of comorbidities associated with thrombotic risk.

“These findings highlight a potential unmet need for improved cardiovascular risk management and coordination between primary and secondary care in the UK,” the study authors wrote in a poster presented at the 2021 European Hematology Association Virtual Congress.

In this retrospective cohort study, researchers assessed information from 2,477 patients with MPN (median age, 68 years; 56% women) from the Clinical Practice Research Datalink to determine the potential cardiovascular and thrombotic risk for all patients with MPN. Patients were included in this database at their first recorded diagnosis of polycythemia vera (n = 1,315), primary myelofibrosis (MF; n = 146) and essential thrombocythemia (n = 336). Some patients also had unspecified MPN (n = 680).

Researchers focused on pre-index assessments of the patients for six or more months before the first diagnosis and for at least 24 months post-index follow-up. During this time, researchers aimed to determine the epidemiological landscape of PMN, thrombotic/cardiovascular risk profiles before diagnosis, the extent of comorbidities using the Charlson score and the occurrence of thromboembolic/cardiovascular events after diagnosis.

Most patients (96.2%) had a low Charlson comorbidity score between 0 and 5. Moreover, the prevalence of MPN was 12.72 per 100,000. Authors noted that polycythemia vera was the most prevalent MPN subtype (6.75 per 100,000), followed by essential thrombocythemia (1.73 per 100,000) and MF (0.75 per 100,000). The rates of polycythemia vera and MF were consistent with other epidemiological reports from the UK, but the prevalence of essential thrombocythemia was lower than previous reports.

The most prevalent risk factors before MPN diagnosis included smoking (59.8%) and ischemic heart disease (27.7%). In contrast, few patients had hypertension (14.6%), diabetes (13.1%), dyslipidemia (12.8%) or obesity (8.8%). Patients with hypertension (88.9%), dyslipidemia (82.4%) and diabetes (77.9%) were prescribed appropriate medications for risk management. Of all the patients with MPN in this cohort, there were 325 cases of thrombosis before diagnosis, with a mean time of thrombosis to MPN diagnosis of 3,100.8 days.

After MPN diagnosis, 372 thromboembolic/cardiovascular events occurred. In particular, 214 events were observed in patients with polycythemia vera, 64 events in those with essential thrombocythemia, 9 events in patients with MF and 85 events in those with unspecified MPN. Authors noted that the most frequent thromboembolic/cardiovascular events were stroke (27.2%), deep vein thrombosis (17.7%) and myocardial infarction (14.8%). More patients with polycythemia vera had myocardial infarction (15.9%) compared with those with essential thrombocythemia (10.9%) or MF (0%).

Chen F, Rabe A, Were J, et al. An Epidemiological Study of the Cardiovascular Health and Thrombotic Risk Profiles of Patients with Myeloproliferative Neoplasms in Primary Care Across the United Kingdom. Presented at: 2021 European Hematologic Association Congress; Virtual. June 9-17, 2021. Abstract E1090.

Although cardiovascular health of patients with myeloproliferative neoplasms was relatively good, an estimated 11% to 22% of patients were not prescribed appropriate medications for management of comorbidities associated with thrombotic risk.

Improvements in Cardiovascular Risk Management Needed for MPN

The addition of lifileucel (LN-144) to pembrolizumab (Keytruda) resulted in an overall response rate (ORR) of 85.7% compared with pembrolizumab alone in patients with immune checkpoint inhibitor (ICI)–naïve advanced melanoma, according to data from the phase 2 IOV-COM-202 trial (NCT03645928) presented during the 2021 ASCO Annual Meeting.

“Advanced melanoma remains a significant health burden with a high unmet clinical need despite treatment advances in immunotherapy,” said Sajeve Samuel Thomas, MD, lead study author and medical oncologist and hematologist at Orlando Health Cancer Institute. “Lifileucel TIL [tumor-infiltrating lymphocyte]-cell therapy has demonstrated efficacy and durability of response in patients with advanced metastatic melanoma who have progressed while on or following treatment with anti-PD-1 or PD-L1 therapy.”

Researchers in the phase 2, multicenter, multi-cohort, open-label study enrolled 7 patients with ICI-naïve advanced melanoma (unresectable or metastatic) as of February 14, 2021. Five of the 7 patients were treatment-naïve, while 1 patient received prior treatment with BRAF inhibitors and MEK inhibitors and the other patient received prior chemotherapy. 

In addition, 71% of patients had liver/brain lesions and 43% had lactate dehydrogenase levels greater than the upper limit of normal. The mean target lesion sum of diameter was 111.4 mm, with 85.7% of patients having a more than 3 target and non-target lesions, “representing advanced disease at baseline for this patient group,” Thomas said.

“The primary efficacy endpoint was investigator-assessed objective response rate using RECIST version 1.1, while the primary safety endpoint measured the incidence of grade 3 or higher treatment-emergent adverse events,” Thomas explained.

Lifileucel is generated at centralized good manufacturing practice facilities during a 22-day process. Researchers administered a nonmyeloablative lymphodepletion using cyclophosphamide and fludarabine before a single infusion of lifileucel. This was followed by no more than 6 doses of lifileucel at 600,000 IU/kg.

Patients were followed-up for a median of 8.2 months, and the mean number of TIL cells infused into patients was 27.3 billion.

Six patients had a confirmed objective response to the treatment. In particular, 1 patient had a complete response, and 5 patients had a partial response. Three patients who originally responded to therapy were no longer taking pembrolizumab due to adverse events at 3 months, 4 months and 13 months, although they continue to have a maintained response.

Of note, the longest duration of response was 16.8 months. The complete response rate was 42.9%.

Treatment-related adverse events occurred in at least 30% of patients in the study and included thrombocytopenia, chills, nausea, pyrexia, vomiting, fatigue, febrile neutropenia, hypertension, neutropenia, alopecia, cough, decreased appetite and peripheral edema. This adverse event profile was consistent with the underlying disease and the known adverse effect profiles of nonmyeloablative lymphodepletion, pembrolizumab and lifileucel. There were no grade 5 treatment-emergent adverse events during this study, and unexpected toxicity was seen in patients related to pembrolizumab after TIL therapy.

“We are encouraged by this data confirming the potential feasibility and activity of combination lifileucel and pembrolizumab in the early-line treatment of patients with advanced metastatic melanoma,” Thomas concluded.

Enrollment to the IOV-COM-202 trial is ongoing.

Thomas SS, In KG, Doger B, et all. Safety and efficacy of lifileucel (LN-144), an autologous, tumor infiltrating lymphocyte cell therapy in combination with pembrolizumab for immune checkpoint inhibitor naïve patients with advanced melanoma. 

. 2021;39(suppl 15):9537. doi:10.1200/JCO.2021.39.15_suppl.9537

The addition of lifileucel to pembrolizumab resulted in an overall response rate of 85.7% compared with pembrolizumab alone in patients with immune checkpoint inhibitor–naïve advanced melanoma.

Lifileucel/Pembrolizumab Elicits Encouraging ORR in ICI-Naïve Advanced Melanoma

Cirmtuzumab and ibrutinib (Imbruvica) led to reported high overall response rates (ORR) in patients with mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL), according to findings from phase 1/2 study presented during the 2021 ASCO Annual Meeting. The safety profile of the treatment regimen was also well tolerated.

“The majority of the patients demonstrated a significant reduction in tumor sizes,” lead study author Hun Ju Lee, MD, assistant professor of medicine in the Department of Lymphoma & Myeloma at The University of Texas MD Anderson Cancer Center said during the presentation.

ORR for patients with MCL was 83.3% and was 91.1% for patients with CLL. The complete response rates were 38.9% and 14.7% for the MCL and CLL arms, respectively. Ultimately, 94.4% of patients with MCL and 100% of patients with CLL elicited a clinical benefit from the cirtuzumab/ibrutinib regimen.

The median progression free survival in both cancers was not reached.

Because MCL and CLL are considered incurable, the study aimed to test the efficacy and safety profile of cirmtuzumab, which inhibits tumor promoting activity of onco-embryonic tyrosine kinase receptor ROR1 found in many solid and hematologic cancers, plus ibrutinib in patients with relapsed/refractory MCL or treatment naïve or relapsed/refractory CLL.

The study was performed in 3 parts with separate arms. Part 1, for dose escalation; part 2, for dose expansion; and part 3, comparing cirmtuzumab plus ibrutinib with ibrutinib alone in CLL.

Overall, 26 patients with refractory MCL (median age 66.5, 15.4% women) and 34 patients with treatment naïve or RR CLL (median age 68, 23.5% women) were enrolled in the study.

For part 1, 12 patients with MCL were enrolled, and 5 into part 2. The median number of prior regimens was 2, including patients relapsing after ibrutinib (n=4), autologous stem-cell transplantation (n=3), autologous stem cell transplantation/allogenic stem cell transplantation (1) and autologous stem cell transplantation /CAR-T (1). For patients with CLL, at least 74% were high risk, as determined by unmutated IGHV, del17p and/or del11q, in parts 1 and 2.

In part 1, cirmtuzumab was given intravenously 5 times every 2 weeks, and then every 4 weeks, at 2 to 16 mg. Three-hundred or 600 mg doses were also examined. Researchers assessed the safety profile of cirmtuzumab during the first 28 days, which was then followed by ibrutinib at approved doses for each indication. A treatment regimen of cirmtuzumab (600 mg) given intravenously 3 times every 2 weeks, and then every 4 weeks, in combination with ibrutinib starting day 0, was chosen as the recommended dosing for parts 2 and 3.

“In summary, cirmtuzumab plus ibrutinib is a very well tolerated regimen,” Lee noted.

Adverse events with 20% or greater incidence were recorded, including fatigue (n=11), diarrhea (n=9), contusion (n=7), dizziness (n=7) and nausea (n=7). “The efficacy is robust in many of these pre-treated patients, [including] high response, rate durable response [and] encouraging PFS, demonstrating clinical benefit,” he concluded.

Of note, the phase 2 study for CLL is completed, and is awaiting a long-term follow-up. Phase 2 for MCL is currently enrolling.

Lee HJ, Choi M, Siddiqi T, et al. Phase 1/2 study of cirmtuzumab and ibrutinib in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL). 

Cirmtuzumab and ibrutinib led to reported high overall response rates in patients with mantle cell lymphoma or chronic lymphocytic leukemia. 

Cirmtuzumab Plus Ibrutinib Had Overall Response Rates in MCL and CLL

The combination of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) was associated with clinical activity in patients with previously treated advanced colorectal cancer, according to findings from the LEAP-005 study presented at the virtual 2021 ASCO Annual Meeting.

“Patients with previously treated advanced non-MSI-high or (proficient mismatch repair) colorectal cancer, lenvatinib plus pembrolizumab demonstrated promising antitumor activity and a manageable safety profile,” said lead study author Carlos A. Gomez-Roca, MD, cancer specialist at the Institut Universitaire du Cancer de Toulouse in France, during the presentation.

The nonrandomized, open-label, phase 2 study included 32 adult patients (median age, 56 years; 19% women; 91% received two prior lines of treatment) with advanced colorectal cancer. Eligible patients were also previously treated with oxaliplatin and irinotecan as separate lines of therapy.

“Pembrolizumab was administered at a dose of 200 milligrams every 3 weeks, and lenvatinib (was) received orally once a day at a dose of 20 milligrams,” Gomez-Roca explained, noting that they were administered for up to 35 cycles or until disease progression, unacceptable toxicity or withdrawal of consent. Treatment with lenvatinib could continue beyond 2 years in patients with clinical benefit.

The primary endpoints of this study included safety/tolerability and overall response rate. Secondary endpoints included duration of response, disease control rate, overall survival and progression-free survival. Responses to the treatment were assessed every 9 weeks until 54 weeks, when follow-up was conducted every 12 weeks until 102 weeks. Once that occurred, follow-up was conducted every 24 weeks.

The median treatment cutoff was 10.6 months. Patients had an overall response rate of 22% (95% CI, 9-40), all of which were partial responses.

“Of note, responders had PD-L1-positive tumors by CPS score equal or more than 1,” Gomez-Roca said. “Twenty-five percent of patients experienced stable disease, while 38% (had) progressive disease. The median duration of response was not reached.”

The 6-month progression free survival rate was 31% (median, 2.3 months; 95% CI, 2-5.2) with a 6-month overall survival rate of 62% (median, 7.5 months; 95% CI, 3.9-not reached).

All patients reported one or more treatment-related adverse events, with the most common being hypertension (44%) and decreased appetite (31%). Grade 3 and 4 treatment-related adverse events occurred in 47% of patients.

“There was one fatal treatment-related adverse event due to intestinal perforation, and three patients discontinued treatment due to treatment-related (adverse events) as increased liver enzymes, ischemic stroke and fat and intestinal perforation,” Gomez-Roca explained. “Fourteen patients experienced immune-mediated adverse events including hypothyroidism and hyperthyroidism. There were no infusion reactions.”

Based on this data, enrollment in the colorectal cancer cohort has been expanded to 100 patients, Gomez-Roca said.

Gomez-Roca CA, Yanez E, Im S-A, et al. LEAP-005: A phase 2 multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors—Results from the colorectal cancer cohort. Presented at: 2021 ASCO Annual Meeting; June 4-8, 2021; Virtual. Abstract 3564.

Some patients with previously treated advanced colorectal cancer responded to treatment with lenvatinib plus pembrolizumab.

Antonia DePace