Lauren M. Green

According to findings of a randomized trial reported at the 2017 ASCO Annual Meeting and published simultaneously online in

patients receiving treatment for metastatic cancer who used a web-based tool to report their symptoms either while at home or during clinic visits lived on average 5 months longer than their counterparts who had standard symptom monitoring.

Those who used the tool also were able to stay on their chemotherapy longer, had fewer visits to the emergency department (ED), and experienced better quality of life and physical function, reported lead author Ethan M. Basch, MD, MSc, FASCO, at an ASCO press conference June 4.

&ldquo;Compared to standard care, patients who self-reported symptoms experienced multiple, statistically significant, clinical benefits,&rdquo; said Basch, MD, MSc, FASCO, professor of medicine at the Lineberger Comprehensive Cancer Center of the University of North Carolina, who was practicing at Memorial Sloan Kettering Cancer Center (MSK) when the study was conducted.

Providing a rationale for the study, Basch said that between visits, patients are often hesitant to call the office, until problems become severe. Even at clinic visits, with many competing topics and limited time, symptoms are often not fully communicated between patients and their doctors and nurses.

&ldquo;We hypothesized that having patients report their own symptomsusing an online system with the information conveyed to their clinicians&mdash;would prompt clinicians to intervene earlier, therefore, improving symptom control and downstream outcomes.&rdquo;

The trial enrolled 766 patients between September 2007 and January 2011 who were being treated with chemotherapy for metastatic solid tumors (breast, lung, genitourinary, or gynecologic) at MSK. Patients in the intervention arm reported on 12 common symptoms, including appetite loss, dyspnea, fatigue, hot flashes, nausea, and pain, and were asked to grade each on a 5-point grading scale based on the Common Terminology Criteria for Adverse Events. Each symptom could be reported either as &ldquo;none,&rdquo; or graded from 1 (mild) to 4 (disabling). Short descriptions were included alongside each of the choices to help patients accurately rate their symptoms.

Participants in the self-report intervention arm (n = 441) completed online questionnaires in 1 of 2 ways. They could respond at home between visits, which generated an automated e-mail alert to nurses any time a severe or worsening symptom was reported by the patient; weekly e-mails were sent to participants reminding them to complete the questionnaire. Patients also could complete the symptom survey at terminals in the waiting room before their clinic visit for immediate dispatch to their oncology team prior to the appointment.

Usual care control participants (n = 325) discussed symptoms during clinic visits and were encouraged to telephone the office between visits if any worrying symptoms arose.

Thirty-one percent of patients who self-reported their symptoms using the web tool had better quality of life and physical function compared with those receiving standard care. Basch noted that, interestingly, patients who were not especially computer-savvy experienced the greatest quality-of-life benefit with this approach. Additionally, investigators reported a 7% reduction in ED visits, and patients were able to remain on potentially life-prolonging chemotherapy for an average of 2 months longer.

Among the most notable study findings, however, according to Basch, is the 5-month increase in median overall survival (OS). Median OS for patients in the self-reporting arm was 31.2 months versus 26.0 months in the standard care cohort (P = .03), which, he said, equated to an almost 20% increase in survival time for these patients. Looking at this finding in the context of 5-year survival, he added, &ldquo;At 5 years, 8% more patients were alive in the self-reporting group,&rdquo; (41% vs 33%, respectively).

Basch posited 3 potential drivers to explain the success of the intervention. One obvious benefit is that the system enables better management of chemotherapy adverse effects, which allows patients to stay on their treatment longer. The system also yielded more responsive care, he said, &ldquo;by alerting clinicians in real time about symptoms as they emerged, prompting them to take early action and manage problems before they became complications.&rdquo;

Finally, Basch said, &ldquo;By controlling symptoms better, this system kept patients more physically functional and kept them from becoming deconditioned or immobile, which we know from multiple prior studies has a strong association with better survival.&rdquo;

The findings are being confirmed in a larger clinical trial being conducted in community practices across the United States, using an updated, more user-friendly online tool that works on both personal computers and mobile devices to make it even easier for patients to communicate with their care team. Basch said the focus now is on how best to integrate these tools into oncology practice and that researchers are building similar ones to enhance understanding of symptoms of patients participating in drug development trials.

ASCO expert Harold J. Burstein, MD, PhD, FASCO, remarked on the significance of the trial, which was chosen to be part of an ASCO plenary session because of its strong potential to influence and improve patient care: &ldquo;If this were a drug that had a survival advantage of this magnitude, it would be retail priced at hundreds of thousands of dollars.&rdquo;

&ldquo;We don&rsquo;t have the kind of resources typically to invest in this kind of electronic communication, nursing care, and other things that made this a reality for these investigators,&rdquo; Burstein continued. &ldquo;A big challenge for our clinicians is going to be: How do we implement such systems, how do we integrate them into electronic health recordkeeping we are currently using, and how do we provide the medical team power in the way of doctors, nurses, and other supportive providers to make this work?&rdquo;

Still, he said, &ldquo;That&rsquo;s a good challenge and a good problem to have. I know that as these data have been circulated, it has been immensely gratifying to the oncology community to see that the kind of things we really believe inpatient-focused care, paying attention to their symptoms, and intervening early&mdash;is really helping these patients to consume fewer healthcare resources in terms of ER visits, feel better, and now&mdash;we have proof&mdash;helping them to live longer.&rdquo;

Basch EM, Deal AM, Dueck AC, et al. Overall survival results of a randomized trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment.

Basch EM, Deal AM, Dueck AC, et al. Overall survival results of a randomized trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment [published online first June 4, 2017].

Articles

Patients receiving treatment for metastatic cancer who used a web-based tool to report their symptoms either while at home or during clinic visits lived on average 5 months longer than their counterparts who had standard symptom monitoring.

Web-Based Tool for Symptom Reporting Leads to Longer Survival in Advanced Cancer Patients

Larotrectinib (LOXO-101), the novel pan-TRK inhibitor, induced responses in 3 out of 4 patients with a

fusionpositive solid tumor, according to findings presented in a press conference June 3 at the 2017 ASCO Annual Meeting. This well-tolerated oral agent could be on its way to becoming a standard of care among adults and children with any advanced cancer with this mutation.

&ldquo;You would be hard-pressed to find a targeted therapy even within a single disease context that has results like this,&rdquo; said David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center, who reported the findings during the press conference.

Twelve percent of patients in the study had a complete response and 64% a partial response; of the latter, Hyman reported, &ldquo;most were not just meeting criteria for partial response, but had very deep tumor regressions.&rdquo;

Larotrectinib is currently the only selective pan-TRK inhibitor in clinical development, Hyman said. He added that the oral agent may become the first to be used in a truly tumor-agnostic manner, and that, &ldquo;To our knowledge, it may be the first cancer therapy ever developed simultaneously in both adults and children.&rdquo;

genes becomes abnormally connected to another gene. This fusion event causes the&nbsp;

gene to be turned on and the cancer to grow. It&rsquo;s estimated that, annually, up to 5000 patients harbor&nbsp;

fusion mutations, but Hyman stressed that &ldquo;this number may significantly underestimate its prevalence due to inadequate ascertainment by many of the existing profiling technologies.&rdquo;

fusions were first discovered in colon cancer in 1982, but only recently has next-generation sequencing enabled them to be systematically detected. To date, more than 50 different partner genes that fuse with 1 of 3

genes (NTRK 1, 2, and 3) have been identified.

fusions typically follow 2 patterns: In adults, they occur rarely in more common cancers, such as brain, lung, colon, pancreatic, sarcoma, and melanoma; or, they occur more frequently in rare cancers, such as salivary and secretory breast cancer. This pattern also prevails in the pediatric setting, where the mutation is rarely seen in glioma and sarcoma, but more frequently in infantile fibrosarcoma and congenital nephroma, for example.

Although relatively rare, Hyman said that it is hard to find a tumor type where TRK fusions have not been reported. &ldquo;One of the defining features of

fusions is that they are not just found in one cancer type, but can be found in dozens of different cancer typesand in both children and adults.&rdquo;

The study he reported at ASCO involved 55

fusionpositive adult and pediatric patients with advanced solid tumors representing 17 unique cancer types, who were enrolled in 1 of 3 clinical phase I/II clinical trials. Hyman emphasized that the patients were identified on the basis of local testing, and thus provide an example of &ldquo;real world&rdquo; experience: &ldquo;We did not perform central screening to find the&nbsp;

fusions; in fact, 15 different laboratories identified the 55 patients who are described in this study.&rdquo;

Hyman reported overall response rates (ORR) based on investigator assessment for 50 patients for whom confirmatory response data were available; larotrectinib (100 mg) was taken twice daily. The ORR was 76% (95% CI, 62%-87%), and this includes a partial response in 64% of patients and a complete response in 12%. Five additional patients, who joined the study too early to have had their confirmatory scans, all had at least a partial response to larotrectinib, Hyman noted.

Among the patients with a partial response to larotrectinib, Hyman said that two had such deep tumor regressions that they were actually able to be downstaged and taken forward to potentially curative surgery with pathologic complete responses.

No trend toward better results was seen with larotrectinib in one tumor type versus another. Responses occurred a median of 1.8 months into therapy, which Hyman explained was actually just a reflection of when the patients had their first scan: &ldquo;In the clinic, patients reported dramatic improvement in their symptoms within days of beginning therapy.&rdquo;

Larotrectinib is notable not only for its tumor- and age-agnostic paradigm, but also for its favorable toxicity profile, said Hyman. The most common side effects were fatigue and mild dizziness.

&ldquo;This is an extremely well-tolerated therapy, with only 13% of patients requiring any form of dose modification and not a single patient discontinuing due to adverse events,&rdquo; he said.

In concluding his presentation, Hyman noted that 93% of responding patients and 75% of all patients have remained on therapy or undergone surgery with curative intent. &ldquo;I believe these data support larotrectinib as a new standard of care for these patients,&rdquo; he said. However, for its potential to be fully realized, this will require that patients be tested more universally for the presence of this mutation, as well as for other tumor-agnostic biomarkers such as microsatellite instability. &ldquo;To really enjoy these benefits,&rdquo; Hyman said, &ldquo;we&rsquo;ll have to change the paradigm by which we test these patients.&rdquo;

Larotrectinib is being developed by Loxo Oncology, Inc. Hyman reported that the company anticipates submitting a new drug application for the novel agent in late 2017 or early 2018.

Hyman DM, Laetsch TW, Kummar S, et al. The efficacy of larotrectinib (LOXO-101), a selective tropomyosin receptor kinase (TRK) inhibitor, in adult and pediatric TRK fusion cancers.

Larotrectinib (LOXO-101), the novel pan-TRK inhibitor, induced responses in 3 out of 4 patients with a&nbsp;<em>TRK</em>&nbsp;fusion&ndash;positive solid tumor, according to findings presented in a press conference June 3 at the 2017 ASCO Annual Meeting.

Responses Stimulated Across All Tumor Types Harboring TRK Fusions With Larotrectinib

Eating tree nuts, like almonds, walnuts, and pecans can improve overall survival and reduce the risk of recurrence in patients with colon cancer, findings of a new prospective study suggest.

Researchers performed a prospective observational study of a subset of 826 patients participating in the randomized CALGB 89803 trial examining adjuvant combination chemotherapy in patients with stage III colon cancer. Among the 19% of patients in the subset who reported consuming 2 or more ounces of nuts per week, risk of disease recurrence was 42% lower and the risk of death was 57% lower.

&ldquo;We observed that nut intake was associated with significant improvement in disease-free survival and overall survival in this patient population of stage III colon cancer patients,&rdquo; said Temidayo Fadelu, MD, presenting the findings during a presscast May 17 in advance of the 2017 ASCO Annual Meeting. &ldquo;This study adds to the evidence that dietary and lifestyle modification can, in fact, yield protective benefits in colon cancer survivors.&rdquo;

Fadelu did note, however, that a secondary analysis found that this association was only limited to tree nuts and not observed with consumption of peanuts or peanut butter. He hypothesized that this is due to the fact that peanuts are technically legumes with a different biochemical composition than the other tree nuts.

Fadelu, a clinical fellow in medicine at Dana Farber Cancer Institute, explained that nut intake was chosen for examination in this observational study, not only because of their known association with lower cardiovascular mortality, but also their link to a lower incidence of obesity, type 2 diabetes, metabolic syndrome, insulin resistanceconditions that are associated with a higher risk of recurrence and death from colon cancer.

Participants in this study filled out a food frequency questionnaire 6 months after completing chemotherapy for their colon cancer. They were asked about dietary intake and, specifically, their consumption and frequency of eating tree nuts (almonds, walnuts, hazelnuts, cashews, and pecans), peanuts, and peanut butter.

The study&rsquo;s primary endpoint was disease-free survival from the time the participants completed the questionnaire to disease recurrence. The overall CALGB clinical trial began in 1999, and the median follow-up for this part of the study was 7 years.

Fadelu reported that the benefits of tree nuts held even after adjusting for several factors associated with colon cancer recurrence, such as patients' total calorie intake, age, sex, number of lymph nodes, baseline performance status, BMI, physical activity, aspirin use, and glycemic load.

&ldquo;The odds of surviving colon cancer, if it is not metastatic, are quite high,&rdquo; said ASCO President Daniel F. Hayes, MD, FACP, FASCO, commenting on the study&rsquo;s findings during the presscast. &ldquo;Healthy people live healthier. I know that sounds pretty self-evident, but one cannot assume, &lsquo;I have colon cancer, it doesn&rsquo;t matter anymore.&rsquo;&rdquo;

Rather, he stressed, colon cancer survivorsafter receiving standard of care treatment for their disease&mdash;can benefit from healthier living, &ldquo;and it might even increase the chances of [their] colon cancer not coming back, as well as the other benefits that come with a healthy lifestyle.&rdquo;

Hayes also noted that because these findings are from a prospective rather than retrospective study, it enhances their significance. That, he said, &ldquo;takes a lot of the biases out of the classic retrospective observational trials where patients are asked, &lsquo;Do you remember what you did several years ago?&rsquo; This was in real time, so it makes these findings even more compelling.&rdquo;

Fadelu said that researchers want to explore the potential positive impact of nut consumption on other stages of colon cancer, especially stage IV, and that a randomized, controlled, clinical trial is needed to better understand nuts&rsquo; protective effect in this population.

Fadelu T, Niedzwiecki D, Zhang S, et al. Nut consumption and survival in stage III colon cancer patients: Results from CALGB 89803 (Alliance).

Eating Nuts Shown to Reduce Recurrence Risk, Improve Survival in Colon Cancer

The FDA has granted  its approval to co-packaging of the oral medications ribociclib (Kisqali) and letrozole (Femara) for the treatment of postmenopausal women with HR-positive, HER2-negative advanced breast cancer.

With the new Kisqali Femara Co-Pack, patients can obtain a full 28-day cycle of the 2 medicines in 1 package with 1 prescription and 1 copay, and the cost will be the same as that for Kisqali alone, according to Novartis, which manufactures both medications.

&ldquo;Providing physicians a convenient 1-package prescribing option for their patients underscores our commitment to deliver innovative treatment solutions to the metastatic breast cancer community&rdquo; said Bill Hinshaw, executive vice president and US head of Novartis Oncology, in a statement announcing the approval.

The company noted that ribociclib, which helps to slow cancer progression by inhibiting the cyclin-dependent kinase 4 and 6 (CDK 4/6) proteins, can continue to be prescribed separately, along with another aromatase inhibitor (AI).

Ribociclib was approved by the FDA on March 13 for use in combination with an AI for this population of women, based on findings from the phase III MONALEESA-2 trial. In that study, the combination of ribociclib and letrozole reduced the risk of progression or death by 44% compared with letrozole plus placebo in the first-line setting for HR+/HER2- advanced breast cancer (HR, 0.556; 95% CI, 0.43-0.72;

At a median follow-up of 15.3 months, the ribociclib group&rsquo;s median progression-free survival (PFS) had yet to be reached, whereas the placebo group had an estimated median PFS of 14.7 months. Blinded PFS assessment by an independent review committee resulted in a hazard ratio of 0.59 in favor of the ribociclib arm (

After an additional 11 months of follow-up, a subsequent analysis showed that the median PFS was 25.3 months with the ribociclib combination versus 16 months with letrozole alone. Overall survival data are still not mature.

Ribociclib did add to treatment-associated toxicity, as 59.3% of patients who received the CDK 4/6 inhibitor developed grade 3/4 neutropenia, as compared with 0.9% of patients who received placebo. Grade 3/4 leukopenia occurred in 21% of the ribociclib arm and 0.6% of the placebo group. Hematologic adverse events were uncomplicated and resolved without incident in most cases.

The most common nonhematologic adverse events (all grades) were nausea (51.5% with ribociclib vs 28.5% with placebo), infections (50.3% vs 42.4%), fatigue (36.5% vs 30.0%), and diarrhea (35% vs 22.1%). The events were grade 1/2 severity in most cases.

MONALEESA-2 represents a paradigm shift for the management of HR+/HER2- advanced breast cancer, because at some point, all breast cancers will become resistant to endocrine therapy alone.

The CDK 4/6 inhibitor also proved effective in a subgroup of patients in this trial of women aged &ge;65 years. The novel regimen was well tolerated among a MONALEESA-2 elderly subgroup, with a safety profile similar to that of the overall study population. Despite a higher rate of patients with an ECOG performance status of 1, the elderly population also had dose interruption and reduction rates consistent with the overall trial results, reported Lowell L. Hart, MD, of Florida Cancer Specialists, at the 2017 Miami Breast Cancer Conference.

The new co-pack is available in 3 ribociclib dosages (600 mg, 400 mg, or 200 mg), and each co-pack will also contain letrozole at the 2.5 mg dose. Novartis announced that the co-pack will be available domestically later this month at both specialty and retail pharmacies, and does not change the indication for either medicine.

Hortobagyi GN, Stemmer SM, Burris HA, et al. First-line ribociclib + letrozole for postmenopausal women with hormone receptor-positive, HER2-negative, advanced breast cancer. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA1.

Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer [published online October 8, 2016].

The FDA has given its approval to co-packaging of the oral medications ribociclib (Kisqali) and letrozole (Femara) for the treatment of postmenopausal women with HR-positive, HER2-negative advanced breast cancer.

Lauren M. Green | Authors

Articles

Web-Based Tool for Symptom Reporting Leads to Longer Survival in Advanced Cancer Patients

Responses Stimulated Across All Tumor Types Harboring TRK Fusions With Larotrectinib

Eating Nuts Shown to Reduce Recurrence Risk, Improve Survival in Colon Cancer

FDA Grants Approval to Co-Packaging of Ribociclib With Letrozole for Metastatic Breast Cancer