ASCO 2008: The Practice-Changing Findings

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http://www.oncologystat.com/home/Editor ... dings.html

Comment: I realize this is about other cancers other than lung cancer albeit, including lung cancer, but rather than excerpt that part, my sense was to offer you all of the article.

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I always approach ASCO with an almost palpable sense of excitement. As the premier venue for presentation of important cancer clinical trials, ASCO holds out the promise each year that I may hear about breakthrough study results that are strong enough—even based on the weight of 1 trial—to literally change practice when I return from the meeting.

In reality, this happens only rarely. However, in recent memory, I think that the presentation of the adjuvant trastuzumab data in 2005 was perhaps the most emotional and transformative ASCO session I have witnessed in almost 25 years of attending the meeting, and I believe that most oncologists would agree with me on that score. A well-deserved standing ovation greeted the results, and, overnight, oncologists changed the way they treated HER2-positive breast cancer—even if insurers and the FDA took a lot longer to follow suit.

So, after reviewing the ASCO 2008 abstract book in advance and waiting for the plenary and late-breaking abstracts to be distributed on site, the question I pondered was, what would be this year's practice-changing presentations? Now that I’ve had time to reflect on ASCO 2008, I feel that while none of the presented studies had breakthrough results per se, several key findings with the potential to alter practice were reported.

Gastrointestinal cancers

The KRAS story in MCRC. Previous reports have indicated that monoclonal antibody–mediated epidermal growth factor receptor (EGFR) inhibition appears to be more effective in the 50% to 60% of patients with metastatic colorectal cancer (MCRC) tumors that express wild-type KRAS, compared with those who harbor a mutated KRAS gene. This makes biologic sense, given that EGFR signals downstream through KRAS, and a mutated gene could be constitutively active, preventing modulation from upstream signaling. Multiple retrospective analyses presented at ASCO this year firmly established the KRAS story. Most notable was an analysis of the large phase III Cetuximab Combined with Irinotecan First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial, a study first presented at last year’s ASCO. This study randomized patients to receive FOLFIRI plus cetuximab as first-line therapy for MCRC. When analyzed by KRAS mutation status, the results were striking: A 32% improvement in progression-free survival and significant improvement in response rate were observed in patients with wild-type KRAS tumors who received cetuximab. In contrast, patients harboring a mutant KRAS gene derived no benefit from cetuximab.

Other retrospective analyses included a randomized phase II trial of FOLFOX plus cetuximab, which showed similar findings, as did a smaller retrospective analysis of cetuximab in irinotecan-refractory patients. Taken together, the cetuximab studies—along with similar previously reported findings from patients treated with panitumumab, another monoclonal EGFR inhibitor—provided strong evidence that essentially all the benefit from EGFR inhibitors occurs in wild-type KRAS tumors. Moreover, sorting patients by KRAS markedly improves the benefit of monoclonal antibody EGFR inhibition.

It is relatively simple to obtain KRAS status from paraffin-embedded primary tumor samples at commercial laboratories in a fairly short time frame. Thus, this approach should now become the standard of care for MCRC. Patients with wild-type KRAS could be considered for first-line FOLFIRI plus cetuximab followed by second-line FOLFOX and bevacizumab as 1 new approach to the paradigm of exposing patients to all active drugs in MCRC. Of course, many other combinations or approaches are conceivable as well. As soon as I came back from ASCO, I informed my practice that KRAS status should be ascertained in all newly diagnosed MCRC patients.

Adjuvant gemcitabine in pancreatic cancer. Also noteworthy in the gastrointestinal tumor area was a positive study of gemcitabine in the adjuvant treatment of pancreatic cancer after a primary resection, whether or not patients achieved an R0 status. A doubling of long-term (5-year) survival was achieved after a 6-month course of adjuvant gemcitabine. Notably, no postoperative radiation therapy was given in this trial. This approach thus becomes a new treatment option for patients who undergo resection, an encouraging development in a poor-prognosis group.

Breast cancer

ABCSG-12 trial. The primary results of the Austrian Breast and Colorectal Cancer Study Group-12 (ABCSG-12) trial were most interesting. This trial compared the aromatase inhibitor (AI) anastrozole with tamoxifen (along with goserelin to achieve ovarian suppression) and also compared zoledronic acid given IV every 6 months with placebo. Zoledronic acid improved both disease-free survival (DFS) by a significant 36% and relapse DFS at a median of 5 years of follow-up. A trend toward improved overall survival (OS) was also observed. No significant increase in serious adverse events was noted with the addition of zoledronic acid. Importantly, the 94% DFS and 98.2% OS for the entire study group represent a remarkable achievement, demonstrating the power of adjuvant endocrine therapy in an estrogen receptor–positive group of breast cancer patients.

While the ASCO discussant of this paper did not feel that this single trial was sufficient basis to make a practice-changing decision, I respectfully disagree. The secondary endpoint of this trial, improvement in bone density for the zoledronic acid group, has been reported previously and shows a clear benefit of the addition of this potent bisphosphonate in maintaining bone mineral density. Moreover, other trials in which zoledronic acid was given along with AIs in postmenopausal women have shown similar results. Therefore, the preponderance of evidence supports the view that twice-yearly IV administration of zoledronic acid in hormone receptor–positive patients receiving AIs or premenopausal patients receiving ovarian suppression plus tamoxifen is a reasonable therapeutic choice, particularly given the apparent improvement in breast cancer–specific outcome, as well as the preservation of bone health. This therapy will be a serious consideration for me as I see my next patients who fit this profile.

Lung cancer

FLEX trial. As in other human malignancies, the role of EGFR in non–small cell lung cancer (NSCLC) continues to be a major and ever-expanding focus of research and treatment. Small-molecule tyrokinase inhibitors of EGFR show clear benefit in certain subgroups of NSCLC. The First-Line in Lung Cancer with Erbitux (FLEX) study, presented at the ASCO plenary session this year, assessed the addition of the monoclonal EGFR inhibitor cetuximab to chemotherapy with cisplatin and vinorelbine in stage IIIB/IV NSCLC. Eligibility criteria included EGFR expression by immunohistochemistry, defined as >1 positive tumor cell. The vast majority (85%) of screened patients met this criterion. Patients randomized to the active treatment arm received a median of 4 cycles of chemotherapy and a median of 18 weeks of cetuximab. Of these patients, 80% were eligible for maintenance cetuximab therapy, which continued until disease progression. Over half the patients in both groups received post–first-line treatment.

The study was significantly positive for its primary endpoint, OS, with a hazard ratio of 0.87; this translated to a net improvement in median survival of 1.2 months. Response rate was significantly increased as well, but progression-free survival was not. Serious adverse events that occurred more commonly in the cetuximab treatment group were a 10% incidence of grade 3 rash and a statistically significant, but numerically small, increase in febrile neutropenia and infusion reactions.

These findings open the door to a new option for patients with advanced NSCLC. In particular, for the large group of patients who are ineligible for bevacizumab-containing regimens for 1 reason or another, the addition of cetuximab to a platinum-based doublet becomes an attractive alternative. The landscape of NSCLC has finally changed with the addition of biologicals, allowing a significant number of patients to experience meaningful improvements in OS and quality of life.

The virtual meeting

ASCO has become an incredibly huge and complex event that is very difficult for the generalist oncologist to negotiate. Indeed, community-based American oncologists seemed to be underrepresented at this year’s meeting, which, as a record gathering of the world’s cancer community, spawns an enormous number of secondary symposia, advisory boards, and business meetings occurring outside the scientific discussions.

One morning at the convention center, I found it very interesting that while I was trying to get to a clinical science session, I was among only a few individuals walking toward a huge meeting room against the tide of a veritable sea of individuals coming out of the hall. I panicked. What unbelievably important finding in the program had I missed that so captivated the vast hoard of attendees? When I finally made it inside the room, I found out that everyone had just attended the Highlights of the Day session, consisting of summaries of selected presentations from the previous day by experts in the field.

These overview discussions are a welcome addition to ASCO. However, I believe that there is no substitute for hearing the primary data from the principal investigator who conducted the study. So my bias is to encourage attendees to go to the sessions that pique their interest to hear the data themselves, to walk through the poster sessions to speak to the investigators, and to participate in the clinical science symposia to learn about state-of-the-art translational research. Of course, even those who share my bias and want to hear the data first hand cannot possibly go to every session of interest, however. Thankfully, the technology that is now employed by ASCO allows almost every session to be available on the society’s website in both video and slide form, including the Highlights of the Day discussions.

While the wonderful days of Dr. James Holland getting up after every oral session to ask a cogent question about study design are gone, occasionally one still hears a dramatic debate or thought-provoking discussions at an annual meeting. There is plenty of time for reading a secondary analysis of the data in the weeks and months after the meeting. Today’s technology enables the enormous amount of information presented in both oral and poster form at ASCO to be available electronically in an enduring fashion, providing all oncologists, whether they made the journey to Chicago or not, with the ability to learn from and ponder about the data. The virtual meeting itself is therefore potentially practice changing.

Conclusions

ASCO 2008 again confirmed that steady, solid progress—coupled with the occasional breakthrough—is being made in the treatment of human cancers. Behind these practice-changing trials is a huge array of preclinical and early and late clinical developments presented at the meeting, which sets the stage for the next series of dramatic therapeutic advances.

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(Oncology Stat, Lee Schwartzberg, M. D., Editor-in-Chief, June 18, 2008)

Disclaimer:

The information contained in these articles may or may not be in agreement with my own opinions. They are not posted as medical advice of any kind.