Beyond Tumor Type: HER2 Link in Leukemia Setting Shows Molecular Profiling Potential

Maurie Markman, MD

Editor-in-Chief of OncologyLive

Senior vice president for Clinical Affairs and National Director for Medical Oncology Cancer Treatment Centers of America, Eastern Regional Medical Center

The truly spectacular advances in genetic sequencing technology herald an era where it will be possible to provide a blueprint of specific actionable abnormalities within individual cancers with a time frame of a few days to several weeks, and at an equivalent or perhaps lower cost than that associated with many currently routine laboratory tests.¹ It is highly likely that this genuine revolution in our understanding of the biology of individual cancers will permit in the relatively near future far more precise antineoplastic management for many, if ultimately not most, cancers.

However, for the present, the large majority of treatment decisions continue to be based on standard morphologic classifications and specific molecular abnormalities observed to be relevant in a particular tumor type. For example, the language of clinical oncology continues to refer to “an activating EGFR mutation in non-small cell lung cancer,” rather than “an activating EGFR mutation in multiple (or all) tumor types” in defining the potential utility of a tyrosine kinase inhibitor of EGFR activity.

The impact of specific molecular abnormalities that can cross somewhat artificial morphologic barriers or the site of origin of a malignancy was strikingly highlighted by the demonstrated major clinical activity of imatinib against chronic myelocytic leukemia and gastrointestinal stromal tumors (GISTs). Despite remarkably different clinical characteristics, as well as histologies and locations within the body, a similar molecular defect characterizes their development and progression. In both cancers, the use of this molecularly targeted therapeutic has revolutionized care, and for many patients has turned the malignancies into very serious but manageable chronic illnesses.

Now, a second highly targeted antineoplastic drug has demonstrated impressive biological and clinical activity across vastly different cancer types. Trastuzumab, a well-characterized inhibitor of HER2, is a recognized standard-of-care in the management of HER2-overexpressing breast cancer in both the metastatic and adjuvant settings.^2,3 More recent data have documented the clinical utility of this agent in gastric cancer in patients whose tumors overexpress the HER2 receptor.⁴

Snapshot of Phase II GRAALL Study

Eligibility Criteria

• ≥18 y
• Relapsed/refractory B-ALL
• HER2+ for ≥30% leukemic blast population in peripheral blood and/or bone marrow

Number of Patients

50 patients screened

15 patients selected

• 62 y median age (24-80 y)
• 2 patients refractory after 2 induction courses
• 2 patients in first untreated relapse
• 11 patients refractory or beyond first relapse

Trastuzumab dosing

4 mg/kg intravenous loading dose followed by 2 mg/kg weekly

B-ALL indicates B-cell acute lymphoblastic leukemia.

Source: Chevallier P, Robillard N, Charbonnier A, et al. Trastuzumab (Herceptin®) for treatment of refractory/relapsed HER2 positive adult B-ALL: results of a phase II GRAALL study. Blood (ASH Annual Meeting Abstracts). 2011;118: abstr 1525.

And in a most provocative report, investigators have confirmed biological and clinical activity associated with trastuzumab in a specific population of patients with B-cell adult acute lymphocytic leukemia (ALL) who exhibit evidence of upregulation of the HER2 receptor, a group that represents approximately one-third of all patients with this malignancy.⁵ Of 15 patients with chemotherapy-refractory disease who possessed this defined molecular abnormality, two (13%) achieved a partial response following delivery of single-agent trastuzumab, with an additional two patients experiencing clearance of blast cells.

This experience, while clearly preliminary, emphasizes the potential relevance of documenting HER2 overexpression in this hematologic malignancy. Future research will need to explore earlier use of trastuzumab in ALL and in combination with cytotoxic chemotherapy, since such agents are currently employed in cancers of both the breast and stomach.

Finally, these data are further testimony to the importance in the not-so-distant future associated with routine molecular testing of individual tumors to search for relevant driver mutations that may be favorably impacted by unique antineoplastic strategies to optimize the opportunity for a positive clinical outcome.

References

1. Tran B, Dancey JE, Kamel-Reid S, et al. Cancer genomics: technology, discovery and translation [published online ahead of print January 23, 2012]. J Clin Oncol. 2012; 30(6):647-660. doi: 10.1200/JCO.2011.39.2316.
2. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that over-expresses HER2. N Engl J Med. 2001; 344(11):783-792.
3. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2 positive breast cancer. N Engl J Med. 2005;353(16):1659-1672.
4. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomized controlled trial [published online ahead of print August 19, 2010]. Lancet. 2010; 376(9742):687-697. doi:10.1016/S0140-6736(10)61121-X.
5. Chevallier P, Robillard N, Charbonnier A, et al. Trastuzumab for treatment of refractory/relapsed HER2-positive adult B-ALL: results of a phase 2 GRAALL study [published online ahead of print January 20, 2012]. Blood. 2012; 1199(11):2474-2477. doi: 10.1182/blood-2011-11-390781.