Clinical Observations Can Change Research Failures Into Successes

Oncology Live®, Vol. 18/ No. 20, Volume 18, Issue 20

There are many elegant examples of basic laboratory research or mathematical modeling studies that resulted, through the conduct of clinical trials, in major paradigm changes in how cancer is managed.

Maurie Markman, MD

One of the basic tenets of scientific investigation is the development of a hypothesis that is then tested in an attempt to prove or disprove its validity. In the clinical cancer domain, basic laboratory observations are followed by clinically relevant translational research strategies and, ultimately, human trials. In the history of clinical cancer investigation, there are many elegant examples of basic laboratory research or mathematical modeling studies that resulted, through the conduct of clinical trials, in major paradigm changes in how cancer is managed.

However, perhaps even more interesting in the history of cancer care advances are examples where insightful translational laboratory investigation in the wake of unanticipated severe drug toxicities or “failed” research efforts has led to the discovery a novel biological explanation that in turn was translated into an important change in disease management.

Perhaps the most poignant example of this turnaround was the profound tragedy associated with thalidomide intake during pregnancy that led to a strikingly favorable outcome for patients with multiple myeloma through the development of an extremely important class of antineoplastic agents.1

In the research arena, a wonderful example of this phenomenon is the “negative” experience associated with the administration of a small-molecule tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) to patients with non—small cell lung cancer (NSCLC).2 Reexamination of the initial “failed” hypothesis that the clinically relevant biological feature was simply measurable overexpression of EGFR, as had previously been shown to be the case with quantitatively evaluated overexpression of HER2 in breast cancer, led to a radically revised concept that, in fact, it was the presence of unique EGFR mutations within the individual cancers that defined the biological and clinical activity of these drugs. Clinical trial findings subsequently confirmed the substantial utility for this class of agents in the presence of this cancer-related biomarker and the approach has now become a recognized component of the standard of care in the management of NSCLC.3

Ovarian Cancer Example

Recently reported experiences with the exciting new class of checkpoint inhibitor immunotherapeutic drugs have raised provocative questions that require a similar degree of examination by the oncology community. Two well-respected investigative groups have noted the disquieting observation of apparently rapid tumor growth when a small number of patients were treated with this class of antineoplastic agents.4,5 Although the objective experience reported thus far is limited, open to considerable speculation, and subject to different interpretations of the data, the 2 groups have made considerable efforts to quantify and detail their observations and to provide a rational explanation for what has been observed in the clinic.Another example of the requirement for clinical investigators to reexamine their existing hypotheses based on the developing clinical data is provided by an older reported experience with the use of intraperitoneal (IP) cisplatin delivery in the primary chemotherapeutic management of advanced ovarian cancer. Preclinical data available prior to these studies had revealed that the actual depth of penetration of cisplatin into tumor masses by direct diffusion (vs delivery to the cancer via capillary flow) was limited to several millimeters or less from the peritoneal surface.6 Further, studies of second-line IP cisplatin following disease progression with a platinum-based frontline strategy had revealed minimal activity for this approach in the presence of even modestsize tumor masses (0.5-1 cm in maximal diameter).

Yet, when the first phase III randomized trial of frontline IP cisplatin-based chemotherapy compared with intravenous treatment was reported, patients in the trial whose maximal IP tumor diameter at the initiation of therapy was 0.5 cm to 2 cm appeared to experience the same— or even superior—relative improvement in overall survival (OS) compared with women with minimal volume disease (maximal tumor diameter ≤0.5 cm).7 The hazard ratio for OS comparing regional treatment with systemic therapy for the group with only minimal volume disease was 0.80: median 51 months versus 46 months, respectively, a 5-month difference. For the entire population, including those with large-volume disease, the hazard ratio was 0.77 in favor of regional treatment, with a median OS of 48 months versus 40 months with systemic therapy, an 8-month difference.

How can these results be explained? Although no hypothesis can ever be considered definitive, it is reasonable to speculate that, in the previously untreated setting, the depth of direct penetration of cisplatin into ovarian tumor nodules is quite limited, but that with each individual regional treatment the substantial concentrations of this highly active cytotoxic agent that reach the systemic circulation and subsequently the tumor itself by capillary flow will kill a major proportion of the tumorous mass. As a result, with each subsequent treatment the high local concentrations (10-20 times greater than present within the systemic compartment) will have an increasing potential to affect the smaller residual tumor volumes. This hypothesis, offered as a rational explanation for the clinical findings in the initial landmark phase III randomized trial whose outcome did not fit with the existing model for regional drug delivery, helps explain the demonstrated utility of IP cisplatin delivery in ovarian cancer even in the presence of known residual masses following primary cytoreductive surgery.

References

  1. Palumbo A, Facon T, Sonneveld P, et al. Thalidomide for treatment of multiple myeloma: 10 years later. Blood. 2008;111(8):3968-3977. doi: 10.1182/blood-2007-10-117457.
  2. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced nonsmall-cell lung cancer: results from a randomized placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005;366(9496):1527-1537. doi: 10.1016/S0140-6736(05)67625-8.
  3. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-smallcell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised phase 3 study. Lancet Oncol. 2011;12(8):735-742. doi: 10.1016/ S1470-2045(11)70184-X.
  4. Champiat S, Dercle L, Ammari S, et al. Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1. Clin Cancer Res. 2017;23(8):1920-1928. doi: 10.1158/1078-0432.CCR-16-1741.
  5. Kato S, Goodman A, Walavalkar V, et al. Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res. 2017;23(15):4242-4250. doi: 10.1158/1078-0432.CCR-16-3133.
  6. Markman M. Intraperitoneal antineoplastic drug delivery: rationale and results. Lancet Oncol. 2003; 4(5):277-283. doi: 10.1016/S1470- 2045(03)01074-X.
  7. Alberts DS, Liu PY, Hannigan EV, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med. 1996;335(26):1950-1955. doi:10.1056/NEJM199612263352603.