Still a long TRK

Encouraging results from the use of larotrectinib, a novel TRK inhibitor, among patients with TRK fusion positive solid tumours were presented in last year’s ASCO annual meeting and generated big discussions in the oncology community. The study has now been published and confirms that in the pooled analysis of a phase 1, a phase1-2, and a phase 2 trial across tumour types, larotrectinib produced a response rate of 75%, with median duration of response and progression free survival not reached after a median follow up 9.4 months. These data are very encouraging, but a few caveats must be kept in mind. First, although these data have been interpreted by some to conclude that the drug would produce response in any TRK-positive tumours, that’s not necessarily the case. For example, only one patient each with appendicular cancer and breast cancer were included in the trials and both didn’t respond. As with all precision oncology projects, biomarker validation remains a first critical step. Is the NGS based detection of TRK fusion the gold standard? Should the results be cross-validated with other assays? Will even biomarker-negative patients benefit via an as-yet-unexplained mechanism? Thus, although encouraging, there are miles to go (and studies to conduct) to address these unanswered questions.

The SPARTAN is meek on overall survival

Enzalutamide is an androgen receptor inhibitor approved for use in metastatic castration resistant prostate cancer. Apalutamide is a new drug (a me-too version of enzalutamide), which was tested in non-metastatic CRPC in the SPARTAN trial and showed impressive improvements in metastasis free survival with a hazard ratio of 0.28. However, overall survival, which was a secondary endpoint, is not mentioned in the Results section of the article, although it appears in table 2 and figure 2B. The secondary end points section of the results read:

“Apalutamide was associated with better results than placebo for all secondary end points (Table 2 and Figure 2, and Fig. S2 in the Supplementary Appendix). Time to metastasis, progression-free survival, and time to symptomatic progression were significantly longer with apalutamide than with placebo (P<0.001 for all comparisons)”

However it doesn’t mention anything about the overall survival where the P was 0.07. Also the supplementary appendix shows that only 28% of patients in placebo cohort received enzalutamide upon failure. If receiving enzalutamide (or apalutamide) upon metastasis would provide similar survival, one could question the need to drug all patients early on.
Enzalutamide has also been tested in this same setting and has shown similar benefits (PROSPER trial; unpublished yet). So I don’t doubt that drugs in this class delay the development of metastases. While patients may value metastasis-free survival, overall survival data is critical to know because knowing whether patients should expect the same duration of life would be a critical part of the conversation with patients about whether to receive enzalutamide (or apalutamide) upfront or upon observing metastasis.

My Oh Myeloma: A Practice-Changing Trial?

Multiple myeloma patients are already on a cocktail of medications. Bortezomib plus melphalan plus prednisone is now an established standard regimen for untreated myeloma patients ineligible for transplant. The ALCYONE trial tested if adding another drug (daratumumab) to this three-drug regimen would provide any added benefit, and concluded that it did. However, the benefit they describe is in progression-free survival (PFS). The overall survival curves are in the supplementary appendix and the curves for the experimental and control arms run collinear. Although I am no myeloma expert, shouldn’t we see survival benefit before adding a fourth and expensive drug to an already difficult-to-tolerate three-drug regimen? With my colleague Vinay Prasad, I have previously argued that at least for combination therapies, overall survival should be the gold-standard endpoint. Adding an extra active drug could add some time before disease progression, but if survival remains the same, the physical and financial toxicities to the patients becomes paramount.

It’s all academic

Sometimes, I hear the argument that most practice changing trials in oncology are industry-sponsored. I agree with that assertion with respect to new drug approvals, but not necessarily for non-drug trials and other practice informing trials conducted outside of the drug approval process. An important example of the latter is the FATA-GIM3 phase 3 RCT conducted with funding from the Italian Drug Agency. This trial answers an important clinical question in oncology: Of anastrozole, letrozole, and exemestane, which hormone therapy is the most efficacious as adjuvant treatment of endocrine positive breast cancer in postmenopausal women. They found that no option could be considered superior to any other (including that of tamoxifen followed by aromatase inhibitors), so patients should choose any based on their preferences, toxicities, and cost.
 

Precision adjuvant oncology?

I’ve lost count of the number of times a drug that improved overall survival in metastatic setting failed to do the same in the adjuvant setting. I thought that perhaps with the precision approach, this would change. BRAF inhibitors in BRAF positive melanoma is the poster child of success of precision approach to cancer treatment. Yet, even this promising biomarker-drug combination failed to impress in the adjuvant setting of melanoma treatment. The authors conclude in the abstract that “1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population.” I agree, because in the adjuvant setting, unlike metastatic disease, improvement in overall survival is a must because the only reason to ask a patient without tumour (adjuvant setting) to take a drug would be to improve survival! Although combination of a BRAF and MEK inhibitor did improve relapse-free survival in a previous study, overall survival was not significant and data on how many patients received BRAF plus MEK inhibitors upon relapse are unclear.

Let me take a selfie

I’ve since long been advocating for a parallel cancer groundshot to implement the strategies for cancer control that we already know work. Last month, we published this concept of “cancer groundshot” in The Lancet Oncology. Although it doesn’t sound as cool as moonshot, we hope that these strategies outlined under the cancer groundshot concept gain enough funds and resources so that we can save more lives by going global before going to the moon.

Dr. Gyawali is a medical oncologist from Nepal who is now working as a research fellow at Program on Regulation, Therapeutics and Law (PORTAL) at Brigham and Women’s Hospital. The opinions expressed herein are his own. You can read his previous blogs here.