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Last Month in Oncology with Dr. Bishal Gyawali: April 2018

Last month was a month of good news, as we had many 'positive' trials announced at the American Association for Cancer Research (AACR) annual meeting. In most such big meetings, there is an optimistic atmosphere, although that doesn’t always translate to similar optimism in the clinic. However, I do hope that some of the big news from AACR 2018 translates to become important advances for cancer patients worldwide.

Non-stop progress in non-small cell lung cancer

Pembrolizumab has become the standard of care for first line treatment of NSCLC with PD-L1 positivity of 50% or more. Nivolumab as a monotherapy failed to improve outcomes in these patients when tested without any PD-L1 cut-off. However, pembrolizumab plus chemotherapy was an approved option on the basis of a previous phase 2 trial irrespective of PD-L1 status. The new phase 3 Keynote-189 trial tested pembrolizumab plus chemotherapy versus chemotherapy alone as a first line treatment of NSCLC patients irrespective of PD-L1 and showed meaningful improvements in overall survival with a hazard ratio of 0.49. However, as with all combination trials, we do not know if the combination is better than using pembrolizumab-chemotherapy in sequence. Since 40.3% patients from the chemo cohort seem to have received immunotherapy as a subsequent treatment, it would be very informative to see the efficacy data broken out for this group of patients. It would also be informative to test pembrolizumab plus chemotherapy against pembrolizumab alone.

Despite failure as a monotherapy, nivolumab was tried in first line NSCLC again, this time in combination with ipilimumab or chemotherapy and using a smarter predictive marker of tumour mutational burden. The PFS for nivolumab plus ipilimumab was better versus chemotherapy alone in high tumour mutational burden (>10 per megabase) tumours but not low tumour mutational burden patients. I do not foresee this result alone as being practice changing, because Keynote-189 showed improved OS using pembrolizumab plus chemotherapy across all patient populations.

All-around happy news in lung cancer, however, is that with the entry of immunotherapy, we are now able to talk about 5 year survival rates. A recent analysis has shown a 5-year survival rate of 16% among patients enrolled in a phase 1 nivolumab trial. The bad news is that there seem to be no predictive markers to identify who would belong to these “long term survivor” cohort. The good news is that the duration of treatment also doesn’t seem to matter much, so probably we can develop “non-inferiority” hypothesis studies testing, for example, a shorter duration of immunotherapy with better toxicity and financial toxicity profile. Only with greater sample will we be able to confidently say that there is a “tail effect” with immunotherapy in lung cancer, similar to what we previously observed with ipilimumab in melanoma.

Off the chart

The CHAARTED and STAMPEDE trials were truly game-changers in the treatment of prostate cancer, showing that the addition of chemotherapy (docetaxel) to androgen deprivation therapy substantially improved overall survival in hormone-naïve prostate cancer patients. Interestingly, the true gamechanger turned out to be a cheap chemotherapy. A new updated analysis shows, however, that this substantial improvement in OS is true only for high volume disease, and patients with low volume disease might not gain much with the addition of docetaxel upfront. This is therefore another nice example of “precision oncology”.  Long term follow up from STAMPEDE and other ongoing trials will confirm this finding as well as answer other questions in this setting including the role of abiraterone versus docetaxel in this setting.

Did Columbus discover America?

America already existed; Columbus and the rest of the world arrived late. Combination of BRAF and MEK inhibitors improve outcomes versus BRAF inhibitor alone in metastatic melanoma. This was already known, but the COLUMBUS trial arrived late to the party by showing that encorafenib plus binimetinib is better than vemurafenib alone in terms of progression free survival. Checking the trial enrollment dates revealed that the trial didn’t breach ethics by giving the control arm vemurafenib alone, since it took place when the data on superiority of combined BRAF plus MEK inhibition was not yet known.

Critical acclaim to the CRITICS trial

Conducting a phase 3 RCT is not easy. Conducting an investigator-initiated phase 3 RCT is more difficult. An investigator-initiated phase 3 RCT that takes 8 years to complete and answers one of the most important clinical questions in oncology deserves a round of applause. Most gastric cancer patients in the US and Europe reportedly receive preoperative chemotherapy but there is debate as to whether they should receive chemotherapy only or chemoradiotherapy postoperatively. The CRITICS trial now has an answer to that debate:

Postoperative chemoradiotherapy did not improve overall survival compared with postoperative chemotherapy in patients with resectable gastric cancer treated with adequate preoperative chemotherapy and surgery. In view of the poor postoperative patient compliance in both treatment groups, future studies should focus on optimising preoperative treatment strategies.”

I disagree with the last sentence though. The standard of care in Asian countries such as Japan and Korea is upfront surgery with adjuvant S-1 or capecitabine-oxaliplatin combination, without important adherence concerns. Also, the survival rates after gastric cancer are among the highest in the world in these countries. So, testing whether these strategies provide superior outcomes to the current perioperative approach for patients in the US and Europe the patients in the West could also be a focus of future research.

Let me take a selfie

In this blog, I have often written about survival gains with cancer drugs, and regulatory approval standards. Most oncologists believe that patients should be chemo-free at least in the last 6 months of their lives. However, regulators commonly approve expensive drugs that provide an overall survival of 6 months or fewer. In a new paper, Siroj Niraula and I explore the ethical challenges of caring for cancer patients in the last 6 months of their lives and discuss how a peaceful life-death transition should be an important metric of quality cancer care.

A final question to ponder

This interesting survey of patients with breast cancer in the US shows that black women experience significantly worse financial impact than white women after adjustment for age, stage at diagnosis, and treatment received. Financial toxicity is certainly high in low- and middle-income countries compared with high-income countries, but why is there such a discrepancy within the same country?

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

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