The ASCO Quick Six

11 minute read

So much data, so little time. Here’s a summary of six studies that could change your practice.

If you didn’t have the chance to get to Chicago this year, take 10 minutes to get a little familiar with some of the practice-changing results presented at this year’s ASCO meeting.

1. Prostate cancer – it’s a no for metformin

Metformin does not prevent progression of low or very low risk prostate cancer in people who were on watch-and-wait, and could be harmful, according to data presented at the American Society of Clinical Oncology in Chicago last month by Associate Professor Anthony Joshua, a medical oncologist at St. Vincent’s Hospital in Sydney.

The study involved 407 people across Canada diagnosed within six months prior to the start of the trial, with stage T1c-T2a, who were randomised 1:1 to receive 850mg metformin twice a day for three years, or placebo.

The difference between the study arms was not statistically significant, but those on metformin did not do as well, with a 7% higher risk of pathologic progression, a 75% higher risk of therapeutic progression, and an 8% combined risk.  

“In men who progressed with a Gleason score greater than eight, there was a trend to an imbalance in men who took metformin,” said Professor Joshua.

“The BMI and metformin did interact … men with a BMI greater than 30 had detriment to taking metformin.”

Professor Joshua said he had “only theories” for why this may be so.

There were also higher rates of GI symptoms in the metformin group – 18% had diarrhoea compared with 8% in the placebo group, and 14% had nausea, bloating and otherwise unspecified GI discomfort, compared to 3%. As expected, those in the metformin group lost weight.

“The key takeaway points again is that metformin does not prevent progression of low-risk, localised prostate cancer suitable for active surveillance,” said Professor Joshua.

Exploratory subgroup analyses indicate potential detriment to patients with a high BMI at study entry and patients who progressed with a high Gleason score at progression.”

2. Colorectal cancer – liver transplantation a new standard option

Liver transplantation and chemotherapy significantly improve survival compared with chemotherapy alone for patients with definitely unresectable colorectal liver metastases, and “offer a potential of cure,” said Professor Rene Adam, Head of Hepato Billiary Surgery at the Hôpital Paul Brousse in Paris, who presented the research.

“It seems to us that these results support liver transplantation plus chemotherapy as a new standard option that could change our practice in treating patients with liver-only, definitively unresectable colorectal liver metastases,” he said.

Liver resection is the best available treatment for this condition, but only 20% of patients are suitable. Chemotherapy could help reduce the size of marginally unresectable tumours and is standard of treatment for definitively unresectable patients but did not bring about long-term survival in this last group.

In this trial that took place in 20 centres and three countries, 94 patients under the age of 65 with definitively unresectable colorectal liver metastases were carefully selected and randomised 1:1 to receive either liver transplantation and chemotherapy or chemotherapy alone. Ultimately, 36 patients completed the experimental treatment, and 38 patients had the chemotherapy alone.

Five-year overall survival was 57% in the transplant plus chemo arm, versus 13% in the chemotherapy alone group.

“This difference was even more significant when we did a per-protocol analysis with a five-year survival of 73% versus only 9% in the chemotherapy-alone group,” said Professor Adam.

There was recurrence for 37 out of the 38 chemotherapy alone patients, and 26 out of the 36 patients who had a transplant and chemotherapy.

Three-year and five-year progression-free survival rates were, respectively, 33% in the transplant groups versus 4% in the standard treatment arm, and 20% versus 0%.

“The eligibility criteria were very strict– young patients; good performance status; confirmed unresectability of metastases by expert surgeon; gold standard resection of the primary; no extrahepatic disease; partial response, mainly, or stability with chemo for at least three months, with up to three lines of chemotherapy; no BRAF mutation; low CEA level; and adequate platelet and white blood cell count,” said Professor Adam.

Liver transplants were done within two months of the end of chemotherapy.

“These results were obtained through a rigorous patient selection and a prioritisation for organ allocation.”

3. HER2 positive breast cancer – How ultralow can you go?

Early treatment with trastuzumab deruxtecan demonstrates a statistically significant and clinically meaningful improvement in progression-free survival when compared to standard chemotherapy in patients with hormone receptor-positive HER2-low or HER2-ultralow metastatic breast cancer with prior endocrine therapy.

“DESTINY Brest06 establishes trastuzumab deruxtecan as an effective new treatment option,” said Professor Giuseppe Curigliano, medical oncologist and director of the Early Drug Development Division at the European Institute of Oncology in Milan, who presented the late-breaking primary results.

Data is not yet mature, but so far, at 18 months median follow-up, progression free survival for those treated with trastuzumab deruxtecan was 13 months versus eight months on the physician’s choice of chemotherapy. Her2-ultralow figures are consistent with overall results.

“This is for sure an unmet medical need because activity of treatment after CDK4/6 inhibitor is very poor. Median progression-free survival is seven months with alpelisib in the post-CDK4/6 inhibitor, is 5.5 months with capivasertib, and single-agent chemotherapy is no more than seven months,” said Professor Curigliano.

“Antitumor activity was really impressive. Overall response rate in intent-to-treat was 57.3% versus 31 in the chemotherapy arm, with 13 patients achieving a complete response, 237 a partial response.

“The clinical benefit rate was 76% in the intent-to-treat and 76% in the HER2 ultralow population.”

“Including HER2 ultralow, the proportion of patients who could benefit from trastuzumab deruxtecan will be close to 85% in HR positive, HER2-negative metastatic breast cancer.

Patients enrolled in the study (730 HER2 low and 153 HER2-ultralow) were randomised 1:1 to receive 5.4 mg/kg trastuzumab deruxtecan (436) or chemotherapy (430).”

The study targeted “a very special population,” said Professor Curigliano – HER2- low1+ and 2+ with /ISH nonamplified and HER2-ultralow.

“Today, we learned new data that tells us that we have to again change how we think about HER2 expression. Even very low levels of HER2 expression matter, and that can be leveraged to improve the treatment for our patients,” said Professor Ian Krop, Director of the Yale Cancer Center Clinical Trials Office, in commentary following the presentation.

Patients in the experimental arm were able to continue treatment for a median of 11 months compared with under six months in the placebo group.

Discontinuation in the trastuzumab deruxtecan was most commonly due to pneumonitis, and in the chemotherapy arm to peripheral sensory neuropathy. Nausea was very common for the former, and for those receiving chemotherapy, who mainly received capecitabine, it was palmar-plantar, erythrodysesthesia, or hand-foot syndrome.

Drug-related interstitial lung disease remains a consideration, occurring in 11.3% of the experimental group and 0.2% of the chemotherapy. It was, however, “very safe from a cardio-oncological point of view,” said Professor Curigliano.

4. Oesophageal adenocarcinoma – scales tipped to favour FLOT

In patients with adenocarcinoma of the oesophagus, perioperative chemotherapy (FLOT protocol) resulted in better survival than neoadjuvant chemoradiation (CROSS protocol).

ESOPEC found that perioperative chemotherapy with FLOT should be preferred over neoadjuvant chemoradiation with the CROSS protocol for improving survival in resectable oesophageal adenocarcinoma,” said presenter Professor Jens Hoeppner from the University of Bielefeld in Germany.

Median overall survival time was 66 months in the FLOT arm and 37 months in the CROSS arm in those who completed the protocol. The three-year overall survival rate was 57% for FLOT and 51% for CROSS. At five years it was 51% in the FLOT arm and 39% in the CROSS arm.

Median progression free survival was 38 months in the FLOT group versus 16 months in the CROSS group.  

The 438 patients from 25 sites in Germany – 90% male reflecting the disease distribution in the general population, median age of 63, with any node positive T stage or node negative stages cT2-cT4a – were randomised 1:1 to receive either FLOT (221) or CROSS (217). The FLOT group received four preoperative cycles of 5-FU, leucovorin, oxaliplatin, and docetaxel every two weeks, followed by surgery, and then four cycles of postoperative chemotherapy started four to six weeks after surgery.

The CROSS group received five weeks of preoperative radiation at a total dose of 41.4 gray, with weekly carboplatin and paclitaxel, followed by surgery and no postoperative adjuvant treatment.

Most study participants started on neoadjuvant treatment (207 FLOT, 196 CROSS) and surgery was performed in 191 of the FLOT group and 180 of the CROSS group. Complete resection was achieved in 351 patients (180 FLOT; 171 CROSS). At three months after surgery, 4.3% of those patients had died (3.2% FLOT; 5.6% CROSS).

After a median follow up of 4.5 years, 218 patients had died (97 FLOT; 121 CROSS).

From the 359 patients with available tumour regression status, 35 in the FLOT group and 24 in the CROSS groups achieved pathological complete response.

“During the course of ESOPEC, new approaches have entered the treatment landscape for oesophageal adenocarcinoma. Adjuvant immunotherapy following neoadjuvant chemoradiation and surgery in case of non-complete response has become a practice standard,” said Professor Hoeppner.

Organ preservation and active surveillance for clinical complete responders after chemoradiation is an emerging new concept. But despite promising initial studies, the impact of these approaches on overall survival is currently still unclear.”

5. Non-small cell lung cancer – longest progression free survival improvement ever reported

First line treatment with lorlatinib significantly improves progression free survival at five years compared with crizotinib in treatment-naïve patients with advanced ALK+ non-small cell lung cancer.

In fact, the median progression free survival has still not been reached for lorlatinib, while with crizotinib it was nine months at just over 4.5 years – so far, that’s an 80% lower risk of progression with lorlatinib.

“This PFS observed with first-line lorlatinib corresponds to the longest PFS reported in ALK positive lung cancer and, indeed, with any targeted therapy in advanced non-small cell lung cancer,” said Professor Ben Solomon, from the Peter MacCallum Cancer Centre in Melbourne, whose presentation was met with applause.

“The systemic efficacy results, coupled with protection from intracranial progression and the absence of new safety signals, indicates that first-line lorlatinib provides an unprecedented improvement in outcomes for patients with advanced ALK positive non-small cell lung cancer.”

At five years, 60% in the lorlatinib group had not progressed, compared to 8% in the crizotinib arm of the trial.

PFS benefit was seen in patients with brain metastases (HR 0.08) and without (HR 0.24).

“These results speak to the ability of lorlatinib, not only to prevent the progression of existing brain metastases, but to prevent the development of new brain metastases,” said Professor Solomon.

Grade 3 or 4 events were experienced by 77% of the lorlatinib group compared with 50% of the crizotinib patients, mainly because of triglyceride and cholesterol elevation, hypertension and weight gain.

“Given the utility of dose reductions as a tool to manage potential toxicities from lorlatinib, a post-hoc analysis was performed looking at efficacy in patients who had dose reductions during the first 16 weeks of treatment. In this analysis, dose reductions did not appear to affect efficacy in terms of progression-free survival or time to intracranial progression,” said Professor Solomon.

“After five years of follow-up in the CROWN study, the median progression-free survival with first-line lorlatinib has still not been reached with a 60-month landmark PFS of 60%. Time to intracranial progression was improved with a 92% probability of being free of intracranial progression with first-line lorlatinib.

“No new safety signals have emerged. Efficacy benefit was seen across all subgroups, including patients with poor prognostic biomarkers.”

6. Limited-stage small-cell lung cancer (SCLC) – first major advance in decades

Durvalumab consolidation treatment significantly increases survival in patients with LS-SCLC who have received prior concurrent chemoradiotherapy, according to findings presented by Dr David Spiegel, chief scientific officer at the Sarah Cannon Research Institute in Tennessee, US.

“Consolidation durvalumab will become the new standard of care for patients with limited stage small cell lung cancer who have not progressed after concurrent chemoradiotherapy,” said Dr Spiegel, whose presentation was interrupted several times by audience applause.

At just over three years median follow-up there was a nearly two-year improvement in median survival. Overall survival was 55.9 months compared to 33.4 months on placebo, with a 27% lower risk of death than with placebo.

And there was a median progression free survival time of 16.6 months compared to 9.2 months – an increase of around seven months and a reduction in risk of progression or death of 24%.

“The three-year landmark overall survival rates were 56.5% for durvalumab and 47.6% for placebo,” said Dr Spiegel.

“By way of background, there have been no major advances in the treatment of limited stage small cell lung cancer in several decades.

“The standard of care is concurrent chemoradiotherapy. But even with that, most patients will have cancer come back within two years, and a minority of patients will survive five years.”

The 730 patients in the ADRIATIC study had inoperable stage I-III LS-SCLC. They were randomised to receive either 1500mg of durvalumab intravenously, daily (264) or placebo (266) or a combination of durvalumab and tremelimumab (a third arm of the study to be reported later) for a maximum of two years, which was reached by around one-third of the durvalumab group and one-quarter of the placebo arm largely due to progression.

Both arms had nine cycles of therapy, and both arms had a grade 3/4 adverse event rate of 24%, leading to discontinuation in 16.4% of patients in the durvalumab group and 10.6% in the placebo arm.

Immune-mediated adverse events were seen in 5.3% of the durvalumab group and only 1.5% of the placebo arm. The most common toxicity was radiation toxicity, occurring at the same rate in both arms.

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