Experts Take Stock of ASCO Research

Oncology Live®, Vol. 17/No. 14, Volume 17, Issue 14

Experts identify practice-changing or noteworthy abstracts in their field from the research presented at the 2016 ASCO Annual Meeting.

GASTROINTESTINAL CANCER

Robert J. Mayer, MD

Dana-Farber Cancer Institute

Pancreatic Cancer

OncologyLive invited several experts to identify practice-changing or noteworthy abstracts in their field from the research presented at the 2016 ASCO Annual Meeting, held June 3-7 in Chicago. Their insights are presented here, along with a list of notable immunotherapy research developed by the Society for the Immunotherapy of Cancer. Full abstracts are available at the American Society of Clinical Oncology website, meetinglibrary.asco.org. ESPAC-4: A multi-center, international, open label randomized controlled phase III trial of adjuvant combination chemotherapy of gemcitabine (GEM) and capecitabine (CAP), versus monotherapy gemcitabine in patients with resected pancreatic ductal adenocarcinoma. Abstract LBA4006.

The administration of 6 months of adjuvant gemcitabine chemotherapy has been shown to prolong survival in patients with pancreatic cancer; gemcitabine and 5-fluorouracil were shown to be equally effective when administered in the adjuvant setting.

In the ESPAC-4 study, 730 patients who had undergone a complete macroscopic resection of a pancreatic adenocarcinoma were randomly assigned to receive gemcitabine or a combination of gemcitabine and capecitabine.

Checkpoint Inhibitors

The gemcitabine/capecitabine combination proved to be statistically superior in terms of median (28.0 months vs 25.5 months) and estimated 5-year (28.8% vs 16.3%) overall survival, and may be considered as a new standard of care.Two abstracts addressed the efficacy of checkpoint inhibitors in patients with microsatellite unstable metastatic colorectal cancer:

Programmed death-1 blockade in mismatch repair deficient colorectal cancer. Abstract 103.

This abstract provides mature data from a phase II trial in which the clinical activity of the anti-PD-1 antibody pembrolizumab was compared in 28 patients with mismatch repair-deficient colorectal cancers to that in 25 patients with mismatch repair-proficient colorectal cancers.

Pembrolizumab therapy resulted in an objective response rate of 57% in the patients with mismatch repair-deficient tumors versus 0% in the patients with mismatch repair—proficient tumors. Remarkably, the responses in the mismatch repair-deficient patients have been durable with the median overall survival time not having been reached and five patients continuing to respond at the 2-year mark.

Nivolumab +/- ipilimumab in treatment (TX) of patients (pts) with metastatic colorectal cancer (mCRC) with and without high microsatellite instability (MSI-H); CheckMate-142 interim results. Abstract 3501.

Colorectal Cancer

In this phase II trial, 47 previously treated patients with metastatic microsatellite unstable colorectal cancers were given monotherapy with the PD-1 inhibitor nivolumab while 27 similar patients were given both nivolumab and the anti-CTLA-4 antibody ipilimumab. The monotherapy cohort experienced a 26% response rate with 46% of patients remaining free of disease progression after 6 months. The patients given combination immunotherapy experienced a 33% response rate with 67% remaining free of progression after 6 months. Only 10% of 20 patients with previously treated microsatellite-stable colorectal cancers who were given the combined immunotherapy experienced a response.Three abstracts assessed the impact of primary tumor sideness and outcome in colorectal cancer:

The relationship between primary tumor sideness and prognosis in colorectal cancer. Abstract 3505.

Prior observations have suggested that patients having colon cancers arising from the right colon have a poorer prognosis than those whose tumors arise in the left colon. This finding was confirmed through a SEER data analysis dealing with 64,770 patient with colon cancer whose disease was diagnosed between 2000 and 2012, showing that patients with metastatic disease whose tumors arose in the right colon experienced an absolute 6% poorer survival outcome than those whose tumors arose in the left colon, leading to a 32% greater likelihood of death.

Impact of primary (10) tumor location on overall survival (OS) and progression free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance). Abstract 3504.

In this 1137 patient multi-institutional cooperative group trial, patients with metastatic KRAS wild-type colorectal cancer were randomized to receive chemotherapy with cetuximab or with bevacizumab.

A median overall survival of 19.4 months was reported for patients with right-sided lesions versus 33.3 months for those with left-sided lesions. The median survival (right-sided vs left-sided) for patients receiving cetuximab was 16.7 months versus 36.0 months while for patients receiving bevacizumab, it was 24 months versus 31 months.

It was proposed that “sideness” represents a surrogate for tumor biology, with further analyses of biospecimens likely to identify the responsible biomarkers.

Association of primary (10) site and molecular features with progression-free survival (PFS) and overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor (aEGFR) therapy. Abstract 3506.

In this single-institution study, 198 patients with metastatic KRAS wild-type colorectal cancer had their tumors analyzed for microsatellite instability, NRAS, BRAF, hypermethylation, and gene expression patterns. Right-sided tumors were associated with an inferior overall survival compared with left-sided tumors, were found to have a greater likelihood of having poor prognostic biomarkers such as a BRAF mutation and hypermethylation, and were also associated with a different gene expression profile than left-sided tumors.

When multivariate analysis was performed, the “sideness” (right vs left) was no longer significant, being replaced by the molecular/genomic patterns.

BREAST CANCER

Joyce A. O’Shaughnessy, MD

Texas Oncology-Baylor Charles A. Sammons Cancer Center

A randomized trial (MA.17R) of extending adjuvant letrozole for 5 years after completing an initial 5 years of aromatase inhibitor therapy alone or preceded by tamoxifen in postmenopausal women with early-stage breast cancer. LBA1.

The long-awaited MA.17R trial showed about a onethird reduction in the risk of recurrence in the patients who were randomized to continue on letrozole after 5 years of tamoxifen and 5 years of letrozole.

These are the first data showing that continuing aromatase inhibitor beyond 5 years is of benefit. The MA.17R findings are truly practice-changing data and we’ll be continuing endocrine therapy for at least 5 years in our node-positive and high-risk node-negative patients. The women who made it through the MA.17 trial were used to aromatase inhibitor—related toxicity. There is an accommodation to the therapy that happens over time. The only toxicity with continuing letrozole is largely preventable increased bone fracture risk. It wasn’t dramatic, and nothing else has come up such as cardiovascular risk.

Predictors of recurrence during years 5-14 in 46,138 women with ER+ breast cancer allocated 5 years only of endocrine therapy (ET). Abstract 505.

The Oxford University analysis looked at risk of recurrence for years 5 through 20 following 5 years of endocrine therapy. This showed a considerable risk of recurrence between years 5 and 20 for patients that was relentless. That is a very important dataset that helps us understand how to talk to women about what their risk is for distant recurrence after they finish their 5 years of endocrine therapy. It’s the largest natural history study that we have.

Heritage: a phase III safety and efficacy trial of the proposed trastuzumab biosimilar Myl-1401O versus Herceptin. LBA503.

This study is in first-line metastatic breast cancer with trastuzumab plus a taxane. The endpoint was the percentage of patients who were progressionfree at 6 months. Basically, the two agents were of superimposable efficacy and safety, and that included response rate.

The only limitation is that the study only followed patients 6 months. Women with HER2-positive metastatic breast cancer live a long time. You would like to see longer follow-up to be sure that there is equal efficacy longer term. We will wait and see whether the FDA licenses the drug just for the metastatic setting or for the other breast cancer labelled indications for trastuzumab as well. It was quite reassuring that the data looked superimposable.

PALOMA-2: Primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2— advanced breast cancer (ABC). 507.

This study corroborated the PALOMA-1 trial results for patients with ER-positive, HER2-negative advanced or metastatic breast cancer. The benefit with palbociclib plus letrozole was 24.8 months versus 14.5 months for letrozole alone, a very nice 10-month improvement in progression-free survival. There were no new safety signals with palbociclib.

No surprises. It’s definitely the standard of care for first-line metastatic disease in this setting.

Interim joint analysis of the ABC (anthracyclines in early breast cancer) phase III trials (USOR 06-090, NSABP B-46I/USOR 07132, NSABP B-49 [NRG Oncology]) comparing docetaxel + cyclophosphamide (TC) v anthracycline/taxane-based chemotherapy regimens (TaxAC) in women with high-risk, HER2-negative breast cancer. Abstract 1000.

The trial failed to show that TC was equivalent to the anthracycline-based regimen. The anthracycline regimen had a superior disease-free survival. In the triple-negative patients, the difference was even larger in favor of the anthracycline-based regimen. In the estrogen receptor (ER)—positive, node-positive population, Tax/AC was superior to TC. There was no apparent difference in the two regimens for ER-positive, node-negative patients.

Definitely for the triple-negative population and higher risk ER-positive patients, a three-drug anthracycline- based regimen remains the standard of care for early-stage breast cancer. Follow-up biomarker studies will try to sort out populations who don’t need anthracycline. It is helpful to know the node-negative, ER-positive population did not benefit from the anthracycline.

Pathologic complete response (pCR) rates after neoadjuvant trastuzumab emtansine (T-DM1 [K]) + pertuzumab (P) vs docetaxel + carboplatin + trastuzumab + P (TCHP) treatment in patients with HER2-positive (HER2+) early breast cancer (EBC) (KRISTINE). Abstract 500.

The neoadjuvant TCHP did achieve a superior pathological complete response (pCR) rate and also a higher breast-conserving surgery rate. The pCR rate in the breast and lymph nodes with the TCHP was 56% versus 44% with T-DM1 plus pertuzumab—and that was statistically significant. It was impressively different in the ER—negative group; there was a pCR of 73% with TCHP versus 54% with T-DM1 and pertuzumab—almost a 20% difference. T-DM1 plus pertuzumab did have a more favorable safety profile.

These data suggest that selective patients could benefit from T-DM1 plus pertuzumab. Fifty-four percent of patients did benefit in the ER-negative group. If we could find out who those patients are, it could spare some patients toxicity, but right TCHP is the superior regimen abd the standard of care.

MELANOMA

Jeffery S. Weber, MD, PhD

Perlmutter Cancer Center, NYU Langone Medical Center

Extended follow-up results of a phase 1B study (BRIM7) of cobimetinib (C) and vemurafenib (V) in BRAF-mutant melanoma. Abstract 9510.

This study provides more long-term follow-up data for the combination of vemurafenib and cobimetinib, and shows an outstanding 31+ month median overall survival for BRAF inhibitor—naïve patients.

Genomic analysis and 3-y efficacy and safety update of COMBI-d: a phase 3 study of dabrafenib (D) + trametinib (T) vs D monotherapy in patients (pts) with unresectable or metastatic BRAF V600E/Kmutant cutaneous melanoma. Abstract 9502.

This work suggests that BRAF V600K—expressing tumors have a much higher mutational load, indicating that they may express more mutated neoantigens and thus be more appropriate for immunotherapy with checkpoint inhibition.

Pembrolizumab (pembro) plus ipilimumab (ipi) for advanced melanoma: results of the KEYNOTE- 029 expansion cohort. Abstract 9506.

This work confirms the excellent response rate for combined ipilimumab and PD-1 inhibition using a second PD-1 antibody, pembrolizumab, and suggests that with a lower dose of ipilimumab the toxicity with grade 3-4 immune-related adverse events might be less at 20%.

Results of NEMO: A phase III trial of binimetinib (BINI) vs dacarbazine (DTIC) in NRAS-mutant cutaneous melanoma. Abstract 9500.

These data provide the first evidence of clinical benefit for a MEK inhibitor versus chemotherapy in a phase III trial of second-line treatment of patients with NRAS-mutated melanoma, with increase in response, progression-free survival, and OS for the MEK drug compared with chemotherapy.

Three-year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Abstract 9503.

These data provide the first long-term survival data with pembrolizumab in a predominantly second-line setting either after ipilimumab or before, with excellent 3-year survivals of 38% to 45%.

GENITOURINARY CANCERS

Maha H. Hussain, MB ChB

University of Michigan Comprehensive Cancer Center

  • Atezolizumab (atezo) as first-line (1L) therapy in cisplatin-ineligible locally advanced/metastatic urothelial carcinoma (mUC): Primary analysis of IMvigor210 cohort 1. LBA4500.
  • Randomized phase II study of AKT blockade with ipatasertib (GDC-0068) and abiraterone (Abi) vs. abi alone in patients with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel chemotherapy (A. MARTIN Study). Abstract 5017.
  • Updated efficacy and >1-y follow up from IMvigor210: Atezolizumab (atezo) in platinum (plat) treated locally advanced/metastatic urothelial carcinoma (mUC). Abstract 4515.
  • Overall survival (OS) in METEOR, a randomized phase 3 trial of cabozantinib (Cabo) versus everolimus (Eve) in patients (pts) with advanced renal cell carcinoma (RCC). Abstract 4506.
  • A randomized trial of a shorter radiation fractionation schedule for the treatment of localized prostate cancer. Abstract 5003.
  • Cabazitaxel vs docetaxel in chemotherapy-naïve (CN) patients with metastatic castration-resistant prostate cancer (mCRPC): A three-arm phase III study (FIRSTANA). Abstract 5006.
  • Phase III non-inferiority study of cabazitaxel (C) 20 mg/m2 (C20) versus 25 mg/m2 (C25) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel (D). Abstract 5008.

IMMUNOTHERAPIES

The Society for Immunotherapy of Cancer (SITC)

SITC, whose members have been leading the development of the modality for more than 30 years, summarized notable abstracts from the 2016 ASCO Annual Meeting in two newsletters available at www.sitcancer.org. Highlighted abstracts include the following:

  • Three-year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Abstract 9503.
  • Avelumab (MSB0010718C; anti-PD-L1) in patients with metastatic Merkel cell carcinoma previously treated with chemotherapy: results of the phase 2 JAVELIN Merkel 200 trial. Abstract 9508.
  • Further evaluations of nivolumab (nivo) versus investigator’s choice (IC) chemotherapy for recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): CheckMate 141. Abstract 6009.
  • Biomarkers and response to pembrolizumab (pembro) in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Abstract 6010.
  • Preliminary results from KEYNOTE-055: Pembrolizumab after platinum and cetuximab failure in head and neck squamous cell carcinoma (HNSCC). Abstract 6011.
  • Efficacy and safety of pembrolizumab in recurrent/ metastatic head and neck squamous cell carcinoma (R/M HNSCC): pooled analyses after long-term follow-up in KEYNOTE-012. Abstract 6012.
  • Randomized, phase II dose optimization study of chimeric antigen receptor (CAR) modified T cells directed against CD19 in patients (pts) with relapsed, refractory (R/R) CLL. Abstract 3009.
  • Anti-CD19 chimeric antigen receptor T cells preceded by low-dose chemotherapy to induce remissions of advanced lymphoma. LBA3010.
  • Safety of pembrolizumab in combination with bevacizumab in recurrent glioblastoma (rGBM). Abstract 2010.
  • Phase 3 randomized controlled study of daratumumab, bortezomib and dexamethasone (DVd) vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma (RRMM): CASTOR. LBA4.
  • Atezolizumab (atezo) as first-line (1L) therapy in cisplatin-ineligible locally advanced/metastatic urothelial carcinoma (mUC): primary analysis of IMvigor210 cohort 1. LBA4500.
  • Phase Ib study of PF-05082566 in combination with pembrolizumab in patients with advanced solid tumors. Abstract 3002.