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ASCO 2016 Review - Dr. Bruce Feinberg

June 2016

The theme for ASCO 2016 was Collective Wisdom: The Future of Patient-Centered Care and Research.

Spanning disciplines, disease sites and treatment approaches, it is our combined knowledge that will shape the future of patient care and research. The latest groundbreaking clinical data in both solid tumors and hematologic malignancies was presented at this year’s conference. Below are select potentially practice-changing abstracts grouped by tumor types with commentary by Dr. Bruce Feinberg, Vice President of Clinical Affairs and Chief Medical Officer of Cardinal Health Specialty Solutions.

For the “research nerds” among us, few things are more fun than picking the most significant abstract from the ASCO annual meeting. My provocative choice from this year’s research is abstract LBA11501: Somatic genomic landscape of over 15,000 patients with advanced-stage cancer from clinical next-generation sequencing analysis of circulating tumor DNA.  Follow my logic and see if you agree.

Biopsy specimens are problematic for many reasons:

  1. Adequate specimens can be difficult to obtain (e.g., lung).
  2. Specimens may be small and limit diagnostic studies (e.g., as many as one-third of non-small cell lung cancer (NSCLC) patients are not tested for EGFR/ALK mutations due to quantity not sufficient).
  3. Procedures have risk (liver, lung).
  4. Tumors are heterogeneous and specimens may not be representative.
  5. Serial biopsies are impractical for all the above reasons.
  6. Biopsy procedures are not performed by oncologists themselves (i.e., provenance over specimens in the hands of a hospital pathology lab limits the treating physician’s ability to direct and control testing, timing and lab, etc.).

Observations made a decade ago that even in local and regional tumors, cancer cells and their DNA may be found circulating in the blood raised the possibility that a new source of tumor from an easily obtained source (blood) may provide an alternative to tissue biopsy. If there were enough circulating tumor cells or an ability to identify and amplify circulating cell-free tumor DNA, then a host of possibilities emerges. Research conducted over the past decade has revealed the following:

  1. Circulating tumor cells and cell-free tumor DNA can be found in high frequency.
  2. DNA can be amplified, thus allowing meaningful testing on small (10cc) liquid specimens.
  3. The presence of circulating tumor cells and DNA in a localized cancer correlate with relapse risk and conversely, the absence of circulating tumor cells and DNA after treatment correlate with remission.
  4. Similar correlates of response are seen with metastatic tumors suggesting that circulating tumor cells and DNA reflect the clones of tumor most likely to threaten life and well-being.
  5. Proof of all these findings is achievable because serial testing is highly feasible.
 

Liquid Biopsy

Abstract LBA11501: Liquid biopsy shows excellent correlation with tissue biopsy in detecting somatic gene mutations in more than 15,000 patients with advanced solid tumors   

  • Test of interest: Guardant360 (by Guardant), a liquid biopsy test based on next-generation sequencing of circulating tumor DNA (ctDNA) targeting 70 genes.
  • Liquid biopsy studies to date have been limited to modest-size cohorts and case studies.
  • This large-scale study involves more than 15,000 patients with advanced solid tumors including lung cancer, breast cancer and colorectal cancer.
  • Among almost 400 patients with matching tissue molecular testing results available, the overall accuracy of ctDNA sequencing in comparison with matched tissue tests was 87 percent.
  • Liquid biopsy can detect mutations when insufficient tissue samples are available and can also monitor resistance mutations following active treatment in real time.
  • The maturation of liquid biopsy could provide an alternative to traditional tissue biopsy and help in moving the oncology field more toward the direction of precision medicine.
  • Other diagnostic companies that are also developing liquid biopsy test for cancer patients include Foundation Medicine and Grail.

The implications of this research are paradigm-changing in oncology. In the very near term, stage IV NSCLC patients can undergo diagnostics for targeted therapy with 10cc of blood drawn in the office. Migration from tissue-based diagnosis to cell-free DNA-based diagnosis may be just a few years away. If correlations between circulating cell-free tumor DNA and treatment response are confirmed and proven to be more sensitive than traditional imaging, we will then see that:

  1. The need for PET decreases markedly.
  2. Medical oncologists control the provenance of specimen and direct molecular diagnostics.
  3. Molecular diagnostics tests will be performed serially the way CT scan has been used for the past 20 years.
  4. Precision medicine leaps forward as its greatest impediment is removed.

The gauntlet is thrown. Can you make a case for a more impactful abstract? We welcome your thoughts. Please provide your feedback and include the rationale for your choice.

Just to be complete, here are my other finalists for the most significant abstracts from ASCO 2016:

 

Acute Myeloid Leukemia

Abstract 7000: Vyxeos significantly improves overall survival in older patients with newly diagnosed high-risk AML

  • Drug of interest: Vyxeos (by Celator), an investigational liposomal formulation of cytarabine and daunorubicin currently under phase III development in AML.
  • Recently, it was announced that Jazz Pharmaceuticals is going to acquire Celator.
  • Orphan drug status, fast track status, and Breakthrough Therapy designation was granted to Vyxeos for this indication.
  • The phase III 301 trial of Vyxeos vs. standard chemotherapy in older patients with newly diagnosed high-risk AML met its primary endpoint of overall survival (median 9.56 months vs. 5.95 months; HR=0.69; P=0.005).
  • Grade 3-5 adverse events were similar in both arms.
  • Based on results from this trial, Celator is expected to submit an NDA for Vyxeos to the FDA in Q3 2016 and estimated approval date in Q3 2017.
  • If approved, Vyxeos would address an unmet need in the treatment of elderly secondary AML patients who typically have a poor response to standard first-line therapy and become a standard of care in this setting.
Liposomal drug reformulation is certainly not novel science. Although Vyxeos consists of drugs first synthesized 30 years ago, a near doubling of median overall survival is significant, which makes Vyxeos a drug with a bright future and likely expanded indications beyond AML in elderly patients.
 

Bladder Cancer

Abstract LBA4500: Tecentriq demonstrates meaningful activity in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma

  • Drug of interest: Tecentriq (atezolizumab; by Genentech), a PD-L1 antibody that recently gained accelerated approval for treating locally advanced or metastatic urothelial carcinoma after platinum-based chemotherapy.
  • The approval was based on response rates and duration of response from the pivotal phase II IMvigor210 trial.
  • Tecentriq became the first PD-L1 antibody approved for any indication.
  • Genentech is also evaluating Tecentriq in a confirmatory phase III IMvigor211 trial that is expecting top-line results by the end of 2016.
  • This abstract showed that Tecentriq resulted in durable responses irrespective of PD-L1 expression level in first-line cisplatin-ineligible patients.
  • These results could encourage the use of Tecentriq as first-line treatment in cisplatin-ineligible patients, which is outside of its current FDA label.
  • A separate phase III trial (IMvigor010) is investigating Tecentriq as adjuvant therapy in bladder cancer with results expected in 2019.
  • Other PD-1/PD-L1 antibodies under phase III investigation in bladder cancer include avelumab (by Pfizer), durvalumab (by AstraZeneca), Keytruda (pembrolizumab; by Merck), and Opdivo (nivolumab; by BMS).
Is there any malignancy for which immuno-oncology (IO) doesn’t work? Urothelial tumors have seen almost no progress in a decade but based on these results, I expect that IO-based treatment will be a standard of care in the very near future.
 

Breast Cancer

Abstract LBA1: Extending hormonal treatment to 10 years significantly improves disease-free survival in women with HR+ early-stage breast cancer

  • Drug of interest: Femara (letrozole; by Novartis), an aromatase inhibitor approved for treating breast cancer in 1997 whose patent expired in 2011. 
  • In postmenopausal women with HR+ early-stage breast cancer, five years of aromatase inhibitor (AI) therapy is the current standard of care.
  • Here, results from the phase III MA.17R trial conducted in Canada demonstrated that extending AI therapy using letrozole from five years to 10 years significantly prolonged disease-free survival (DFS) in HR+ early-stage breast cancer (five-year DFS rate: 95 percent vs. 91 percent; HR=0.66; p=0.01).
  • However, the five-year overall survival rate was similar (93 percent vs. 94 percent).
  • Although DFS was improved with extended AI therapy, further analyses are needed to provide a comprehensive picture of toxicities and patient quality of life.
  • Since generic letrozole is available, cost of therapy is not an issue. The adoption of this new approach will depend on the assessment of overall benefit/risk ratio by oncologists for their individual patients.
We have definitive proof that 10-year adjuvant hormonal therapy is better than five. What is worrisome is similar proof that a significant percent of patients are non-compliant with the current five years of therapy. Medication therapy management to address persistence, compliance and adherence will be critical to realizing the full benefit of extended therapy.

Abstract 510: Abemaciclib monotherapy demonstrates promising activity in heavily pretreated HR+/HER2- metastatic breast cancer

  • Drug of interest: abemaciclib (Eli Lilly), an investigational CDK 4/6 inhibitor currently under phase III development in breast cancer and non-small cell lung cancer.
  • One of the four drugs granted Breakthrough Therapy designation in metastatic breast cancer (MBC).
  • This phase II trial (MONARCH1) showed an ORR of 20 percent (median duration: 8.6 months), clinical benefit rate of 42 percent, median PFS of 6.0 months, and median OS of 17.7 months in patients with heavily pretreated HR+/HER2- MBC. 
  • Safety profile of abemaciclib was consistent with previous experience (diarrhea, fatigue and neutropenia are the main toxicities).
  • Two phase III trials (MONARCH2 and MONARCH3) of abemaciclib combined with fulvestrant or an aromatase inhibitor as first-line treatment of HR+/HER2- MBC are ongoing with interim data expected later this year.
  • If approved, abemaciclib will compete directly with Ibrance (palbociclib; by Pfizer) in this disease setting. The other CDK4/6 inhibitor to watch for is ribociclib by Novartis, which is also under phase III investigation in HR+/HER2- MBC.
To some extent, oncologists have been too complacent with HR+/HER2- MBC. We need to be reminded that what we considered the good kind of MBC has a median PFS in first line of 10 months and a median OS of just a few years. It’s time for better therapy for this significant patient subset.
 

Kidney Cancer

Abstract 4506: Cabometyx demonstrates a five-month improvement in median OS compared to Afinitor in patients with pretreated advanced renal cell carcinoma

  • Drug of interest: Cabometyx (cabozantinib; by Exelixis), a multi-targeted tyrosine kinase inhibitor recently approved for treating advanced renal cell carcinoma (RCC) after prior anti-angiogenic therapy.
  • The approval was based on results from the phase III METEOR trial showing significant benefit of Cabometyx compared to Afinitor in patients with pretreated advanced RCC.
  • To be noted, Cabometyx has a different formulation from Cometriq (tablets vs. capsules), which was approved in thyroid cancer.
  • Here, final OS results from the METEOR trial showed a five-month improvement in median OS (21.4 months vs. 16.5 months; HR=0.67; P=0.0003).
  • Cabometyx will compete directly with Opdivo (nivolumab; by BMS) and Lenvima (lenvatinib; by Eisai), which were also approved recently for the same indication.
  • In contrast to Opdivo, which only demonstrated an OS benefit with no PFS benefit, Cabometyx significantly prolonged both OS and PFS.
  • Whereas both Cabometyx and Opdivo were approved as single agents, Lenvima was approved as combination therapy with Afinitor.
Like Batman vs. Superman, the titans of oncolytics do battle, as targeted therapies challenge IO for cancer treatment strategy dominance. IO has been landing more punches in recent years but one is given pause when a clinical trial demonstrates statistical significance for ORR, PFS and OS, a feat that IO can’t claim.
 

Melanoma

Abstract 9500: Binimetinib demonstrates robust PFS benefit in NRAS+ metastatic melanoma 

  • Drug of interest: Binimetinib (by Array); an investigational MEK inhibitor under phase III development in NRAS+ metastatic melanoma.
  • NRAS mutations occur in approximately 15-20 percent of patients with metastatic melanoma and currently there are no agents approved in this patient population.
  • Here, results from the phase III NEMO trial of binimetinib vs. dacarbazine in NRAS+ metastatic melanoma showed a significant improvement in median PFS (2.8 months vs. 1.5 months; HR=0.62; P<0.001).
  • In patients pretreated with immunotherapy, median PFS was 5.5 months and 1.6 months, respectively (HR=0.46).
  • Based on these results, Array is planning to file an NDA for binimetinib in NRAS+ metastatic melanoma before the end of June 2016.
  • Given the unmet need, binimetinib is likely to gain FDA approval for treating NRAS+ metastatic melanoma. Although binimetinib would be the third MEK inhibitor on the market for treating metastatic melanoma, its label would allow differentiation from the other two MEK inhibitors (Mekinist [by Novartis] and Cotellic [by Genentech/Exelixis]), which are indicated in BRAF+ patients.
The expanding arsenal of targeted therapies in melanoma highlights the confrontation between IO and precision medicine. Is the IO tail of the curve too tantalizing to relegate it to later-line therapy, even if targeted agents have higher ORR and longer median PFS? It appears that molecular diagnostics are desperately needed to identify likely IO durable responders.
 

Multiple Myeloma

Abstract LBA4: The addition of Darzalex to Velcade/dexamethasone significantly improves PFS in relapsed/refractory multiple myeloma

  • Drug of interest: Darzalex (daratumumab; by Janssen), a CD38 antibody that was granted accelerated approval in November 2015 in heavily pretreated multiple myeloma (MM) patients based on the phase II SIRUS trial.
  • Since its approval, Darzalex has been enjoying rapid adoption in the myeloma community.
  • During the plenary session, results from the phase III CASTOR trial of Darzalex plus Velcade (bortezomib; by Takeda)/dexamethasone vs. Velcade/dexamethasone in relapsed/refractory MM were presented.
  • Adding Darzalex to Velcade/dexamethasone showed unprecedented PFS benefit (HR=0.39) as well as significant improvement in time to progression and ORR.
  • Darzalex is currently being examined in several other phase III trials as combination therapy besides CASTOR.
  • The phase III POLLUX trial of Darzalex plus Revlimid /dexamethasone vs. Revlimid/dexamethasone alone in relapsed/refractory MM also met its primary endpoint of PFS according to a recent press release.
  • These positive results from two pivotal trials should lead to full approval of Darzalex and its advancement earlier into the treatment paradigm of MM, where it will compete with other newly approved agents.
  • The key question will be how to sequence therapies in MM given the ever-growing treatment options.
 

Non-Small Cell Lung Cancer

Abstract 3001: Opdivo/Yervoy combination demonstrates promising activity as first-line treatment in metastatic NSCLC 

  • Drugs of interest: Opdivo (nivolumab; by BMS) and Yervoy (ipilimumab; by BMS).
  • Opdivo and Yervoy are both approved in metastatic melanoma either as single agents or in combination. Opdivo is also indicated for treating metastatic NSCLC as a single-agent second-line therapy.
  • Here, results from the phase I CheckMate-012 trial demonstrated clinical activity and a manageable safety profile of Opdivo/Yervoy in first-line metastatic NSCLC.
  • Across different cohorts, ORRs ranged from 13 to 39 percent and median duration of response was not reached.
  • Currently, there are two ongoing phase III trials investigating Opdivo in first-line metastatic NSCLC: CheckMate-026 (Opdivo single agent vs. chemotherapy) and CheckMate-227 (Opdivo with or without Yervoy vs. chemotherapy).
  • Top-line results from CheckMatge-026 are expected in Q3 this year and those from CheckMate-227 are expected to be available in 2018.
The results of these two trials are making heads spin – not only because of the clinical outcomes but the realization that combinations of new targeted and/or immunologic drugs create costs of treatment that were unconceivable just a few years ago. Whether Darzalex + Velcade or Opdivo + Yervoy, these highly clinically effective combination therapies have price-tags that the market may not be able to bear.

Abstract 9007: Brigatinib demonstrates substantial efficacy in patients with ALK+ metastatic NSCLC who progressed on Xalkori 

  • Drug of interest: Brigatinib (by Ariad), an investigational next-generation ALK tyrosine kinase inhibitor under phase III development in ALK+ metastatic NSCLC.
  • Brigatinib was granted a Breakthrough Therapy Designation in October 2014.
  • Here, results from the phase II ALTA trial of brigatinib in patients with ALK+ metastatic NSCLC who progressed on Xalkori demonstrated an ORR of 54 percent and intracranial response rate of 67 percent, which compares favorably to other second-generation ALK inhibitors on the market.
  • Based on these results, Ariad is planning to file an NDA for brigatinib in Q3 2016.
  • If approved, brigatinib will compete directly with Zykadia (ceritinib; by Novartis) and Alecensa (alectinib; by Genentech).
  • Besides, Ariad just initiated a phase III head-to-head trial of brigatinib vs. Xalkori in first-line ALK+ metastatic NSCLC.

Abstract 9008: Alecensa demonstrates significantly prolonged PFS compared to Xalkori as first-line treatment in Japanese patients with ALK+ metastatic NSCLC

  • Drug of interest: Alecensa (alectinib; by Genentech), an ALK tyrosine kinase inhibitor that was recently approved in second-line ALK+ metastatic NSCLC following Xalkori.
  • Here, the phase III J-ALEX trial showed a very significant PFS benefit (HR=0.34) in Japanese patients with ALK+ metastatic NSCLC who received Alecensa compared to those receiving Xalkori as first-line treatment.
  • Overall, Alecensa’s safety profile was more tolerable compared to Xalkori.
  • These results should help position Alecensa for future first-line label expansion in ALK+ metastatic NSCLC.
  • Genentech is planning to file an sNDA for Alecensa in the first-line setting in 2017 after results from the separate phase III ALEX trial (same trial design as J-ALEX; conducted outside of Japan) become available later this year.
  • Given the J-ALEX results, it will be interesting to see whether oncologists would elect to use Alecensa as first-line treatment even before its label expansion.
The number of agents available now, or coming soon, to treat 3 to 5 percent of NSCLC patients, half of whom may not even be identified by molecular diagnostics for the myriad reasons discussed in my liquid biopsy commentary, is mind-boggling and begs for clinical pathways and/or value-based care tools to aid treating physicians in the one or two patients per year they will treat.
 

Pancreatic Cancer

Abstract LBA4006: Adding capecitabine to gemcitabine significantly improves overall survival in patients with resected pancreatic cancer 

  • Drugs of interest: Gemzar (gemcitabine; by Eli Lilly) and Xeloda (capecitabine; by Roche).
  • Gemzar was approved for treating pancreatic cancer in 1996; its patent expired in 2009. Xeloda, which also faces generic competition, was approved in breast cancer and colorectal cancer but not in pancreatic cancer.
  • Currently, gemcitabine is the standard of care as adjuvant therapy in resected pancreatic cancer.
  • Here, results from the phase III ESPAC-4 trial conducted in Europe demonstrated that adding capecitabine to gemcitabine significantly prolonged overall survival in resected pancreatic cancer (median: 28.0 months vs. 25.5 months; HR=0.82; p=0.032).
  • There were no significant differences in grade 3/4 adverse events between the arms.
  • Based these results, capecitabine/gemcitabine combination adjuvant therapy could become a new standard of care in patients with resected pancreatic cancer.

Abstract 6561: Adding Abraxane to gemcitabine is more efficacious in locally advanced or metastatic pancreatic cancer in real-world setting

  • Drug of interest: Abraxane (protein-bound paclitaxel; by Celgene), a nanoparticle albumin-bound formulation of paclitaxel currently approved in pancreatic cancer, breast cancer and non-small cell lung cancer.
  • The approval in pancreatic cancer was based on results from the phase III MPACT trial showing that adding Abraxane to gemcitabine improves both OS and PFS in first-line metastatic pancreatic cancer (mPC).
  • There are no clinical trials that directly compare the efficacy of Abraxane plus gemcitabine, FOLFIRINOX (a commonly used chemotherapy regimen in mPC), and gemcitabine alone.
  • This study using real-world data from British Columbia in Canada showed that both FOLFIRINOX and Abraxane/gemcitabine confers greater effectiveness over gemcitabine alone in real-world setting as measured by OS and PFS.
  • In the absence of randomized trials comparing all three regimens, real-world data can provide evidence on the effectiveness of different regimens.
  • Also to be noted, Abraxane plus gemcitabine is being examined in the phase III APACT trial as an adjuvant treatment with initial results expected in 2017.

As an oncologist, my three most dreaded cancers were glioblastoma (GBM), melanoma and pancreatic cancer. In the past few years, breakthroughs in GBM and melanoma were giving me reasons for hope. Although there is much to be done, now pancreatic cancer can be added to the list of dreaded cancers that are finally seeing therapeutic progress.

 

Think there was a more significant abstract? Let us know.

 
 
 
 
   

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