Jonathan Alicea

Amultihistology basket study proved the targetability of the

mutation in human cancers by treating patients with various types of cancer harboring an

mutation with AZD5363, an oral pan-AKT inhibitor, according to findings published in the

The PI3K/AKT pathway is one of the most frequently activated pathways across cancers and can be triggered by one of several mutations.

mutation can be found in many cancer types, they nonetheless occur at a relatively low prevalence in individual tumor lineages despite being the most common

mutation. The oncogenic nature of these gain-of-function mutations means they can be targeted with an AKT inhibitor in the hopes of improving patient outcomes.

The safety and efficacy of the AKT inhibitor had previously been investigated in patients with

-mutant estrogen receptor (ER)-positive breast cancer, HER2-positive breast cancer, or gynecologic cancers. Three of 51 patients experienced a partial response, and the optimal dose and schedule for AZD5363 was set.

mutations, 58 heavily pretreated patients were enrolled to receive 480 mg twice daily of AZD5363 on a 21-day cycle for 4 days followed by 3 days off, repeated weekly.

Of the enrolled patients, 52 showed expression of an E17K mutation, 2 patients had an

mutation; one patient had an undetectable mutation. Patients were a median 59 years (range, 31-77) and had received a median of 5 treatment regimens (range, 1-14). A majority of the patients (91.4%) were female and had a WHO performance status of 1 (53.4%); the remainder had a performance status of 0.

Following enrollment, patients were divided into 3 cohorts based on the location of their primary tumor: ER-positive breast cancer (n = 20), gynecologic cancers (n = 18), and other solid tumors (n = 20) (Table).

Table. Primary tumor location of enrolled patients

Once treatment commenced, patient disease was assessed and analyzed at baseline, every 6 weeks for 6 months, then every 12 weeks until any occurrence of a significant change in progression or withdrawal. The primary endpoint of this study was safety; response according to RECIST v1.1 criteria and progression-free survival (PFS) were key secondary endpoints.

Partial responses were confirmed in AKT1 E17K-mutant patients, including in 4 patients with ER-positive breast cancer, 2 with endometrial cancer, and 1 patient each with cervical cancer, triple-negative breast cancer, and lung adenocarcinoma. One patient with ovarian cancer with a Q17K mutation experienced stable disease and tumor regression lasting 14 months.

In treated patients with E17K mutations, the median

PFS was 5.5 months (95% CI, 2.9-6.9) for patients with ER-positive breast cancer, 6.6 months (95% CI, 1.5-8.3) for gynecologic cancers, and 4.2 months (95% CI, 2.1-12.8) for other solid tumor types. Researchers concluded that there was no apparent correlation between tumor type and response.

Grade &ge;3 adverse events (AEs) were observed in 70.7% of patients, and 51.7% were deemed to have a casually related AE, as assessed by the investigator. Hyperglycemia (24.1%), diarrhea (17.2%), and maculopapular rash (15.5%) were the common grade &ge;3 AEs reported. A dose reduction was necessitated in 34% of patients, with the above AEs being the leading causes. Serious AEs were experienced by 15.5% of patients, and the authors, led by David M. Hyman, MD, chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, noted that the toxicity profile was consistent with that of previous studies with AZD5363.

Prior to treatment, researchers collected and sequenced tumor samples and tumor-derived cell-free DNA (cfDNA) for retrospective and comparative analysis purposes and to see whether response could be predicted through examination of biomarkers. Interestingly, in 1 evaluable sample in which the

mutation could not be confirmed in either cfDNA or archival tumor, the patient experienced rapid disease progression.

During cycle 1, a &ge;50% decrease in the

mutant allele in cfDNA was observed in 22 of 23 patients (95.5%) that showed no correlation with response. Observations of an ongoing decrease in mutant alleles going into cycle 2 showed an association with an increase in PFS (median PFS, 5.6 vs 2.6 months in those who did not demonstrate a decline; HR, 0.18;

= .004). Five patients experienced a clearance of

mutant alleles in cfDNA lasting more than 21 days that correlated with objective responses lasting &ge;18 weeks (

Through whole-exome or targeted sequencing in a smaller population of patients (n = 37), researchers tested to see if there was a correlation between the genomic configuration of the mutation and response to AZD5363. An allelic imbalance of

was observed in 57% of the tested patients (n = 21). Further testing revealed that 10 of these patients exhibited a copy-neutral loss of heterozygosity (CN-LOH), whereby 1 patient had acquired 2 copies of a mutant AKT1 E17K allele with no remaining wild-type allele. The authors noted that those patients experienced a longer PFS than those who did not exhibit CN-LOH (median PFS, 8.2 vs 4.1 months, respectively; HR, 0.41;

= .04), and they found this association to be clinically and statistically significant. Furthermore, they concluded that this E17K allelic imbalance was more commonly found in patients with breast or gynecologic cancers (90% vs 10% of other tumor types).

Clonality, or degree of tumor cell presence, of the

mutation may have some type of correlation with respones to AZD5363. Although 92% of patients (34 of 37) had

mutations present in all tumor cells, 2 of the remaining 3 patients with subclonal mutations exhibited a rapid increase in disease progression, and the third patient, who had ovarian granulosa cell cancer, experienced a mixed response. Hyman and his colleagues suspected that the third patient&rsquo;s overall tumor regression of 24% that lasted 253 days was caused by the later acquisition of the

driver mutation, which led to a response from treatment.

Researchers also looked into the influence of commutations and concurrent activation of adjacent signaling pathways on sensitivity to inhibition. Additional mutation and activation of the PI3K/mTOR signaling pathway (Figure

) was found to correlate with longer PFS (median PFS, not reached vs 4.3 months without additional pathway mutations; HR, 0.21;

= .045). Five patients exhibited this coincident mutation in upstream or downstream effectors of signaling of the PI3K/ mTOR pathway. The potential of increased sensitivity to PI3K pathway inhibition due to concomitant pathway mutations is an area worthy of further research, the authors noted.

Other cases include an achievement of durable partial response in 2 of 5 patients with loss-of-function NF1 mutations (cervical and breast cancer), where 1 exhibited a subclonal FGFR3 S249C hotspot mutation; detection of an AZD5363- resistant subclonal KRAS A146T mutation in 1 patient with colorectal cancer; and mutations in the ligand-binding domain of ESR1 in 7 of 20 patients (35%) who experienced a shorter median PFS than those without the mutation (

Overall, the results of this clinical study strongly suggest that AKT1 E17K mutations can be a promising target for cancer therapy. &ldquo;To our knowledge, this study provides the first robust clinical evidence that AKT1 E17K is a targetable oncogene in human cancer,&rdquo; the authors wrote in the study.

The authors also noted that the AZD5363 response in these mutations was greater than that seen with

mutations, which further confirms the efficacy of

inhibition. Yet, they observed that the PFS of these treated patients was disappointingly lower than other therapeutic options targeting

. Thus, they suggested that AZD5363 may be most effective in a combination setting. Studies examining AKT inhibition with antiestrogen therapies are underway in patients with ER-positive,

Hyman and his co-authors feel confident that their study will illuminate further studies and advance the understanding of inhibition in a mutation-specific context. &ldquo;By incorporating comprehensive tissue- and plasma-based correlative studies,&rdquo; they conclude, &ldquo;we elucidate the multifaceted genomic basis of response in a manner that facilitates simultaneous translational genomic discoveries and clinical hypothesis validation to inform future studies."

Hyman D, Smyth LM, Donoghue MTA, et al. AKT1 inhibition in solid tumors with AKT1 mutations. J Clin Oncol. 2017;35(20):2251- 2259. doi: 10.1200/JCO.2017.73.0143

Holmes D. PI3K pathway inhibitors approach junction. Nat Rev Drug Discov. 2011;10(8):563-564. doi: 10.1038/nrd3527.

Articles

Amultihistology basket study proved the targetability of the AKT1 E17K mutation in human cancers by treating patients with various types of cancer harboring an AKT1 E17K mutation with AZD5363, an oral pan-AKT inhibitor, according to findings published in the Journal of Clinical Oncology.

Study Shows AKT1 E17K a Targetable Mutation Through AKT Inhibition Across Various Cancer Types

While challenges remain for patients with nonbiomarker, nonsquamous, nonsmall cell lung cancer (NSCLC), ongoing trials are looking at, and testing, various immunotherapy and chemotherapy combinations in the frontline setting, according to Corey Langer, MD.

In general, patients without an oncogenic driver have more limited options in their treatment course compared with those who have a driver mutation. Investigators are aiming to change this with recent studies.

In the ongoing phase III KEYNOTE-189 trial, the efficacy of pembrolizumab (Keytruda), the PD-1 inhibitor, combined with platinum/pemetrexed chemotherapy versus platinum-based chemotherapy without pembrolizumab is being studied. Progression-free survival will be measured post treatment to determine wheth-er pembrolizumab plus a platinum/pemetrexed combination is more effective in improving outcomes for patients with nonsquamous NSCLC versus chemotherapy alone (NCT02578680).

This is a follow-up study to cohort G of the KEYNOTE-021 trial, in which the pembrolizumab triplet elicited an objective response rate of 55% compared with 29% with the chemotherapy agents alone (P = .0032). The FDA approved the regimen in May 2017 based on the small-study findings.

Moreover, practicing clinicians have the standard therapeutic option of bevacizumab (Avastin), the angiogenesis inhibitor, in this patient population. In 2006, the FDA granted approval for a labeling extension for bevacizumab administered in combination with carboplatin/paclitaxel as frontline treatment of patients with unresectable, locally advanced, recurrent, or metastatic nonsquamous disease.

, Langer, director of thoracic oncology at the Hospital of the University of Pennsylvania, provides additional details on the goals and implications of this clinical trial. Moreover, he discusses the current arena in NSCLC treatment and the obstacles that remain in treating patients without driver mutations effectively.

What is the prevalence of patients with nondriver NSCLC?

The incidence of patients with nondriver mutations in NSCLC, specifically adenocarcinoma, is close to 70%. In squamous cell carcinoma, it&rsquo;s 95% or higher. The vast majority of individuals we treat with advanced NSCLC, either metastatic at diagnosis or recurrent, do not have driver mutations or trans- locations. For those individuals specifically with nonsquamous disease, the standard options generally include pemetrexed with carboplatin or a taxane with carboplatin. Now, [we have] the option of pembrolizumab combined with a platinum-based combination and, of course, bevacizumab combined with a platinum-based combination.

What are the current treatment strategies for nonsquamous NSCLC? Also, what are the considering factors for bevacizumab?

The standard approach for nonsquamous NSCLC, at least in 2017, involves a platinum combination in individuals who do not have an oncogenic driver. Usually that platinum combination in the United States is carboplatin and pemetrexed. In individuals who are not candidates for pemetrexed, it is carboplatin plus a taxane either every 3 weeks or weekly.

Up until recently, in individuals who do not have a history of hemoptysis or untreated brain metastases, I would generally add bevacizumab onto the platinum combination of either carboplatin and paclitaxel or carboplatin and pemetrexed. With the recent approval of pembrolizumab in this settingspecifically, pembrolizumab in combination with pemetrexed and carboplatin&mdash;our therapeutic options have expanded. However, they have also gotten a bit more confusing.

Pembrolizumab was approved based on a randomized phase II trial that compared the combination of pembrolizumab with chemotherapy to just chemotherapy alone. Bevacizumab was not included in the control arm. We have no direct head-to-head comparisons of pemetrexed/carboplatin plus bevacizumab versus pemetrexed/carboplatin plus pembrolizumab.

That is really the root of one of my dilemmas. There are some patients who have an autoimmune disease or other contraindications to pembrolizumab where I will certainly, and preferentially, use bevacizumab.

The other interesting population [is] those with oncogenic driversbe it an EGFR mutation or ALK translocation. Here, immunotherapy does not work that well. If you look at the randomized phase III trials in the second-line setting that compared single agents with docetaxel, the 1 group that consistently failed to derive any benefit were those with oncogenic drivers. The response rates were quite low: they were 3% or 4%. Survival advantages were not seen in that group. In fact, in some of these studies, there was a survival advantage for chemotherapy. Inevitably, those individuals will develop disease progression on the original tyrosine kinase inhibitor (TKI).

At that point, chemotherapy is the standard. In my mind, chemotherapy, specifically a carboplatin combination with bevacizumab, is the standard for that population. I would much sooner use bevacizumab in those with oncogenic drivers once their disease has progressed on the initial TKI ahead of using an immunotherapy such as pembrolizumab, nivolumab (Opdivo), or atezolizumab (Tecentriq). Whereas, in a wild-type patient particularly a patient with a high mutation burden, perhaps KRAS mutations&mdash;I would preferentially use immunotherapy in that setting.

What are some ongoing clinical trials with therapies for nondriver NSCLC?

There are trials specific to squamous and nonsquamous patients. Then there are the immunotherapy combinations versus chemotherapy. Since 2015 and 2016, there have been a number of prospective randomized phase II and, now, phase III trials that are looking at immunotherapy &ldquo;cocktails,&rdquo; if you will, or combinations in the frontline setting. Many of these trials the majority, in fact&mdash;continue to use the chemotherapy backbone. It is standard chemotherapy, [with or without] a new immunotherapy drug&mdash;be it nivolumab, pembrolizumab, or atezolizumab&mdash;both in nonsquamous and squamous cell NSCLC.

One of the more interesting trials is KEYNOTE-189, which is essentially a phase III follow-up of cohort G of the randomized phase II KEYNOTE-021 trial. Looking at pemetrexed and carboplatin alone or combined with pembrolizumab, it has a primary endpoint of disease-free survival. It has crossover built into the trial. Hence, overall survival is not a legitimate primary endpoint; it is still an important secondary endpoint. This trial will either confirm or refute the benefits that we have seen in cohort G, which led to the approval of that 3-drug combination.

There is a similar trial looking at a taxane/platinum combination in squamous cell NSCLC. Atezolizumab, which is a PD-L1 inhibitor, is being looked at prospectively in phase III trials, again with several different chemotherapy backbones. There are a number of trials now that are looking at immunotherapy combinations, particularly CTLA-4 inhibitors and either PD-1 or PD-L1 inhibitors together versus chemotherapy. Those trials are truly exciting. I have some degree of skepticism whether immunotherapy combinations will actually prove superior to chemotherapy in this setting, but I would not be the least bit surprised if they prove equivalent.

What are some ongoing challenges with the nonbiomarker population?

There are a number of major challenges that we are dealing with in the nondriver population. First off, the absence of an oncogenic driver limits the therapeutic options. Unfortunately, historically, median survival in this group is inferior to those with oncogenic drivers.

There is a subpopulation, maybe 5% or 10%, where immunotherapy not only doesn&rsquo;t work, it may work to the patient&rsquo;s detriment. We have seen this phenomenon of accelerated or hyperprogression in some individuals, which is quite frightening. An individual might have had progressive disease, they are treated with immunotherapy, and then their disease takes off. We have no way of identifying those patients.

Intriguingly, individuals who have been exposed to immunotherapysome of whom include those with hyperprogression&mdash;and are re-challenged with chemotherapy may actually do fairly well.

We may actually be seeing some abscopal effect that makes chemotherapy work better.

Subsequently, we need to gure out what the optimal sequence is. We need to do a far better job of identifying individuals who are more likely to respond to immunotherapy agents. PD-L1 testing has become our new standard in the upfront setting. It identifies the 30% or so with high levels of expression who do better with immunotherapyspecifically, pembrolizumab&mdash;over chemotherapy alone. I am convinced that there are other markers that can predict who is likely to benefit; tumor mutation burden is just one example. Now, with next-generation sequencing, we can identify the number of mutations that each individual has. There are retrospective studies that show that the mutation load can correlate with the response benefit to these new agents.

For those who are lucky to respond, we have no idea how long to continue these treatments. There are increasing data that show that treatment beyond 2 years doesn&rsquo;t necessarily benefit these individuals any further. There are now trials that are looking at those who have had a response that are comparing 1 year to 2 years with indefinite treatmentobviously, with the option of resuming treatment should disease ultimately progress.

These are all unanswered questions. For those who have enjoyed a response, that&rsquo;s a good dilemma to have. The bigger challenge is with those who don&rsquo;t respond all that well. Some sort of combination immunotherapy strategy or unique combinations between immunotherapy and chemotherapy could overwhelm or overcome intrinsic resistance. That, to me, is probably the biggest challenge.

Langer CJ, Gadgeel SM, Borghaei H, et al; KEYNOTE-021 Investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497-1508. doi: 10.1016/S1470-2045(16)30498-3.

Corey Langer, MD,&nbsp;provides details on the goals and implications of the KEYNOTE-021 trial. Moreover, he discusses the current arena in NSCLC treatment and the obstacles that remain in treating patients without driver mutations effectively.

Therapeutic Options Developing for Nondriver NSCLC, But Challenges Remain

The conversations practitioners are having today regarding the treatment options for patients with melanoma who have non-nodal metastases or regionally advanced disease are much different than they were in the past, according to Russell Berman, MD. Moreover, thanks to refined techniques, select patients who were not deemed eligible for surgery are now able to undergo it.

&ldquo;It is an incredibly exciting time to be involved in melanoma, which sounds a little odd, but it&rsquo;s actually true,&rdquo; explains Berman. &ldquo;At the large oncology conferences, melanoma was once confined to a small, offshoot room in the corner and wasn&rsquo;t at the plenary presentations. [Now], we have certainly dominated the plenary presentations and [have had very] exciting developments over the past few years.&rdquo;

, Berman, division chief of Surgical Oncology at New York University Langone Medical Center in New York, shared his enthusiasm over ongoing surgical advances in the treatment of melanoma.

What did you discuss in your lecture on melanoma?

I spoke about non-nodal regional metastases, which, in melanoma, we refer to as in-transit metastases. I also spoke a little bit about systemic metastasis. Now, what is fascinating is that, with new systemic therapies that are effective for melanoma, such as the checkpoint inhibitors in targeted therapy, people think, &ldquo;Well, is surgery no longer applicable? Do we ever need it again?&rdquo; In fact, it may actually be defining a role for surgery that we didn't previously appreciate.

A lot of time when we have these advanced diseasesbe it multiple in-transits, unresectable in-transit disease, or systemic metastases&mdash;in the past, we would only operate on very select people with it. It was maybe 1 or 2 metastatic lesions that were relatively easy for us to get to without causing a lot of potential harm to the patient.

Now, patients who we never would have considered operating on because of the quantity of metastases, [might] respond to the systemic therapy, and then only have a few persistent lesions1 or 2 or 3. Then, they all of a sudden become surgical candidates, and they had not been previously before. Rather than thinking of it as, &ldquo;Well, gee, no longer do we need surgery for melanoma,&rdquo; it is quite the opposite. We really choose these selected people who would benefit most. It is actually an exciting time.

What advancements have you seen in surgical therapy for melanoma?

We have refined a lot of surgical techniques. We were taking out huge margins 40 years ago that were incredibly debilitating and doing large lymph node dissections with potentially no significant benefit to those patients. We did that routinely, and we thought we were truly doing the right thing. That has evolved over time to the point where our margins have decreased in size based on data and worldwide randomized trials. There is actually science behind it.

The results of the long-awaited MSLT-II trial came out, which continues to have the lymph node dissection story evolve, and that clearly is a game changer in terms of whether or not to complete a lymph dissectionalthough there are still some variables that we haven't truly examined.

Then, of course, there is advanced disease. Previously, if I could not help patients with regionally advanced disease in any way, shape, or form, there were not many other options. Sure, we had our medical oncology colleagues come in, but they didn&rsquo;t have really effective therapy.

It has totally changed now with the checkpoint inhibitors and targeted therapy. When I have patients with advanced regional disease or systemic metastasis, the entire conversation has changed, the entire mood has changed, and the outcomes have changed. It has truly never been a more exciting time to be a melanoma surgeon or a melanoma practitioner.

That&rsquo;s great to hear. You mentioned the MSLT-II trial. What other ongoing trials in this space right now are you excited about?

On a metastatic front, there are things such as brain metastases, which, previously, weren't included in clinical trials. Now, all of a sudden, we have multiple abstracts from the 2017 ASCO Annual Meeting, which is truly encouraging. That&rsquo;s a space that nobody would ever go to previously. It really has evolved tremendously.

From the surgical side, the MSLT-II trial was long awaited. There had been some small trialsthe DeCOG trial out of Europe, for example&mdash;but the MSLT-II multinational study was very well designed and executed. We&rsquo;ve been waiting a long time for the results. The editorial that accompanied that result in the New England Journal of Medicine clearly stated that completion lymph node dissection is not the standard of care.

There are still a few areas that we need to look at: patients with large-volume disease in the sentinel node, and patients who have multiple sentinel nodes removed to have positive disease multiple sentinel nodes. Plus, we need to not forget that the observation aspect of the MSLT-II trial was ultrasonography surveillance of the nodal basin at risk, and there may be institutions that are not ramped up to doing that ultrasound observation.

What do we do in that setting? There are clinical trials ongoing with systemic therapy or adjuvant therapy, where completion lymph node dissection is still considered the entry criteria to those adjuvant trials. We will have to make a decision on what to do with that. The story is not entirely written yet.

What other unanswered questions might still exist for surgery in melanoma?

What I&rsquo;m speaking aboutnon-nodal regional disease&mdash;I find to be more fascinating, especially the in-transit disease. These cases are the ones that have basically palpable or visible lesions between where the primary tumor site was and the first nodal basin that drains that primary tumor.

It&rsquo;s a pattern of metastasis relatively unique to melanoma, and it is palpable. When it&rsquo;s palpable, that means we have access to the tissue easily. It is an incredible opportunity for us to run translational trials where we can get the biopsy prior to initiating checkpoint inhibitors or targeted therapy, then get more tissue during the time that we&rsquo;re having treatment, and then to see what the end result is. If there isn't a response, we could always surgically salvage as I had mentioned before. What better paradigm [is there] for translational research?

What do you want community oncologists to take away from your lecture in this area?

Russell Berman, MD, discusses&nbsp;ongoing surgical advances in the treatment of melanoma.

Jonathan Alicea | Authors

Articles

Study Shows AKT1 E17K a Targetable Mutation Through AKT Inhibition Across Various Cancer Types

Therapeutic Options Developing for Nondriver NSCLC, But Challenges Remain

Expert Highlights Encouraging Surgical Advances in Melanoma