By Neil Canavan
There is no end to the brilliance on display at the annual meeting of the American Association of Clinical Oncology (ASCO). Detailed here are five emanations that are poised to light the way to vastly improved patient care.
Tissue Agnostic, Tumor Targeting
Question: If a tumor has a mutation – a target – and there exists a drug that can hit that target, does it matter from whence the tumor originated? Could the tumor be from a lung cancer, colon, or thyroid? Would it matter? If your tumor has a tropomyosin receptor kinase (TRK; pronounced “track”) genetic fusion the answer is, no.
Why? Because newly reported data for the TRK fusion-targeting drug, larotrectinib, suggest that its mechanism of action is tumor agnostic – it doesn’t matter what tissue the tumor came from – if you have the target, it works.
“What TRK fusions are defined by is one of the TRK genes becoming abnormally connected to another gene,” explains David Hyman, MD, of Memorial Sloan Kettering, New York. “Whereas TRK has a very limited role in the function in normal biology after birth. This fusion event causes the TRK protein to be turned on, and the cancer to grow, and the cancer becomes addicted to this event.”
Another defining feature of TRK fusions is that you find them not just in one type of cancer – they’re found in dozens of cancer types in both children and adults – and this aspect is reflected in the study presented by Dr. Hyman on the potential utility of the TRK-targeting agent, larotrectinib.
The analysis involved the combined results from three separate, phase I/II clinical trials with distinct age-related patient populations: one study enrolled children (n=12), one with adolescents (n=35), and one with adults (n=8). All patients had TRK-positive disease represented by 17 unique cancer types, including gliomas, lung cancer, cancer of the pancreas, GIST, and multiple subtypes of sarcoma.
Source: 2017 ASCO Annual Meeting, press briefing presentation. Presented by David Hyman, MD.
Though this range of tumor types is remarkable in and of itself, the overall incidence of TRK fusions is not clear. “Roughly five thousand TRK patients are identified each year,” says Hyman, “But this may significantly underestimate the rate due to inadequate [genetic profiling] using existing technologies.”
In the current study, all patients were treated with 100 mg of drug twice a day in 28-day cycles, with treatment slated to continue until disease progression.
Of the 50 patients evaluable for treatment efficacy at the time of this report, there was a 76% overall response rate, with 12% of those outcomes being complete responses. “To me this was really striking – more than 3 out of 4 patients responded to therapy,” says Hyman. “You would be hard pressed to find a targeted therapy – even within a single disease context – that has results like this.” In fact, responses were so good that two patients were down-staged and will now undergo potentially curative surgery.
For now, 93% of responders remain on therapy, with duration of response ranging out as long as 24 months.
Response to larotrectinib was deep, and it was rapid. “Patients reported dramatic improvements in symptoms within days of being on therapy,” observed Dr. Hyman adding that, in his opinion, the drug represented the new standard of care for patients identified with TRK fusions.
Seemingly racing out of nowhere was the data reported at 2017 ASCO on the newest, and most efficacious CAR-T (chimeric antigen receptor T cell) currently in clinical testing: that being a genetically engineered construct that targets the BCMA (B-cell maturation antigen) in patients with multiple myeloma.
“This is just like placing a GPS system on your immune T cells,” explains Wanhong Zhao, MD, of Jiao Tong University, Xi’an China, offering perhaps the simplest and most evocative description of this exotic technology to date.
The T cell construct, LCAR-B38M, from Nanjing Legend Biotech, is created in the same ultra-personalized way as all CAR-Ts: T cells are extracted from each individual patient and placed in vitro where the cells are transduced with a viral vector containing genes that express a CAR (in this case, BCMA-targeting genes). Following this, clinicians expand the population of engineered T cells from thousands of cells to billions, and then administer to the patient.
Using this approach, Dr. Zhao treated 35 multiple myeloma patients with three cycles of CAR-T cell infusions.
The results with the BCMA CAR were beyond impressive – the overall response rate was 100%. “We even had 33 of 35 patients go into remission after only two months,” says Zhao. Those followed for more than four months (patients treated earliest in the trial) accounted for 14 complete responses – an outstanding achievement. In fact, “There are five patients that received treatment more than a year ago and they remain in CR, and this raises hope of a cure.”
The treatment is not without its downside – most patients experienced the serious, CAR-drug class effect of cytokine release syndrome, but these events are considered manageable.
Commenting on the extraordinary efficacy of CAR technology, Carl June, MD, Ph.D., CAR-T aficionado from the University of Pennsylvania said: “This is the last ASCO without an FDA approved CAR.”
Improved Survival in Prostate Cancer
Another study presented at ASCO as having an immediate impact on patient care was an investigation that added the androgen-blocking agent, abiraterone, to the current standard of care for newly diagnosed, high-risk, metastatic prostate cancer patients.
“Historically, androgen depravation therapy (ADT) has been the standard of care (SOC) in these patients,” explains Karim Fizazi, MD, Ph.D., of Institut Gustave Roussy, Paris. “This is because it basically works in 100% of patients – at least at the beginning – but after a year or so on ADT roughly half of these men with metastatic disease have developed cancer progression due to so-called castration resistance.” Thus, there is a large unmet need for optimization of the ADT paradigm.
Since abiraterone already has an approval for second-line use in patients with castration resistance, moving the drug into the front-line setting is predicted to delay the time to onset of ADT resistance.
In the phase III, randomized, blinded LATITUDE study, abiraterone and prednisone were added to standard ADT and compared with ADT alone in a cohort of men with metastatic prostate cancer (N=1,199) Note: The addition of prednisone is to ameliorate the side effects of abiraterone.
Results for the enhanced ADT approach were extremely encouraging. After a median follow-up of 30.4 months there was a significant improvement in overall survival with the new combination as compared with SOC, with a reduction in risk of death by 38%, as well as a 53% improvement in progression-free survival (for both results: p<0.0001).
The median time for overall survival for the control group was 34.7 months – a measure that concurs with past investigations – whereas the median has not yet been reached for the abiraterone combination, “and this is telling you something very important,” says Fizazi. Indeed, at the three-year time point, 66% of patients in the abiraterone cohort were still alive versus 49% in the control arm.
Source: 2017 ASCO Annual Meeting, press briefing presentation. Presented by Karim Fizazi, MD, PhD.
Commenting on the study, Sumanta Kumar Pal, MD, City of Hope Medical Center, Duarte, California, suggested another advantage to the proposed ADT combination by comparing it to a regimen of ADT/docetaxel, a combination approved in 2014 that demonstrated an equivalent improvement in overall survival to that just observed with ADT/abiraterone.
“Extending overall survival with chemotherapy is no small feat,” says Pal. “But toxicity associated with chemotherapy is a concern, particularly in the older population typically seen in prostate cancer – toxicity like nerve damage, etc, is often very difficult for these patients to handle. These data offer an important alternative to chemo… and should become the new standard of care for men with high-risk metastatic prostate cancer.”
Head-to-Head Comparison of ALK Inhibitors, Combos with PD-1
Until very recently, the prognosis for someone with non-small cell lung cancer (NSCLC) was nothing short of grim. However, for molecular subsets of NSCLC patients there is now hope in the form of ALK inhibitors, and checkpoint immunotherapy.
ALK stands for anaplastic lymphoma kinase, the mutated gene of which is present in roughly 5% of NSCLC patients. The ALK-targeting drug, crizotinib, approved in late fall of 2013 demonstrated a vast improvement over SOC for ALK-positive NSCLC patients, and since there were (are) so few treatment options in this disease setting, the approval made headlines, and the drug became the new standard overnight.
But there was a problem. “While crizotinib can very effective initially, most patients will develop worsening disease within the first year of treatment,” says Alice Shaw, MD, Massachusetts General Hospital, Boston, “And one of the most common sites of worsening disease is the CNS, and this likely reflects the drug’s poor penetration into the brain.”
The second generation ALK inhibitor, alectinib, might overcome this limitation – as early stage testing in crizotinib-resistant patients suggested.
To explore this possibility, the phase III ALEX study compared crizotinib with alectinib in a cohort of treatment naive, ALK-positive, advanced NSCLC patients (N=303). The primary endpoint for the trial was progression-free survival (PFS).
Results from this head-to-head comparison showed an extraordinary improvement in PFS – a median of 25.7 months for alectinib versus 10.4 months for crizotinib (p<0.0001). Further, regarding the incidence of disease progression in the CNS, alectinib was again greatly superior to crizotinib; at the one-year time point, the rate of CNS progression was 9.4 months versus 41.4 months, respectively.
Source: 2017 ASCO Annual Meeting, press briefing presentation. Presented by Alice T. Shaw, MD, PhD.
This corresponds to an 84% reduction in the risk of CNS progression with alectinib. Regarding adverse events, not only was alectinib more effective, it was better tolerated.
Source: 2017 ASCO Annual Meeting, press briefing presentation. Presented by Alice T. Shaw, MD, PhD.
“I view this as a watershed moment for the treatment of ALK-positive lung cancer,” commented John Heymach, MD, Ph.D. of Houston’s M.D. Anderson Cancer Center. “Studies of mechanistically similar agents will often show only incremental improvements, but this one is really different because of the dramatic improvement in efficacy. Prior to this moment, I’d say the biggest advance in the field was the study comparing crizotinib to chemo (the standard at the time), and for that study the difference in PFS was 7 versus 11.9 months, so, a four month improvement – but this is a doubling.”
Heymach has no doubt that alectinib should be the new standard for first-line treatment of ALK-positive NSCLC.
NSCLC: Immunotherapy Combo for the ALK-Negative Patient
Here’s the equation that at least half of the pharmaceutical industry is trying to solve:
Anti-PD-1/PD-L1 + drug X = synergistically improved response rates, and a huge pile of money.
Solve for drug X.
One proposed solution is combining an anti-PD-1/PD-L1 agent with an inhibitor of a molecule called, indoleamine (2, 3)-dioxygenase, or IDO, an enzyme involved in the catabolism of tryptophan. Though IDO has a proper role in promoting immunologic homeostasis, it has also been associated with the downregulation of T cell activity in the setting of cancer.
As for treatment with anti-PD-1/PD-L1 agents, this approach was just recently approved for the front-line treatment of NSCLC patients with PD-1-positive histology. However, response rates in this setting, though much improved, are still less than 50%, and resistance to anti-PD-1 has been observed. It was hypothesized that the addition of an IDO inhibitor – the mechanism of which is completely separate from the PD-1 pathway – would result in a synergistic improvement in treatment response.
In a phase I/II “basket trial” study presented at ASCO, PD-1-positive patients were treated with the anti-PD-1 agent, pembrolizumab, combined with the anti-IDO drug epacadostat (ECHO-202/KEYNOTE-037; NSCLC cohort: N=58). Early results from this investigation suggest enhanced activity in NSCLC patients.
In lung cancer patients with from 0-2 prior lines of treatment, the PD-1/IDO combination had an overall response rate of 39%, with 2 patients achieving a complete response, and 12 patients achieving a partial response. Responses were observed regardless of the extent of PD-1 expression.
Perhaps understating the importance of this finding, especially given the crowd around the poster at the time of its presentation, study authors concluded: “The efficacy of epacadostat plus pembrolizumab in NSCLC patient with 0-2 prior lines of treatment supports phase III investigation of this combination in NSCLC.”