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ALK LungCancer Story of Lorla, Sprungschanzenweg, Berlin (2026)

23/04/2026

23/04/2026

Story of Lorla
Prolog

This story is about Lorla, my shortname for
‘(10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h] [2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile'
or PF-06463922 or lorlatinib or Lorbrena or Lorviqua.
All names for a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical exposure in the brain and a broad spectrum of activity against ALK-resistant mutations, depending on who has had and continues to have anything to do with Lorla.

Pfizer, the sponsor of Lorla, also plays a role in this story.
Yes, Pfizer, the manufacturer of the little blue pill for men.
No, Lorla is not blue, but dark pink or much smaller and light pink. Actually, it would be helpful if only the small light pink pills were available (!), but I'll come to that later in the story.

Lorla is currently the best drug available for metastatic non-small cell lung cancer (NSCLC) with an ALK fusion - essentially for patients in the terminal stage. But for many patients, it’s actually more for patients in an advanced stage, cause for them Lorla means the opposite of the end: namely, the hope of a life that’s still quite long.

Not least because I’m one of these patients myself, I would like to emphasize in advance that I’m very, very grateful to Pfizer for developing Lorla. 🙏
And yet, Pfizer comes off badly in some parts of this story.
Because this is a true story!

The events described here took place between 2010 and 2025, mainly in New York City and Boston, but also in San Diego, Nashville, Melbourne, Barcelona, Paris, and elsewhere.
Without regards for the survivors, the names of the persons involved have not been changed. And out of respect for the dead, everything is told as it happened.. or as a German ALK patient imagines it happened.

And anyone who now thinks, “I've heard that before, it's plagiarism, where did he steal it from?”, is only half right.
In the season of the Coen brothers’ “Fargo” series, the opening text is a little different!

One thing is certain: very little of what you’re about to read can be found by googling and certainly not on Wikipedia.

It’s interesting to note that history is repeating itself in many ways with Nuvalent and Neladalkib. However, lessons have been learned from past mistakes, and today there are no longer attempts to make both ALK and ROS1 patients happy with ONE pill.

The story was originally told over 120 days.
Because writing this story was also my 120-day challenge!
Similar to the 90-day challenge by dr Ross Camidge, the seemingly lone champion of independence and truth among thoracic oncologists. He, too, was diagnosed with metastatic NSCLC, only not with an ALK fusion but with an EGFR mutation.
But whether it’s Lorla or Osimertinib, the patient takes pills, and after the scan is before the scan.
And for me, it took 120 days from one head MRI to the next head MRI.

Berlin, end of April 2026
Bernie Alkman

23/04/2026

Story of Lorla
Episode 1: How it all began

In 2007, scientists discovered that anaplastic lymphoma kinase (ALK) gene rearrangements are present in a small subset of non–small-cell lung cancers.

Crizotinib (PF-02341066) from Pfizer was the first TKI used to treat lung cancer patients with ALK gene rearrangements, initially in the PROFILE 1001 study in 2008 and later in other clinical trials.
From the end of 2009, patients with ROS1 gene rearrangements were also included in the first Crizotinib study PROFILE 1001.
***
Note:
It should be noted here that all of these Crizotinib studies, as well as the phase I/II trial on Lorlatinib [4], which will be mentioned in later episodes of this story, were led by Alice Shaw who was practicing at Boston General Hospital at the time. Incidentally, the later PROFILE 1007 study, on whose results the first approval of Crizotinib was based, is also known as the “Shaw study”.
***
Due to the low brain pe*******on of the substance, unfortunately many of the patients treated with Crizotinib developed brain metastases within a short time or resistance mutations within a few years, in particular the L1196M mutation in ALK patients and the G2032R mutation in ROS1 patients.

While ROS1 inhibitors developed in the meantime remained ineffective, especially against the ROS1 G2032R mutation, several brain-penetrating (2nd generation) TKIs had been developed for ALK-positive lung cancer to overcome Crizotinib resistance: Ceritinib (LDK378), Alectinib (CH5424802) and Brigatinib (AP26113). These TKIs were even more effective in Crizotinib-naive patients, i.e., in the first-line therapy.
However, as with Crizotinib, new resistances also developed with 2nd gen ALK TKIs, regardless of whether they were used after Crizotinib or as the first TKI. The most common causes here were mutations G1202R, I1171T/N/S or V1180L.

And so it came to pass that Pfizer set out for a second time to develop a TKI for the treatment of ALK and ROS1 patients - in close collaboration with Dr Shaw’s laboratory and Boston General Hospital.
The goal was
- to cover all known resistance mutations that had occurred in ALK and ROS1 patients under Crizotinib and 2nd gen ALK inhibitors.
- to cross the blood-brain barrier of patients so effectively that not only the development of new brain metastases can be prevented, but also brain metastases developed under brain-penetrating 2nd gen ALK inhibitors can be effectively treated.

References:
[1]
Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol. 2013
[2]
Shaw AT et al. Crizotinib in ROS1-Rearranged Non–Small-Cell Lung Cancer. N Engl J Med. 2014
[3]
Shaw AT et al. Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer. N Engl J Med. 2013
[4]
Shaw AT, Chen J et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol. 2017

23/04/2026

Story of Lorla
Episode 2: Breaking Good – Heisenbergs at La Jolla Laboratories

Once the goals had been defined, the chemists could get to work.
Anyone who has seen Walter White in ‘Breaking Bad’ knows roughly how it went!
The Heisenbergs at Pfizer described it as follows after the work was done:

“Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms.“

And the result was impressive:
Allow me to introduce myself, my name is PF-06463922
[ (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h] [2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile ],
a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical exposure in the brain and a broad spectrum of activity against ALK-resistant mutations.😉
Lorla was born!

An important means of evaluation in this in-vitro phase, i.e., the laboratory phase of cancer drug development, is the IC50 value.
IC50 is defined as the concentration of a drug required to inhibit the growth of cancer cells in vitro (in a test tube) by 50%. IC50 values therefore indicate the relative efficacy of e.g. PF-06463922 against specific target structures such as ALK wild type or ROS1 G2032R.
A lower IC50 value means that less active ingredient is needed to achieve significant inhibition, which indicates higher efficacy.
And the following IC50 values were determined for Lorla :
ALK WT(Wildtyp) : 2,3 nmol/L
ROS1 WT : 0,7 nmol/L
ALK-G1202R : 49,9 nmol/L
ROS1-G2032R : 196,6 nmol/L

However, it is not IC50 values that are decisive for the therapeutic effect of the Lorla tablet ultimately taken by patients, but rather the concentrations of Lorla
- in plasma, i.e., in the blood (serum concentration)
- in cerebrospinal fluid, i.e., in brain fluid (CSF concentration).
of the patients.
And this must be therapeutically effective, i.e., it must not be too low, but it must also not be toxic, i.e., too high!

Because administered tablets are absorbed differently by the human organism, the serum concentration varies from patient to patient.
And because the blood-brain barrier and cerebrospinal fluid barrier of different patients allow PF-06463922 in the blood to pass through at different rates, the CSF concentration varies additionally from patient to patient.

After the hour of the alchemists and before the first clinical trial (on humans), it was then time for preclinical models and animal experiments.
So I'd better skip this phase of Lorla's development with reference to the respect for the dead already paid in the foreword
– it was mainly mice, rats and I've also read about dogs ...

The result of this preclinical phase was the establishment of so-called exposure thresholds, i.e., minimum serum and cerebrospinal fluid concentrations for the various gene rearrangements and resistance mutations in order to achieve a sufficient therapeutic effect of Lorla.
This are the exposure (plasma concentration) thresholds for Lorla to reach in the dose finding study :
ALK-WT : 7.6 ng/mL
L1196M : 62 ng/mL
G1202R. : 150 ng/mL
and the minimal Lorla concentrations in CSF were estimated to
2.6ng/mL, 21ng/mL and 51ng/mL for ALK-WT, L1196M and G1202R, resp.

Are you missing the threshold values for ROS1, especially for the G2032R mutation?
Unfortunately, all ROS1-related publications on Lorla's dose determination are only accessible to medical experts 🤔
Yes, this will happen to us more often as this story progresses 🤷🏻‍♂️

Well, given the IC50 values of 49.9nmol/L for ALK-G1202R and 196.6nmol/L for ROS1-G2032R, the threshold value for G2032R is likely to have been significantly above the 150ng/ml for G1202R ‼️

Note:
It is conceivable, and certainly not unlikely, that the Lorlatinib standard dose as a result of the dose-finding study was set to 100mg (instead of 75mg) in order to be effective against the ROS1-G2032R mutation as well.
It later became apparent that even with 100mg the concentrations were not sufficient to inhibit the G2032R mutation in all ROS1 patients!
I don’t know whether there were any patients with G2032R mutation among the ROS1 patients in the dose-finding study, but later Lorlatinib showed no clinical efficacy against G2032R in numerous cases, and the G2032R mutation persisted in patients treated with Lorlatinib, as e.g. in the PFROST study.
But I'm getting ahead of myself...

References:
[1]
Johnson, T.W. et al. Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ROS oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations. J. Med. Chem. 2014.
[2]
Zou HY et al. PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models. Cancer Cell. 2015
[3]
Lin JJ, Choudhury NJ, Yoda S et al. Spectrum of Mechanisms of Resistance to Crizotinib and Lorlatinib in ROS1Fusion-Positive Lung Cancer. Clin Cancer Res. 2021
[4]
Jóri B, Falk M, Hövel I, Weist P, Tiemann M, Heukamp LC, Griesinger F. Acquired G2032R Resistance Mutation in ROS1 to Lorlatinib Therapy Detected with Liquid Biopsy. Curr Oncol. 2022
[5]
Shaw AT, Chen J et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol. 2017
[6]
Landi, L. et al. Secondary ROS1 mutations and lorlatinib sensitivity in crizotinib-refractory ROS1 positive NSCLC: Results of the prospective PFROST trial. Ann. Oncol. 2019
[7]
Chen J et al. Pharmacokinetics of Lorlatinib After Single and Multiple Dosing in Patients with Anaplastic Lymphoma Kinase(ALK)-Positive Non-Small Cell Lung Cancer: Results from a Global Phase I/II Study. Springer NaturE Link. May 2021

23/04/2026

Story of Lorla
Episode 3 – Dose-finding – MTD/3+3 and Bayesian models

Rob Camidge, US professor of medical oncology and recognized expert in the ALK universe, will state in an OncLive interview in 2025:
“Lorlatinib is an effective drug, but a good example of how wonderful it would have been if the Optimus project had already been in place at the time of its development.”
Since Project Optimus was initiated by the FDA in 2021, it would have been perfectly sufficient if the workshop ‘Dose finding of small molecule oncology drugs’ organized by the FDA and AACR in May 2015 had already taken place.
But for our Lorla, both came too late! Clinical development began back in 2013, and there was a procedure that had been established for years:
In a dose-finding study (dose escalation study), the phase 1 of a phase 1/2 study, a maximum tolerated dose (MTD) is determined, i.e. the highest dose that does not cause unacceptable adverse effects. The dose determined in this way is the ‘recommended phase 2 dose’ (RP2D) and is tested further as the only dose in the immediately following pivotal study (phase 2) with expansion cohorts, i.e. larger patient groups for specific indications (e.g., ‘without prior TKI therapy’ or ‘after progression under Crizotinib’).

Traditionally, dose-finding was done using the classic 3+3 design [see appendix 1 in the comments below and Fig. 1 A] with cohorts of 3 patients each, not as in ancient Rome, but as was already the case in the development of chemotherapeutic agents and also of the 1st ALK inhibitor Crizotinib.
The strategy was easy to implement, did not require any special software, and was very safe for the study patients. The disadvantage was an excessive number of escalation steps, which could lead to patients being treated with low, therapeutically ineffective doses and only a few patients actually receiving doses close to the RP2D.

Accelerated titration designs [Fig. 1 B] were intended to speed up the escalation process and treat fewer patients with too low doses by having cohorts (instead of 3) consist of only 1 patient for initial dose increases until 1 DLT (severe [CTCAE grade >=3) adverse effect) or 2 moderate [CTCAE grade 2] adverse effects occurred during the 1st treatment cycle.

It later became apparent that the MTD/3 + 3 approach with these rule-based methods can lead to doses in kinase inhibitor (KI) therapies that are either unacceptably toxic or therapeutically insufficient for many patients in everyday clinical practice.

Pharmacologically guided dose escalation (PGDE method) [FIG. 1 C] was virtually impossible to implement in practice.

Simulations of model-based designs [Fig. 1D] showed a more accurate estimate of the RP2D without treating too many patients with suboptimal doses.
These newer strategies create a dose-toxicity curve prior to patient enrollment and then use Bayesian statistical models and the toxicity data of each newly enrolled patient to gradually modify and update the curve over the course of the study.
The implementation of related methods, such as e.g.
* Continuous Reassessment Method (CRM)
* Modified CRM (mCRM)
* Escalation with overdose control (EWOC
* Time-to-event continual reassessment method (TITE-CRM)
* TriCRM
* Mixed-effect proportional odds model (POM)
is complex, requires suitable software and biostatistical expertise, as well as experts who are familiar with the preclinical data or have experience with similar drugs.
The logistical simplicity of the classic 3+3 design and the familiarity of physicians with its rules could be the reason why model-based designs were very rarely integrated into clinical trials at that time.
Note:
The narrator admits that he also did not understand how the escalation process works in detail from the descriptions available to him [1,2] ‼️🤷🏻‍♂️

But the astute reader will already have guessed who sponsor Novartis believed was capable of understanding and applying model-based methods for dose-finding. That's right, after having to settle for the classic MTD/3+3 approach in the Crizotinib escalation study, Alice Shaw was also allowed to lead the clinical development of the 2nd ALK inhibitor Ceritinib and was now learning about the model-based EWOC method.

Before we finally return to Lorla and reveal in episode 5 which design Pfizer and Dr. Shaw used for the Lorla escalation study, the next episode must report on how satisfied patients were with the dosages found prior to Lorla in the dose-finding studies of kinase inhibitors (KIs) and specifically ALK inhibitors.

Note:
Pharmacokinetic-pharmacodynamic (PKPD) models were already used in the development of Crizotinib and Ceritinib to estimate the e.g. plasma concentration(s) required for therapeutic use in patients based on preclinical animal studies. The achievement of these exposure thresholds by the study patients should confirm the associated sufficient ALK inhibition when administering the MTD or RP2D [see also the end of episode 2 of this story].

References:
[1] Le Tourneau C et al. Dose Escalation Methods in Phase I Cancer Clinical Trials. J Natl Cancer Inst. 2009
[2] Hansen A et al. Phase 1 Trial Design: Is 3 + 3 the Best?. Cancer Control. 2014

Fig 1: Dose escalation methods for phase I cancer clinical trials

23/04/2026

Story of Lorla
Episode 4 : Dose-finding – Early ALK inhibitors

By the end of 2014, the FDA had approved a total of almost 30 kinase inhibitors (KIs), including the ALK inhibitors Crizotinib in August 2011 and Ceritinib in July 2014.
Numerous other KIs had already completed dose-finding studies but were still in subsequent studies on the path to approval. These included the ALK inhibitors Brigatinib (since September 2011) and Alectinib (since September 2013).
At that time, Lorla was still in the middle of dose-finding.

80% of the phase 1 dose-finding studies of the KIs used the classic 3+3 design with the aim of determining the MTD or RP2D by observing DLTs in a 28- or 30-day observation window [the last episode hopefully explained how this worked 🤓].

Many of the associated pivotal studies showed high rates of treatment discontinuation, dose interruption and dose reduction.
For some KIs, the sponsor [manufacturer] was required by the FDA to perform dose optimization [see Appendix 1 in the comments below], i.e. to test alternative dosages or dosing regimens, e.g., ‘take tablets on an empty stomach’ or ‘take tablets with food’).

Unfortunately, this also applied to Crizotinib and Ceritinib, whose paths from phase 1 trials to everyday clinical practice are briefly summarized in the appendices [see Appendices 2 and 3 in the comments].

'Dose interruption and dose reduction’ – translated into patient language means that in addition to the advanced cancer patients already have, they have been given a hefty dose of ‘suffering and crap’, which could be taken quite literally in the case of Crizotinib and Ceritinib in particular.

With Crizotinib, there were dose interruptions in 36-45% and dose reductions in 29-44% of study patients; with Ceritinib, there were even 61% dose interruptions and 59% dose reductions.
Let's be blunt: despite the model-based design [I hope you’ve read episode 3], no optimal dose was found for Ceritinib in phase 1, and many of the study patients are likely to have experienced severe gastrointestinal problems, i.e. the feeling of food poisoning on a continuous loop.
The dosing regimen for Ceritinib was changed due to PMR request by the FDA and although tolerability improved somewhat, it remained a problem in everyday clinical practice.

Fig. 1 shows the number of discontinuations [ 🟩 column on the left], dose reductions [🟥 column], and dose interruptions [ 🟦 column on the right] in the approval studies of kinase inhibitors for which approval was sought from the EMA (European Medicines Agency) between 2015 and 2020 [since EMA approvals can take up to 12 months or more than those by the FDA, Fig. 1 shows the data for KI approved by the FDA from approximately 2014 to 2019].

Fig. 1 already contains data on
Alectinib [approved by the FDA in December 2015 and by the EMA in February 2017],
Brigatinib [approved by the FDA in April 2017 and by the EMA in November 2018] and
Lorla, which appears quite inconspicuous in the figure, so that no one suspects what stress it will cause and that it will later be cited so often as an example of suboptimal dose finding.

As can be seen, the dose reductions of 12-16% for Alectinib and 20% for Brigatinib, as well as the treatment interruptions of 29-36% for Alectinib and 36% for Brigatinib, were significantly lower than those for the frontrunners, which included Ceritinib.
There were also no subsequent PMR or PMC requirements from the FDA for the sponsors of Alectinib or Brigatinib, and there will be no such requirements for Pfizer, the sponsor of Lorla, at a later date.

Nevertheless, it is important to mention the dose findings for these ALK inhibitors, as they were curious in the case of Alectinib and exciting in the case of Brigatinib.
Let’s start with Alectinib!

In Japan, dose finding for Alectinib had already begun in September 2010 [i.e., 2 years before Ceritinib in the US], using the MTD/3+3 design, the dose was escalated to the highest planned dose of 300mg twice daily (BID) without any DLT occurring [see Appendix 4 in the comments].
Because the 300mg dose, which was nevertheless chosen as the RP2D, led to a response rate of 93.5% in phase 2 and to very good results in the later J-ALEX study, it was believed that the optimal Alectinib dose had been found – at least for Japanese patients.

In the US, the Japanese were not trusted, so in September 2013, a new Phase 1 study was started, also with an MTD/3+3 design, and enough DLTs were then obtained at a dose of 900mg BID [see Appendix 5 in the comments]. The resulting RP2D of 600mg BID was also confirmed in Phase 2 and by the later ALEX study with very good results. This higher dose was then approved for the rest of the world except Japan.
This mismatch was then attributed to the allegedly lower body weight of the Japanese population. This is because, in addition to the correlation between exposure and efficacy, a correlation between body weight and exposure had been found for Alectinib, i.e. lightweight patients require a lower dose than heavyweight patients.
Unfortunately, no conclusions were drawn from this knowledge and so all female patients outside Japan are likely to be given too high a dose, at least if they weigh less than 60kg or have not reduced the dose for other reasons.
The optimal dose of Alectinib remains unknown!
Note:
It is debatable whether the 600mg BID determined in the US study is actually the maximum tolerated dose (MTD). This is because one of the grade 3 adverse events assessed as DLT at a dosage of 900mg BID was ‘headache’. But it was determined ultimately that the headache was not caused by Alectinib therapy, but by radiation necrosis that had developed in a previously irradiated brain metastasis!
Alectinib patients in everyday clinical practice are therefore fortunate that they are not given 1800mg daily instead of the often already excessive 1200mg daily.🤗

Ok, enough for today!
What happened with Brigatinib during the early clinical trials and
how the FDA actually responded to the many treatment discontinuations, dose interruptions and dose reductions in the approval studies of kinase inhibitors, will be discussed later in this story.

References:
[1]
Lu, D. et al. A survey of new oncology drug approvals in the USA from 2010 to 2015: a focus on optimal dose and related postmarketing. Cancer Chemother Pharmacol. 2016
[2]
Maliepaard M et al. Dose selection and tolerability of anticancer agents evaluated by the European Medicines Agency in the period 2015-2020. Elsevier ESMO Open. 2021
[3]
Ou, S. H. I. Crizotinib: a novel and first-in-class multitargeted tyrosine kinase inhibitor for the treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer and beyond. Drug Design, Development and Therapy. 2011
[4]
Shaw A et al. Ceritinib in ALK-Rearranged Non–Small-Cell Lung Cancer. N Engl J Med 2014
[5]
Seto T et al. CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1–2 study. The Lancet Oncology. 2013
[6]
Gadgeel SM et al.
Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol. 2014
[7]
Kim J et al. Clinical Relevance of Starting Alectinib at a Reduced Dose in Patients with ALK-Positive Non-Small Cell Lung Cancer. Cancer Res Treat 2025

Fig.1 : Discontinuation, dose reduction and dose interruptions due to adverse events

23/04/2026

Story of Lorla
Episode 5 : Dose-finding – Don't worry, the FDA is taking care of it

And the FDA?
By the end of 2014 at the latest, in view of the many treatment discontinuations, dose interruptions, dose reductions, and PMR requests to be issued, the FDA realized that something was going wrong with the dose-finding of kinase inhibitors.
The classic 3+3 design and, in particular, the small 28- or 30-day observation window were blamed for this.

The approach was probably suitable for DLTs [toxicities in early clinical trials] that occurred within the first 4 weeks, but what about DLTs that occurred later?
Or the moderate adverse effects that had a serious impact on patients' quality of life during longer periods of therapy?
Both were common during therapy with kinase inhibitors, but the strategy did not address this intolerance.
In addition, while treatment breaks and dose reductions may have led to a reduction in adverse effects for patients, what about the efficacy of the KI, not least in comparison to other KIs for the same disease?

The narrator does not know to what extent the FDA was already aware of the current course of dose-finding for e.g. Brigatinib or Alectinib. Or about the course of development of Osimertinib, the counterpart to Lorla among EGFR inhibitors, for which the sponsor had chosen a different strategy for dose-finding.
But the bang from the Pfizer headquarters in New York City [or from one of the 5 centers of Lorla escalation], 6 months after the Lorla escalation study began, was surely heard all the way to the FDA headquarters in Silver Spring, MA [🤫readers will have to wait until episode 7 to find out more].

But by early 2015 at the latest, the FDA had recognized the problems!
And in May 2015, the FDA and AACR held a workshop for a small, exclusive group.
Alice Shaw, Pasi Jänne, and Mark Ratain as experts from the scientific community, 1 representative each from the major sponsors [drug manufacturers] and several FDA staff members were to discuss best practices in dose-finding for future cancer drugs and, ideally, propose new approaches for dose optimization.
Alice was there because she was one of the few clinicians who had practical experience with model-based designs, which were expected to yield more optimal dosages.
Pasi Jänne, who could be called the EGFR king if Alicia is to be called the ALK queen, among other studies was responsible for the clinical management of the above-mentioned Osimertinib development.
We’ll only meet Mark Rattain in a later episode of this story, when he and Garth Strohbehn call for a retrospective optimization of the Lorla dose in the Journal of Clinical Pharmacology and Therapeutics in 2022.
At the workshop Alice was supposed to give a presentation on ‘Practical considerations for implementing dose optimization strategies in the clinic’, but her colleagues were also interested in finding out exactly how things would go on with Lorla [🤫the narrator asks readers to be patient once again].

The workshop should really be reported on. Better still, the results should be reported on, which were published in 2016 in the form of a series of articles in the ‘Clinical Cancer Research Journal’ as recommendations for determining the dosage of future kinase inhibitors and combination therapies. This is because some of the proposals made there will also be reflected in the results of the project Optimus initiated by the FDA 5 years later and in the resulting updated FDA guidelines on dose optimization.
One of the most important findings of the workshop and the project Optimus was probably the recommendation not to proceed immediately to the approval study(ies) with a MTD/RP2D after the dose escalation study, but rather to first conduct a randomized optimization study with several alternative dosages, in which the dose for the approval study(ies) would then be determined [see Fig. 1 below].

Note:
In phase 1 of the clinical development of NVL-655, the planning for which is likely to have begun in 2021 and for which the Optimus project came too late, a similar approach to that outlined in Fig. 1 below was taken.
The BOIN designs, rediscovered in 2016, were already available for dose-escalation phase. These are model-assisted designs that later replaced both classic designs and model-based approaches.
In addition to using a BOIN design in the dose escalation study of ALKOVE-1, similar to the Osimertinib development, an expansion cohort was launched for each tolerable dose for which there was a response [PR or CR].
Patients in the indication-specific cohorts of Phase 2 (e.g. ‘1 prior 2nd gen’, ‘2 or 3 prior with Lorla as last’) then received a dose that had already been optimized in this way – hopefully!

By the way:
Rob Camidge was not present at the 2015 FDA workshop, even though he had probably found the ‘philosopher's stone’ much earlier – unknowingly!
But that will be covered in the next episode, when we finally get to the adventurous journey of Brigatinib and its consequences.

References:
[1]
Jänne P et al. AZD9291 in EGFR Inhibitor–Resistant Non–Small-Cell Lung Cancer. N Engl J Med. 2015
[2]
Jänne P, Shaw A et al. Dose Finding of Small-Molecule Oncology Drugs: Optimization throughout the Development Life Cycle. Clin Cancer Res 2016
[3]
Nie L et al. Rendering the 3 + 3 Design to Rest: More Efficient Approaches to Oncology Dose-Finding Trials in the Era of Targeted Therapy. Clin Cancer Res. 2016
[4]
Dambach D et al. Nonclinical Evaluations of Small-Molecule Oncology Drugs: Integration into Clinical Dose Optimization and Toxicity Management. Clin Cancer Res. 2016
[5]
Sachs JR et al. Optimal Dosing for Targeted Therapies in Oncology: Drug Development Cases Leading by Example. Clin Cancer Res. 2016
[6]
Drilon A, LinJJ et al.
1253O Phase I/II ALKOVE-1 study of NVL-655 in ALK-positive (ALK+) solid tumours. ESMO Annonc. 2024
[7]
Yuan Y et al. Bayesian Optimal Interval Design: A Simple and Well-Performing Design for Phase I Oncology Trials. Clin Cancer Res. 2016

Fig. 1 :

ALK LungCancer Story of Lorla

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